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1
Holloway, Graham P., Swati S. Jain, Veronic Bezaire, Xiao Xia Han, Jan F. C. Glatz, Joost J. F. P. Luiken, Mary-Ellen Harper, and Arend Bonen. "FAT/CD36-null mice reveal that mitochondrial FAT/CD36 is required to upregulate mitochondrial fatty acid oxidation in contracting muscle." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 297, no. 4 (October 2009): R960—R967. http://dx.doi.org/10.1152/ajpregu.91021.2008.
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The plasma membrane fatty acid transport protein FAT/CD36 is also present at the mitochondria, where it may contribute to the regulation of fatty acid oxidation, although this has been challenged. Therefore, we have compared enzyme activities and rates of mitochondrial palmitate oxidation in muscles of wild-type (WT) and FAT/CD36 knockout (KO) mice, at rest and after muscle contraction. In WT and KO mice, carnitine palmitoyltransferase-I, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase activities did not differ in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria of WT and FAT/CD36 KO mice. Basal palmitate oxidation rates were lower ( P < 0.05) in KO mice (SS −18%; IMF −13%). Muscle contraction increased fatty acid oxidation (+18%) and mitochondrial FAT/CD36 protein (+16%) in WT IMF but not in WT SS, or in either mitochondrial subpopulation in KO mice. This revealed that the difference in IMF mitochondrial fatty acid oxidation between WT and KO mice can be increased ∼2.5-fold from 13% under basal conditions to 35% during muscle contraction. The FAT/CD36 inhibitor sulfo- N-succinimidyl oleate (SSO), inhibited palmitate transport across the plasma membrane in WT, but not in KO mice. In contrast, SSO bound to mitochondrial membranes and reduced palmitate oxidation rates to a similar extent in both WT and KO mitochondria (∼80%; P < 0.05). In addition, SSO reduced state III respiration with succinate as a substrate, without altering mitochondrial coupling (P/O ratios). Thus, while SSO inhibits FAT/CD36-mediated palmitate transport at the plasma membrane, SSO has undefined effects on mitochondria. Nevertheless, the KO animals reveal that FAT/CD36 contributes to the regulation of mitochondrial fatty acid oxidation, which is especially important for meeting the increased metabolic demands during muscle contraction.
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Martonosi, Anthony N., and Slawomir Pikula. "The network of calcium regulation in muscle." Acta Biochimica Polonica 50, no. 1 (March 31, 2003): 1–30. http://dx.doi.org/10.18388/abp.2003_3711.
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In this review the molecular characteristics and reaction mechanisms of different Ca(2+) transport systems associated with various membranes in muscle cells will be summarized. The following topics will be discussed in detail: a brief history of early observations concerning maintenance and regulation of cellular Ca(2+) homeostasis, characterization of the Ca(2+) pumps residing in plasma membranes and sarco(endo)plasmic reticulum, mitochondrial Ca(2+) transport, Ca(2+)-binding proteins, coordinated expression of Ca(2+) transport systems, a general background of muscle excitation-contraction coupling with emphasis to the calcium release channels of plasma membrane and sarcoplasmic reticulum, the structure and function of dihydropyridine and ryanodine receptors of skeletal and cardiac muscles, and finally their disposition in various types of muscles.
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Picard, Martin, Benoit J. Gentil, Meagan J. McManus, Kathryn White, Kyle St. Louis, Sarah E. Gartside, Douglas C. Wallace, and Douglass M. Turnbull. "Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle." Journal of Applied Physiology 115, no. 10 (November 15, 2013): 1562–71. http://dx.doi.org/10.1152/japplphysiol.00819.2013.
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A unique property of mitochondria in mammalian cells is their ability to physically interact and undergo dynamic events of fusion/fission that remodel their morphology and possibly their function. In cultured cells, metabolic perturbations similar to those incurred during exercise influence mitochondrial fusion and fission processes, but it is unknown whether exercise acutely alters mitochondrial morphology and/or membrane interactions in vivo. To study this question, we subjected mice to a 3-h voluntarily exercise intervention following their normal physical activity patterns, and quantified mitochondrial morphology and membrane interactions in the soleus using a quantitative electron microscopy approach. A single exercise bout effectively decreased blood glucose ( P < 0.05) and intramyocellular lipid content ( P < 0.01), indicating increased muscle metabolic demand. The number of mitochondria spanning Z-lines and proportion of electron-dense contact sites (EDCS) between adjacent mitochondrial membranes were increased immediately after exercise among both subsarcolemmal (+116%, P < 0.05) and intermyofibrillar mitochondria (+191%, P < 0.001), indicating increased physical interactions. Mitochondrial morphology, and abundance of the mitochondrial pro-fusion proteins Mfn2 and OPA1 were unchanged. Collectively, these results support the notion that mitochondrial membrane dynamics are actively remodelled in skeletal muscle, which may be regulated by contractile activity and the metabolic state. Future studies are required to understand the implications of mitochondrial dynamics in skeletal muscle physiology during exercise and inactivity.
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Holloway, Graham Paul. "The role of protein-mediated transport in regulating mitochondrial long-chain fatty acid oxidation." Applied Physiology, Nutrition, and Metabolism 33, no. 1 (February 2008): 141–42. http://dx.doi.org/10.1139/h07-172.
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This thesis is an investigation of the role of fatty acid translocase (FAT/CD36), plasma membrane associated fatty acid binding protein (FABPpm), and carnitine palmitoyltransferase I (CPTI) in transporting long-chain fatty acids (LCFAs) across mitochondrial membranes. Maximal CPTI activity, as well as the sensitivity of CPTI for its substrate palmitoyl-CoA (P-CoA) and its inhibitor malonyl-CoA (M-CoA), were measured in mitochondria isolated from human vastus lateralis muscles at rest and following muscle contraction. Exercise did not alter maximal CPTI activity or the sensitivity of CPTI for P-CoA. In contrast, exercise progressively attenuated the ability of M-CoA to inhibit CPTI activity. Mitochondrial FAT/CD36 protein content was also measured at rest, during, and following 2 h of cycling at ~60% maximal oxygen uptake. Exercise progressively increased the content of mitochondrial FAT/CD36 (+59%), which was significantly (p < 0.05) correlated with palmitate oxidation during exercise (r = 0.52), while palmitate oxidation was inhibited ~80% by the administration of a specific FAT/CD36 inhibitor. These data suggest that alterations in CPTI M-CoA sensitivity and increases in mitochondrial FAT/CD36 coordinate exercise-induced increases in fatty acid oxidation. FABPpm, another plasma membrane transport protein, has identical amino acid sequence to mitochondrial aspartate aminotransferase (mAspAT). Since FABPpm contributes to plasma membrane fatty acid transport, the role of FABPpm with respect to mitochondrial LCFA transport was investigated. However, unlike FAT/CD36, muscle contraction did not induce an increase in mitochondrial FABPpm protein in rat or human skeletal muscle. In addition, electrotransfecting FABPpm cDNA into rat skeletal muscle upregulated this protein in mitochondria by 80% without altering mitochondrial palmitate oxidation. In contrast, electrotransfection increased mAspAT activity by 90%, and this was correlated (r = 0.75; p < 0.01) with FABPpm protein. These data suggest that FABPpm does not contribute to the regulation of mitochondrial LCFA transport. Previously, it has been suggested that mitochondria from obese individuals contain an inherent dysfunction to oxidize LCFAs. In age-matched lean (BMI = 23.3 ± 0.7 kg·m–2) and obese (BMI = 37.6 ± 2.2 kg·m–2) individuals, isolated mitochondrial palmitate oxidation was not altered. In addition, mitochondrial FAT/CD36 content was not different in lean and obese individuals. In contrast, citrate synthase and β-hydroxyacyl-CoA dehydrogenase, common markers of total mitochondrial content, were decreased with obesity. Therefore, the decrease in mitochondrial content appeared to account for the observed reductions in whole-muscle LCFA oxidation.
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Guigni, Blas A., Dennis K. Fix, Joseph J. Bivona, Bradley M. Palmer, James A. Carson, and Michael J. Toth. "Electrical stimulation prevents doxorubicin-induced atrophy and mitochondrial loss in cultured myotubes." American Journal of Physiology-Cell Physiology 317, no. 6 (December 1, 2019): C1213—C1228. http://dx.doi.org/10.1152/ajpcell.00148.2019.
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Muscle contraction may protect against the effects of chemotherapy to cause skeletal muscle atrophy, but the mechanisms underlying these benefits are unclear. To address this question, we utilized in vitro modeling of contraction and mechanotransduction in C2C12 myotubes treated with doxorubicin (DOX; 0.2 μM for 3 days). Myotubes expressed contractile proteins and organized these into functional myofilaments, as electrical field stimulation (STIM) induced intracellular calcium (Ca2+) transients and contractions, both of which were prevented by inhibition of membrane depolarization. DOX treatment reduced myotube myosin content, protein synthesis, and Akt (S308) and forkhead box O3a (FoxO3a; S253) phosphorylation and increased muscle RING finger 1 (MuRF1) expression. STIM (1 h/day) prevented DOX-induced reductions in myotube myosin content and Akt and FoxO3a phosphorylation, as well as increases in MuRF1 expression, but did not prevent DOX-induced reductions in protein synthesis. Inhibition of myosin-actin interaction during STIM prevented contraction and the antiatrophic effects of STIM without affecting Ca2+ cycling, suggesting that the beneficial effect of STIM derives from mechanotransductive pathways. Further supporting this conclusion, mechanical stretch of myotubes recapitulated the effects of STIM to prevent DOX suppression of FoxO3a phosphorylation and upregulation of MuRF1. DOX also increased reactive oxygen species (ROS) production, which led to a decrease in mitochondrial content. Although STIM did not alter DOX-induced ROS production, peroxisome proliferator-activated receptor-γ coactivator-1α and antioxidant enzyme expression were upregulated, and mitochondrial loss was prevented. Our results suggest that the activation of mechanotransductive pathways that downregulate proteolysis and preserve mitochondrial content protects against the atrophic effects of chemotherapeutics.
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Aldrich, Kennedy, Deborah Velez-Irizarry, Clara Fenger, Melissa Schott, and Stephanie J. Valberg. "Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses." PLOS ONE 16, no. 2 (February 10, 2021): e0244556. http://dx.doi.org/10.1371/journal.pone.0244556.
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Recurrent exertional rhabdomyolysis (RER) is a chronic muscle disorder of unknown etiology in racehorses. A potential role of intramuscular calcium (Ca2+) dysregulation in RER has led to the use of dantrolene to prevent episodes of rhabdomyolysis. We examined differentially expressed proteins (DEP) and gene transcripts (DEG) in gluteal muscle of Thoroughbred race-trained mares after exercise among three groups of 5 horses each; 1) horses susceptible to, but not currently experiencing rhabdomyolysis, 2) healthy horses with no history of RER (control), 3) RER-susceptible horses treated with dantrolene pre-exercise (RER-D). Tandem mass tag LC/MS/MS quantitative proteomics and RNA-seq analysis (FDR <0.05) was followed by gene ontology (GO) and semantic similarity of enrichment terms. Of the 375 proteins expressed, 125 were DEP in RER-susceptible versus control, with 52 ↑DEP mainly involving Ca2+ regulation (N = 11) (e.g. RYR1, calmodulin, calsequestrin, calpain), protein degradation (N = 6), antioxidants (N = 4), plasma membranes (N = 3), glyco(geno)lysis (N = 3) and 21 DEP being blood-borne. ↓DEP (N = 73) were largely mitochondrial (N = 45) impacting the electron transport system (28), enzymes (6), heat shock proteins (4), and contractile proteins (12) including Ca2+ binding proteins. There were 812 DEG in RER-susceptible versus control involving the electron transfer system, the mitochondrial transcription/translational response and notably the pro-apoptotic Ca2+-activated mitochondrial membrane transition pore (SLC25A27, BAX, ATP5 subunits). Upregulated mitochondrial DEG frequently had downregulation of their encoded DEP with semantic similarities highlighting signaling mechanisms regulating mitochondrial protein translation. RER-susceptible horses treated with dantrolene, which slows sarcoplasmic reticulum Ca2+ release, showed no DEG compared to control horses. We conclude that RER-susceptibility is associated with alterations in proteins, genes and pathways impacting myoplasmic Ca2+ regulation, the mitochondrion and protein degradation with opposing effects on mitochondrial transcriptional/translational responses and mitochondrial protein content. RER could potentially arise from excessive sarcoplasmic reticulum Ca2+ release and subsequent mitochondrial buffering of excessive myoplasmic Ca2+.
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Hyatt, Hayden W., and Scott K. Powers. "The Role of Calpains in Skeletal Muscle Remodeling with Exercise and Inactivity-induced Atrophy." International Journal of Sports Medicine 41, no. 14 (July 17, 2020): 994–1008. http://dx.doi.org/10.1055/a-1199-7662.
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AbstractCalpains are cysteine proteases expressed in skeletal muscle fibers and other cells. Although calpain was first reported to act as a kinase activating factor in skeletal muscle, the consensus is now that calpains play a canonical role in protein turnover. However, recent evidence reveals new and exciting roles for calpains in skeletal muscle. This review will discuss the functions of calpains in skeletal muscle remodeling in response to both exercise and inactivity-induced muscle atrophy. Calpains participate in protein turnover and muscle remodeling by selectively cleaving target proteins and creating fragmented proteins that can be further degraded by other proteolytic systems. Nonetheless, an often overlooked function of calpains is that calpain-mediated cleavage of proteins can result in fragmented proteins that are biologically active and have the potential to actively influence cell signaling. In this manner, calpains function beyond their roles in protein turnover and influence downstream signaling effects. This review will highlight both the canonical and noncanonical roles that calpains play in skeletal muscle remodeling including sarcomere transformation, membrane repair, triad junction formation, regulation of excitation-contraction coupling, protein turnover, cell signaling, and mitochondrial function. We conclude with a discussion of key unanswered questions regarding the roles that calpains play in skeletal muscle.
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Barbeau, Pierre-Andre, Paula M. Miotto, and Graham P. Holloway. "Mitochondrial-derived reactive oxygen species influence ADP sensitivity, but not CPT-I substrate sensitivity." Biochemical Journal 475, no. 18 (September 28, 2018): 2997–3008. http://dx.doi.org/10.1042/bcj20180419.
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The mechanisms regulating oxidative phosphorylation during exercise remain poorly defined; however, key mitochondrial proteins, including carnitine palmitoyltransferase-I (CPT-I) and adenine nucleotide translocase, have redox-sensitive sites. Interestingly, muscle contraction has recently been shown to increase mitochondrial membrane potential and reactive oxygen species (ROS) production; therefore, we aimed to determine if mitochondrial-derived ROS influences bioenergetic responses to exercise. Specifically, we examined the influence of acute exercise on mitochondrial bioenergetics in WT (wild type) and transgenic mice (MCAT, mitochondrial-targeted catalase transgenic) possessing attenuated mitochondrial ROS. We found that ablating mitochondrial ROS did not alter palmitoyl-CoA (P-CoA) respiratory kinetics or influence the exercise-mediated reductions in malonyl CoA sensitivity, suggesting that mitochondrial ROS does not regulate CPT-I. In contrast, while mitochondrial protein content, maximal coupled respiration, and ADP (adenosine diphosphate) sensitivity in resting muscle were unchanged in the absence of mitochondrial ROS, exercise increased the apparent ADP Km (decreased ADP sensitivity) ∼30% only in WT mice. Moreover, while the presence of P-CoA decreased ADP sensitivity, it did not influence the basic response to exercise, as the apparent ADP Km was increased only in the presence of mitochondrial ROS. This basic pattern was also mirrored in the ability of ADP to suppress mitochondrial H2O2 emission rates, as exercise decreased the suppression of H2O2 only in WT mice. Altogether, these data demonstrate that while exercise-induced mitochondrial-derived ROS does not influence CPT-I substrate sensitivity, it inhibits ADP sensitivity independent of P-CoA. These data implicate mitochondrial redox signaling as a regulator of oxidative phosphorylation.
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Takahashi, Mark, Alan Chesley, Damien Freyssenet, and David A. Hood. "Contractile activity-induced adaptations in the mitochondrial protein import system." American Journal of Physiology-Cell Physiology 274, no. 5 (May 1, 1998): C1380—C1387. http://dx.doi.org/10.1152/ajpcell.1998.274.5.c1380.
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We previously demonstrated that subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial subfractions import proteins at different rates. This study was undertaken to investigate 1) whether protein import is altered by chronic contractile activity, which induces mitochondrial biogenesis, and 2) whether these two subfractions adapt similarly. Using electrical stimulation (10 Hz, 3 h/day for 7 and 14 days) to induce contractile activity, we observed that malate dehydrogenase import into the matrix of the SS and IMF mitochondia isolated from stimulated muscle was significantly increased by 1.4- to 1.7-fold, although the pattern of increase differed for each subfraction. This acceleration of import may be mitochondrial compartment specific, since the import of Bcl-2 into the outer membrane was not affected. Contractile activity also modified the mitochondrial content of proteins comprising the import machinery, as evident from increases in the levels of the intramitochondrial chaperone mtHSP70 as well as the outer membrane import receptor Tom20 in SS and IMF mitochondria. Addition of cytosol isolated from stimulated or control muscles to the import reaction resulted in similar twofold increases in the ability of mitochondria to import malate dehydrogenase, despite elevations in the concentration of mitochondrial import-stimulating factor within the cytosol of chronically stimulated muscle. These results suggest that chronic contractile activity modifies the extra- and intramitochondrial environments in a fashion that favors the acceleration of precursor protein import into the matrix of the organelle. This increase in protein import is likely an important adaptation in the overall process of mitochondrial biogenesis.
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Joseph, Anna-Maria, Vladimir Ljubicic, Peter J. Adhihetty, and David A. Hood. "Biogenesis of the mitochondrial Tom40 channel in skeletal muscle from aged animals and its adaptability to chronic contractile activity." American Journal of Physiology-Cell Physiology 298, no. 6 (June 2010): C1308—C1314. http://dx.doi.org/10.1152/ajpcell.00644.2008.
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Evidence exists that mitochondrial content and/or function is reduced in muscle of aging individuals. The purposes of this study were to investigate the contribution of outer membrane protein import and assembly processes to this decline and to determine whether the assembly process could adapt to chronic contractile activity (CCA). Tom40 assembly into the translocases of the outer membrane (TOM complex) was measured in subsarcolemmal mitochondria obtained from young (6 mo old) and aged (36 mo old) Fischer 344 × Brown Norway animals. While the initial import of Tom40 did not differ between young and aged animals, its subsequent assembly into the final ∼380 kDa complex was 2.2-fold higher ( P < 0.05) in mitochondria from aged compared with young animals. This was associated with a higher abundance of Tom22, a protein vital for the assembly process. CCA induced a greater initial import and subsequent assembly of Tom40 in mitochondria from young animals, resulting in a CCA-induced 75% increase ( P < 0.05) in Tom40 within mitochondria. This effect of CCA was attenuated in mitochondria from old animals. These data suggest that the import and assembly of proteins into the outer membrane do not contribute to reduced mitochondrial content or function in aged animals. Indeed, the greater assembly rate in mitochondria from aged animals may be a compensatory mechanism attempting to offset any decrements in mitochondrial content or function within aged muscle. Our data also indicate the potential of CCA to contribute to increased mitochondrial biogenesis in muscle through changes in the outer membrane import and assembly pathway.
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Ornatsky, O. I., M. K. Connor, and D. A. Hood. "Expression of stress proteins and mitochondrial chaperonins in chronically stimulated skeletal muscle." Biochemical Journal 311, no. 1 (October 1, 1995): 119–23. http://dx.doi.org/10.1042/bj3110119.
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Molecular chaperones and cytosolic stress proteins are actively involved in the stabilization, import and refolding of precursor proteins into mitochondria. The purpose of the present study was to evaluate the relationship between mitochondrial content under steady-state conditions, and during the induction of organelle biogenesis, with the expression of stress proteins and mitochondrial chaperonins. A comparison of steady-state levels of mitochondrial enzyme activity [cytochrome c oxidase (CYTOX)] with chaperonin levels [the heat-shock protein HSP60, the glucose-regulated protein GRP75 (mtHSP70)] in striated muscles possessing a wide range of oxidative capacities revealed a proportional expression between the two. This relationship was disrupted by chronic contractile activity brought about by 10 days of 10 Hz stimulation of the tibialis anterior (TA) muscle, which induced 2.4-fold increases in CYTOX activity, but 3.2- and 9.3-fold increases in HSP60 and GRP75 respectively. The inducible stress protein HSP70i was detected at low levels in control TA muscle, and was increased 9.6-fold by chronic contractile activity, to values comparable with those found in the unstressed soleus muscle. This increase occurred in the absence of changes in type I MHC levels, indicating independent regulation of these genes. Despite the increases in HSP60 and HSP70i proteins, contractile activity did not alter their respective mRNA levels, illustrating post-transcriptional mechanisms of gene regulation during contractile activity. In contrast, the mRNA levels encoding the co-chaperonin CPN10 were increased 3.3-fold by contractile activity. Thus, the expression of individual mitochondrial chaperonins is independently regulated and uncoordinated. The extent of the induction of these stress proteins and chaperonins by contractile activity exceeded that of membrane enzymes (e.g. CYTOX). It remains to be determined whether this marked induction of proteins comprising part of the protein import machinery is beneficial for the translocation of enzyme precursors into the mitochondria during conditions of accelerated biogenesis.
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Block, B. A., and C. Franzini-Armstrong. "The structure of the membrane systems in a novel muscle cell modified for heat production." Journal of Cell Biology 107, no. 3 (September 1, 1988): 1099–112. http://dx.doi.org/10.1083/jcb.107.3.1099.
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A thermogenic organ, modified from an eye muscle, warms the brain and eyes of several oceanic fish. The extraocular muscles associated with thermogenesis are composed of modified muscle cells that are structurally distinct from all other types of muscle previously described. In "heater" cells, contractile filaments are virtually absent and the cell volume is packed with mitochondria and smooth membranes. Freeze-fracture studies and negative staining of microsomal fractions treated with vanadate indicate that most of the membrane system of heater cells has a high Ca2+-ATPase density and is equivalent to skeletal muscle sarcoplasmic reticulum (SR). High voltage electron micrographs of heater cells infiltrated with the Golgi stain demonstrate that the cells also have an extensive transverse tubule system with a complicated three-dimensional structure. Junctional regions between transverse tubules and SR occur in the heater cell and contain feet protein. Activation of thermogenesis in heater cells may occur through the same protein components involved in excitation-contraction coupling and appears to be associated with the ATP-dependent cycling of calcium at the SR.
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Ploug, T., J. Wojtaszewski, S. Kristiansen, P. Hespel, H. Galbo, and E. A. Richter. "Glucose transport and transporters in muscle giant vesicles: differential effects of insulin and contractions." American Journal of Physiology-Endocrinology and Metabolism 264, no. 2 (February 1, 1993): E270—E278. http://dx.doi.org/10.1152/ajpendo.1993.264.2.e270.
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Collagenase treatment of skeletal muscle results in the formation of large spheres of membranes (3–30 microns diam). A procedure is described for purification and concentration of these giant membrane vesicles prepared from rat muscle. Morphological observations, marker enzyme analysis, and immunoblotting demonstrate that the vesicles are of plasma membrane origin and that sarcoplasmic reticulum, T-tubules, and mitochondrial inner membranes are absent from the preparation. Western blots demonstrate that the vesicles contain GLUT-4 glucose transporters, whereas GLUT-1 could not be detected. Vesicles prepared from control muscle display specific transport of D-glucose with a maximum velocity (Vmax) for glucose influx of approximately 2,500 pmol.mg plasma membrane protein-1.s-1 and an apparent Michaelis constant (Km) of 16 mM measured at zero-trans conditions at room temperature. Muscle contractions in vivo doubled the Vmax of vesicle glucose transport and membrane GLUT-4 content but did not change Km. In contrast, in vivo administration of insulin did not affect vesicle glucose transport or membrane GLUT-4 content. The combination of insulin and contractions caused similar changes as did contractions alone. It is concluded that the present vesicle population contains membrane components almost exclusively derived from the plasma membrane and contains very little if any GLUT-1 but substantial amounts of GLUT-4. Thus the preparation allows the study of transport kinetics of pure GLUT-4 transporters. The procedure for preparing vesicles probably results in activation of the glucose transport system similar to the activation by insulin but not by contractions.(ABSTRACT TRUNCATED AT 250 WORDS)
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Glancy, Brian, and Robert S. Balaban. "Energy metabolism design of the striated muscle cell." Physiological Reviews 101, no. 4 (October 1, 2021): 1561–607. http://dx.doi.org/10.1152/physrev.00040.2020.
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The design of the energy metabolism system in striated muscle remains a major area of investigation. Here, we review our current understanding and emerging hypotheses regarding the metabolic support of muscle contraction. Maintenance of ATP free energy, so called energy homeostasis, via mitochondrial oxidative phosphorylation is critical to sustained contractile activity, and this major design criterion is the focus of this review. Cell volume invested in mitochondria reduces the space available for generating contractile force, and this spatial balance between mitochondria acontractile elements to meet the varying sustained power demands across muscle types is another important design criterion. This is accomplished with remarkably similar mass-specific mitochondrial protein composition across muscle types, implying that it is the organization of mitochondria within the muscle cell that is critical to supporting sustained muscle function. Beyond the production of ATP, ubiquitous distribution of ATPases throughout the muscle requires rapid distribution of potential energy across these large cells. Distribution of potential energy has long been thought to occur primarily through facilitated metabolite diffusion, but recent analysis has questioned the importance of this process under normal physiological conditions. Recent structural and functional studies have supported the hypothesis that the mitochondrial reticulum provides a rapid energy distribution system via the conduction of the mitochondrial membrane potential to maintain metabolic homeostasis during contractile activity. We extensively review this aspect of the energy metabolism design contrasting it with metabolite diffusion models and how mitochondrial structure can play a role in the delivery of energy in the striated muscle.
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Hood, David A., and Anna-Maria Joseph. "Mitochondrial assembly: protein import." Proceedings of the Nutrition Society 63, no. 2 (May 2004): 293–300. http://dx.doi.org/10.1079/pns2004342.
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The protein import process of mitochondria is vital for the assembly of the hundreds of nuclear-derived proteins into an expanding organelle reticulum. Most of our knowledge of this complex multisubunit network comes from studies of yeast and fungal systems, with little information known about the protein import process in mammalian cells, particularly skeletal muscle. However, growing evidence indicates that the protein import machinery can respond to changes in the energy status of the cell. In particular, contractile activity, a powerful inducer of mitochondrial biogenesis, has been shown to alter the stoichiometry of the protein import apparatus via changes in several protein import machinery components. These adaptations include the induction of cytosolic molecular chaperones that transport precursors to the matrix, the up-regulation of outer membrane import receptors, and the increase in matrix chaperonins that facilitate the import and proper folding of the protein for subsequent compartmentation in the matrix or inner membrane. The physiological importance of these changes is an increased capacity for import into the organelle at any given precursor concentration. Defects in the protein import machinery components have been associated with mitochondrial disorders. Thus, contractile activity may serve as a possible mechanism for up-regulation of mitochondrial protein import and compensation for mitochondrial phenotype alterations observed in diseased muscle.
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Eshima, Hiroaki, Shinji Miura, Nanami Senoo, Koji Hatakeyama, David C. Poole, and Yutaka Kano. "Improved skeletal muscle Ca2+ regulation in vivo following contractions in mice overexpressing PGC-1α." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 312, no. 6 (June 1, 2017): R1017—R1028. http://dx.doi.org/10.1152/ajpregu.00032.2017.
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In skeletal muscle, resting intracellular Ca2+ concentration ([Ca2+]i) homeostasis is exquisitely regulated by Ca2+ transport across the sarcolemmal, mitochondrial, and sarcoplasmic reticulum (SR) membranes. Of these three systems, the relative importance of the mitochondria in [Ca2+]i regulation remains poorly understood in in vivo skeletal muscle. We tested the hypothesis that the capacity for Ca2+ uptake by mitochondria is a primary factor in determining [Ca2+]i regulation in muscle at rest and following contractions. Tibialis anterior muscle of anesthetized peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-overexpressing (OE, increased mitochondria model) and wild-type (WT) littermate mice was exteriorized in vivo and loaded with the fluorescent probe fura 2-AM, and Rhod 2-AM Ca2+ buffering and mitochondrial [Ca2+] were evaluated at rest and during recovery from fatiguing tetanic contractions induced by electrical stimulation (120 s, 100 Hz). In addition, the effects of pharmacological inhibition of SR (thapsigargin) and mitochondrial [carbonyl cyanide- 4-(trifluoromethoxy) phenylhydrazone (FCCP)] function were examined at rest. [Ca2+]i in WT remained elevated for the entire postcontraction recovery period (+6 ± 1% at 450 s), but in PGC-1α OE [Ca2+]i returned to resting baseline within 150 s. Thapsigargin immediately and substantially increased resting [Ca2+]i in WT, whereas in PGC-1α OE this effect was delayed and markedly diminished (WT, +12 ± 3; PGC-1α OE, +1 ± 2% at 600 s after thapsigargin treatment, P < 0.05). FCCP abolished this improvement of [Ca2+]i regulation in PGC-1α OE. Mitochondrial [Ca2+] accumulation was observed in PGC-1α OE following contractions and thapsigargin treatment. In the SR, PGC-1α OE downregulated SR Ca2+-ATPase 1 (Ca2+ uptake) and parvalbumin (Ca2+ buffering) protein levels, whereas mitochondrial Ca2+ uptake-related proteins (Mfn1, Mfn2, and mitochondrial Ca2+ uniporter) were upregulated. These data demonstrate a heretofore unappreciated role for skeletal muscle mitochondria in [Ca2+]i regulation in vivo following fatiguing tetanic contractions and at rest.
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Picard, Martin, Ilan Azuelos, Boris Jung, Christian Giordano, Stefan Matecki, Sabah Hussain, Kathryn White, et al. "Mechanical ventilation triggers abnormal mitochondrial dynamics and morphology in the diaphragm." Journal of Applied Physiology 118, no. 9 (May 1, 2015): 1161–71. http://dx.doi.org/10.1152/japplphysiol.00873.2014.
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The diaphragm is a unique skeletal muscle designed to be rhythmically active throughout life, such that its sustained inactivation by the medical intervention of mechanical ventilation (MV) represents an unanticipated physiological state in evolutionary terms. Within a short period after initiating MV, the diaphragm develops muscle atrophy, damage, and diminished strength, and many of these features appear to arise from mitochondrial dysfunction. Notably, in response to metabolic perturbations, mitochondria fuse, divide, and interact with neighboring organelles to remodel their shape and functional properties—a process collectively known as mitochondrial dynamics. Using a quantitative electron microscopy approach, here we show that diaphragm contractile inactivity induced by 6 h of MV in mice leads to fragmentation of intermyofibrillar (IMF) but not subsarcolemmal (SS) mitochondria. Furthermore, physical interactions between adjacent organellar membranes were less abundant in IMF mitochondria during MV. The profusion proteins Mfn2 and OPA1 were unchanged, whereas abundance and activation status of the profission protein Drp1 were increased in the diaphragm following MV. Overall, our results suggest that mitochondrial morphological abnormalities characterized by excessive fission-fragmentation represent early events during MV, which could potentially contribute to the rapid onset of mitochondrial dysfunction, maladaptive signaling, and associated contractile dysfunction of the diaphragm.
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Zolfaghari, Parjam S., Jane E. Carré, Nadeene Parker, Nancy A. Curtin, Michael R. Duchen, and Mervyn Singer. "Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis." American Journal of Physiology-Endocrinology and Metabolism 308, no. 9 (May 1, 2015): E713—E725. http://dx.doi.org/10.1152/ajpendo.00562.2014.
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Muscle dysfunction is a common feature of severe sepsis and multiorgan failure. Recent evidence implicates bioenergetic dysfunction and oxidative damage as important underlying pathophysiological mechanisms. Increased abundance of uncoupling protein-3 (UCP3) in sepsis suggests increased mitochondrial proton leak, which may reduce mitochondrial coupling efficiency but limit reactive oxygen species (ROS) production. Using a murine model, we examined metabolic, cardiovascular, and skeletal muscle contractile changes following induction of peritoneal sepsis in wild-type and Ucp3−/−mice. Mitochondrial membrane potential (Δψm) was measured using two-photon microscopy in living diaphragm, and contractile function was measured in diaphragm muscle strips. The kinetic relationship between membrane potential and oxygen consumption was determined using a modular kinetic approach in isolated mitochondria. Sepsis was associated with significant whole body metabolic suppression, hypothermia, and cardiovascular dysfunction. Maximal force generation was reduced and fatigue accelerated in ex vivo diaphragm muscle strips from septic mice. Δψmwas lower in the isolated diaphragm from septic mice despite normal substrate oxidation kinetics and proton leak in skeletal muscle mitochondria. Even though wild-type mice exhibited an absolute 26 ± 6% higher UCP3 protein abundance at 24 h, no differences were seen in whole animal or diaphragm physiology, nor in survival rates, between wild-type and Ucp3−/−mice. In conclusion, this murine sepsis model shows a hypometabolic phenotype with evidence of significant cardiovascular and muscle dysfunction. This was associated with lower Δψmand alterations in mitochondrial ATP turnover and the phosphorylation pathway. However, UCP3 does not play an important functional role, despite its upregulation.
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Binas, Bert, Xiao-Xia Han, Erdal Erol, Joost J. F. P. Luiken, Jan F. C. Glatz, David J. Dyck, Rafat Motazavi, Peter J. Adihetty, David A. Hood, and Arend Bonen. "A null mutation in H-FABP only partially inhibits skeletal muscle fatty acid metabolism." American Journal of Physiology-Endocrinology and Metabolism 285, no. 3 (September 2003): E481—E489. http://dx.doi.org/10.1152/ajpendo.00060.2003.
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The low-molecular-mass, cytosolic heart-type fatty acid-binding protein (H-FABP) is thought to be required for shuttling FA through the cytosol. Therefore, we examined the effects of an H-FABP-null mutation on FA and carbohydrate metabolism in isolated soleus muscle at rest and during a period of increased metabolic demand (30-min contraction). There were lower concentrations of creatine phosphate (-41%), ATP (-22%), glycogen (-34%), and lactate (-31%) ( P < 0.05) in H-FABP-null soleus muscles, but no differences in citrate synthase and β-3-hydroxyacyl-CoA dehydrogenase activities or in the intramuscular triacylglycerol (TAG) depots. There was a 43% increase in subsarcolemmal mitochondria in H-FABP-null solei. FA transport was reduced by 30% despite normal content of sarcolemmal long-chain fatty acid transporters fatty acid translocase/CD36 and plasma membrane-associated FABP transport proteins. Compared with wild-type soleus muscles, the H-FABP-null muscles at rest hydrolyzed less TAG (-22%), esterified less TAG (-49%), and oxidized less palmitate (-71%). The H-FABP-null soleus muscles retained a substantial capacity to increase FA metabolism during contraction (TAG esterification by +72%, CO2 production by +120%), although these rates remained lower (TAG esterification -26% and CO2 production -64%) than in contracting wild-type soleus muscles. Glycogen utilization during 30 min of contraction did not differ, whereas glucose oxidation was lower at rest (-24%) and during contraction (-32%) in H-FABP-null solei. Although these studies demonstrate that the absence of H-FABP alters rates of FA metabolism, it is also apparent that glucose oxidation is downregulated. The substantial increase in FA metabolism in contracting H-FABP-null muscle may indicate that other FABPs are also present, a possibility that we were not able to completely eliminate.
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Merle, Audrey, Maxence Jollet, Florian A. Britto, Bénédicte Goustard, Nadia Bendridi, Jennifer Rieusset, Vincent Ollendorff, and François B. Favier. "Endurance exercise decreases protein synthesis and ER-mitochondria contacts in mouse skeletal muscle." Journal of Applied Physiology 127, no. 5 (November 1, 2019): 1297–306. http://dx.doi.org/10.1152/japplphysiol.00196.2019.
Full textAbstract:
Exercise is important to maintain skeletal muscle mass through stimulation of protein synthesis, which is a major ATP-consuming process for cells. However, muscle cells have to face high energy demand during contraction. The present study aimed to investigate protein synthesis regulation during aerobic exercise in mouse hindlimb muscles. Male C57Bl/6J mice ran at 12 m/min for 45 min or at 12 m/min for the first 25 min followed by a progressive increase in velocity up to 20 m/min for the last 20 min. Animals were injected intraperitoneally with 40 nmol/g of body weight of puromycin and euthanized by cervical dislocation immediately after exercise cessation. Analysis of gastrocnemius, plantaris, quadriceps, soleus, and tibialis anterior muscles revealed a decrease in protein translation assessed by puromycin incorporation, without significant differences among muscles or running intensities. The reduction of protein synthesis was associated with a marked inhibition of mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, a mechanism consistent with reduced translation initiation. A slight activation of AMP-activated protein kinase consecutive to the running session was measured but did not correlate with mTORC1 inhibition. More importantly, exercise resulted in a strong upregulation of regulated in development and DNA damage 1 (REDD1) protein and gene expressions, whereas transcriptional regulation of other recognized exercise-induced genes ( IL-6, kruppel-like factor 15, and regulator of calcineurin 1) did not change. Consistently with the recently discovered role of REDD1 on mitochondria-associated membranes, we observed a decrease in mitochondria-endoplasmic reticulum interaction following exercise. Collectively, these data raise questions concerning the role of mitochondria-associated endoplasmic reticulum membrane disruption in the regulation of muscle proteostasis during exercise and, more generally, in cell adaptation to metabolic stress. NEW & NOTEWORTHY How muscles regulate protein synthesis to cope with the energy demand during contraction is poorly documented. Moreover, it is unknown whether protein translation is differentially affected among mouse hindlimb muscles under different physiological exercise modalities. We showed here that 45 min of running decreases puromycin incorporation similarly in 5 different mouse muscles. This decrease was associated with a strong increase in regulated in development and DNA damage 1 protein expression and a significant disruption of the mitochondria and sarcoplasmic reticulum interaction.
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Bonen, Arend, Shannon E. Campbell, Carley R. Benton, Adrian Chabowski, Susan L. M. Coort, Xiao-Xia Han, Debby P. Y. Koonen, Jan F. C. Glatz, and Joost J. F. P. Luiken. "Regulation of fatty acid transport by fatty acid translocase/CD36." Proceedings of the Nutrition Society 63, no. 2 (May 2004): 245–49. http://dx.doi.org/10.1079/pns2004331.
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Fatty acid (FA) translocase (FAT)/CD36 is a key protein involved in regulating the uptake of FA across the plasma membrane in heart and skeletal muscle. A null mutation of FAT/CD36 reduces FA uptake rates and metabolism, while its overexpression increases FA uptake rates and metabolism. FA uptake into the myocyte may be regulated (a) by altering the expression of FAT/CD36, thereby increasing the plasmalemmal content of this protein (i.e. streptozotocin-induced diabetes, chronic muscle stimulation), or (b) by relocating this protein to the plasma membrane, without altering its expression (i.e. obese Zucker rats). By repressing FAT/CD36 expression, and thereby lowering the plasmalemmal FAT/CD36 (i.e. leptin-treated animals), the rate of FA transport is reduced. Within minutes of beginning muscle contraction or being exposed to insulin FA transport is increased. This increase is a result of the contraction- and insulin-induced translocation of FAT/CD36 from an intracellular depot to the cell surface. Neither PPARα nor PPARγ activation alter FAT/CD36 expression in muscle, despite the fact that PPARα activation increases FAT/CD36 by 80% in liver. A novel observation is that FAT/CD36 also appears to be involved in mitochondrial FA oxidation, as this protein is located on the mitochondrial membrane and seems to be required to participate in moving FA across the mitochondrial membrane. Clearly, FAT/CD36 has an important role in FA homeostasis in skeletal muscle and the heart.
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Gough, Nancy R. "Papers of note in Science." Science Signaling 9, no. 411 (January 19, 2016): ec14-ec14. http://dx.doi.org/10.1126/scisignal.aaf2519.
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Muscle PhysiologyAnother micropeptide flexes its muscleA long noncoding RNA encodes a small peptide that activates a calcium pump regulating muscle contraction.B. R. Nelson, C. A. Makarewich, D. M. Anderson, B. R. Winders, C. D. Troupes, F. Wu, A. L. Reese, J. R. McAnally, X. Chen, E. T. Kavalali, S. C. Cannon, S. R. Houser, R. Bassel-Duby, E. N. Olson, A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science351, 271–275 (2016). [Abstract]F. Payre, C. Desplan, Small peptides control heart activity. Science351, 226–227 (2016). [Abstract]MetabolismHow to shape mitochondrial networksAn energy-sensing kinase phosphorylates a mitochondrial membrane protein that initiates fragmentation.E. Q. Toyama, S. Herzig, J. Courchet, T. L. Lewis Jr., O. C. Losón, K. Hellberg, N. P. Young, H. Chen, F. Polleux, D. C. Chan, R. J. Shaw, AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science351, 275–281 (2016). [Abstract]
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Jackson, Malcolm J. "Redox regulation of muscle adaptations to contractile activity and aging." Journal of Applied Physiology 119, no. 3 (August 1, 2015): 163–71. http://dx.doi.org/10.1152/japplphysiol.00760.2014.
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Superoxide and nitric oxide are generated by skeletal muscle, and these species are increased by contractile activity. Mitochondria have long been assumed to play the primary role in generation of superoxide in muscle, but recent studies indicate that, during contractile activity, membrane-localized NADPH oxidase(s) rapidly generate(s) superoxide that plays a role in redox signaling. This process is important in upregulation of rapid and specific cytoprotective responses that aid maintenance of cell viability following contractile activity, but the overall extent to which redox signaling contributes to regulation of muscle metabolism and homeostasis following contractile activity is currently unclear, as is identification of key redox-sensitive protein targets involved in these processes. Reactive oxygen and nitrogen species have also been implicated in the loss of muscle mass and function that occurs with aging, although recent work has questioned whether oxidative damage plays a key role in these processes. A failure of redox signaling occurs in muscle during aging and may contribute to the age-related loss of muscle fibers. Whether such changes in redox signaling reflect primary age-related changes or are secondary to the fundamental mechanisms is unclear. For instance, denervated muscle fibers within muscles from aged rodents or humans appear to generate large amounts of mitochondrial hydrogen peroxide that could influence adjacent innervated fibers. Thus, in this instance, a “secondary” source of reactive oxygen species may be potentially generated as a result of a primary age-related pathology (loss of neurons), but, nevertheless, may contribute to loss of muscle mass and function during aging.
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Alves, Gabriel A., Luisa R. Silva, Eloi F. Rosa, Jeannine Aboulafia, Edna Freymüller-Haapalainen, Caden Souccar, and Viviane L. A. Nouailhetas. "Intestine of dystrophic mice presents enhanced contractile resistance to stretching despite morphological impairment." American Journal of Physiology-Gastrointestinal and Liver Physiology 306, no. 3 (February 1, 2014): G191—G199. http://dx.doi.org/10.1152/ajpgi.00314.2013.
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Protein dystrophin is a component of the dystrophin-associated protein complex, which links the contractile machinery to the plasma membrane and to the extracellular matrix. Its absence leads to a condition known as Duchenne muscular dystrophy (DMD), a disease characterized by progressive skeletal muscle degeneration, motor disability, and early death. In mdx mice, the most common DMD animal model, loss of muscle cells is observed, but the overall disease alterations are less intense than in DMD patients. Alterations in gastrointestinal tissues from DMD patients and mdx mice are not yet completely understood. Thus, we investigated the possible relationships between morphological (light and electron microscopy) and contractile function (by recording the isometric contractile response) with alterations in Ca2+handling in the ileum of mdx mice. We evidenced a 27% reduction in the ileal muscular layer thickness, a partial damage to the mucosal layer, and a partial damage to mitochondria of the intestinal myocytes. Functionally, the ileum from mdx presented an enhanced responsiveness during stretch, a mild impairment in both the electromechanical and pharmacomechanical signaling associated with altered calcium influx-induced contraction, with no alterations in the sarcoplasmic reticulum Ca2+storage (maintenance of the caffeine and thapsigargin-induced contraction) compared with control animals. Thus, it is evidenced that the protein dystrophin plays an important role in the preservation of both the microstructure and ultrastructure of mice intestine, while exerting a minor but important role concerning the intestinal contractile responsiveness and calcium handling.
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Nickerson, James G., Iman Momken, Carley R. Benton, James Lally, Graham P. Holloway, Xiao-Xia Han, Jan F. C. Glatz, Adrian Chabowski, Joost J. F. P. Luiken, and Arend Bonen. "Protein-mediated fatty acid uptake: regulation by contraction, AMP-activated protein kinase, and endocrine signals." Applied Physiology, Nutrition, and Metabolism 32, no. 5 (October 2007): 865–73. http://dx.doi.org/10.1139/h07-084.
Full textAbstract:
Fatty acid transport into heart and skeletal muscle occurs largely through a highly regulated protein-mediated mechanism involving a number of fatty acid transporters. Chronically altered muscle activity (chronic muscle stimulation, denervation) alters fatty acid transport by altering the expression of fatty acid transporters and (or) their subcellular location. Chronic exposure to leptin downregulates while insulin upregulates fatty acid transport by altering concomitantly the expression of fatty acid transporters. Fatty acid transport can also be regulated within minutes, by muscle contraction, AMP-activated protein kinase activation, leptin, and insulin, through induction of the translocation of fatty acid translocase (FAT)/CD36 from its intracellular depot to the plasma membrane. In insulin-resistant muscle, a permanent relocation of FAT/CD36 to the sarcolemma appears to account for the excess accretion of intracellular lipids that interfere with insulin signaling. Recent work has also shown that FAT/ CD36, but not plasma membrane associated fatty acid binding protein, is involved, along with carnitine palmitoyltransferase, in regulating mitochondrial fatty acid oxidation. Finally, studies in FAT/CD36 null mice indicate that this transporter has a key role in regulating fatty acid metabolism in muscle.
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Zaobornyj, Tamara, Laura B. Valdez, Pablo La Padula, Lidia E. Costa, and Alberto Boveris. "Effect of sustained hypobaric hypoxia during maturation and aging on rat myocardium. II. mtNOS activity." Journal of Applied Physiology 98, no. 6 (June 2005): 2370–75. http://dx.doi.org/10.1152/japplphysiol.00986.2004.
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Mitochondrial nitric oxide (NO) production was assayed in rats submitted to hypobaric hypoxia and in normoxic controls (53.8 and 101.3 kPa air pressure, respectively). Heart mitochondria from young normoxic animals produced 0.62 and 0.37 nmol NO·min−1·mg protein−1 in metabolic states 4 and 3, respectively. This production accounts for a release to the cytosol of 29 nmol NO·min−1·g heart−1 and for 55% of the NO generation. The mitochondrial NO synthase (mtNOS) activity measured in submitochondrial membranes at pH 7.4 was 0.69 nmol NO·min−1·mg protein−1. Rats exposed to hypobaric hypoxia for 2–18 mo showed 20–60% increased left ventricle mtNOS activity compared with their normoxic siblings. Left ventricle NADH-cytochrome- c reductase and cytochrome oxidase activities decreased by 36 and 12%, respectively, from 2 to 18 mo of age, but they were not affected by hypoxia. mtNOS upregulation in hypoxia was associated with a retardation of the decline in the mechanical activity of papillary muscle upon aging and an improved recovery after anoxia-reoxygenation. The correlation of left ventricle mtNOS activity with papillary muscle contractility (determined as developed tension, maximal rates of contraction and relaxation) showed an optimal mtNOS activity (0.69 nmol·min−1·mg protein−1). Heart mtNOS activity is regulated by O2 in the inspired air and seems to play a role in NO-mediated signaling and myocardial contractility.
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Talanian, Jason L., Graham P. Holloway, Laelie A. Snook, George J. F. Heigenhauser, Arend Bonen, and Lawrence L. Spriet. "Exercise training increases sarcolemmal and mitochondrial fatty acid transport proteins in human skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 299, no. 2 (August 2010): E180—E188. http://dx.doi.org/10.1152/ajpendo.00073.2010.
Full textAbstract:
Fatty acid oxidation is highly regulated in skeletal muscle and involves several sites of regulation, including the transport of fatty acids across both the plasma and mitochondrial membranes. Transport across these membranes is recognized to be primarily protein mediated, limited by the abundance of fatty acid transport proteins on the respective membranes. In recent years, evidence has shown that fatty acid transport proteins move in response to acute and chronic perturbations; however, in human skeletal muscle the localization of fatty acid transport proteins in response to training has not been examined. Therefore, we determined whether high-intensity interval training (HIIT) increased total skeletal muscle, sarcolemmal, and mitochondrial membrane fatty acid transport protein contents. Ten untrained females (22 ± 1 yr, 65 ± 2 kg; V̇o2peak: 2.8 ± 0.1 l/min) completed 6 wk of HIIT, and biopsies from the vastus lateralis muscle were taken before training, and following 2 and 6 wk of HIIT. Training significantly increased maximal oxygen uptake at 2 and 6 wk (3.1 ± 0.1, 3.3 ± 0.1 l/min). Training for 6 wk increased FAT/CD36 at the whole muscle (10%) and mitochondrial levels (51%) without alterations in sarcolemmal content. Whole muscle plasma membrane fatty acid binding protein (FABPpm) also increased (48%) after 6 wk of training, but in contrast to FAT/CD36, sarcolemmal FABPpm increased (23%), whereas mitochondrial FABPpm was unaltered. The changes on sarcolemmal and mitochondrial membranes occurred rapidly, since differences (≤2 wk) were not observed between 2 and 6 wk. This is the first study to demonstrate that exercise training increases fatty acid transport protein content in whole muscle (FAT/CD36 and FABPpm) and sarcolemmal (FABPpm) and mitochondrial (FAT/CD36) membranes in human skeletal muscle of females. These results suggest that increases in skeletal muscle fatty acid oxidation following training are related in part to changes in fatty acid transport protein content and localization.
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Narayanan, Damodaran, Adebowale Adebiyi, and Jonathan H. Jaggar. "Inositol trisphosphate receptors in smooth muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 11 (June 1, 2012): H2190—H2210. http://dx.doi.org/10.1152/ajpheart.01146.2011.
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Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of tetrameric intracellular calcium (Ca2+) release channels that are located on the sarcoplasmic reticulum (SR) membrane of virtually all mammalian cell types, including smooth muscle cells (SMC). Here, we have reviewed literature investigating IP3R expression, cellular localization, tissue distribution, activity regulation, communication with ion channels and organelles, generation of Ca2+ signals, modulation of physiological functions, and alterations in pathologies in SMCs. Three IP3R isoforms have been identified, with relative expression and cellular localization of each contributing to signaling differences in diverse SMC types. Several endogenous ligands, kinases, proteins, and other modulators control SMC IP3R channel activity. SMC IP3Rs communicate with nearby ryanodine-sensitive Ca2+ channels and mitochondria to influence SR Ca2+ release and reactive oxygen species generation. IP3R-mediated Ca2+ release can stimulate plasma membrane-localized channels, including transient receptor potential (TRP) channels and store-operated Ca2+ channels. SMC IP3Rs also signal to other proteins via SR Ca2+ release-independent mechanisms through physical coupling to TRP channels and local communication with large-conductance Ca2+-activated potassium channels. IP3R-mediated Ca2+ release generates a wide variety of intracellular Ca2+ signals, which vary with respect to frequency, amplitude, spatial, and temporal properties. IP3R signaling controls multiple SMC functions, including contraction, gene expression, migration, and proliferation. IP3R expression and cellular signaling are altered in several SMC diseases, notably asthma, atherosclerosis, diabetes, and hypertension. In summary, IP3R-mediated pathways control diverse SMC physiological functions, with pathological alterations in IP3R signaling contributing to disease.
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Villa, A., P. Podini, M. C. Panzeri, H. D. Söling, P. Volpe, and J. Meldolesi. "The endoplasmic-sarcoplasmic reticulum of smooth muscle: immunocytochemistry of vas deferens fibers reveals specialized subcompartments differently equipped for the control of Ca2+ homeostasis." Journal of Cell Biology 121, no. 5 (June 1, 1993): 1041–51. http://dx.doi.org/10.1083/jcb.121.5.1041.
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Cryosection immunofluorescence and immunogold labeling with antibodies against specific markers were used in rat vas deferens smooth muscle fibers to reveal the molecular arrangement of the endomembrane system (referred to variously in the text as ER or sarcoplasmic reticulum [SR]; S-ER or ER/SR) known to participate in the control of Ca2+ homeostasis. The lumenal ER chaperon, immunoglobulin binding protein (BiP), as well as protein disulfide isomerase, and calreticulin, a Ca2+ binding protein expressed by most eukaryotic cells, appeared to be evenly distributed throughout the entire system (i.e., within [a] the nuclear envelope and the few rough-surfaced cisternae clustered near the nucleus; [b] single elements scattered around in the contractile cytoplasm; and [c] numerous, heterogeneous, mainly smooth-surfaced elements concentrated in the peripheral cytoplasm, part of which is in close apposition to the plasmalemma). All other structures, including nuclei, mitochondria, Golgi complex, and surface caveolae were unlabeled. An even distribution throughout the endomembrane system appeared also for the proteins recognized by anti-ER membrane antibodies. In contrast, calsequestrin (the protein that in striated muscles is believed to be the main actor of the rapidly exchanging Ca2+ storage within the lumen of the sarcoplasmic reticulum) was found preferentially clustered at discrete lumenal sites, most often within peripheral smooth-surfaced elements of moderate electron density. Within these elements dual labeling revealed intermixing of calsequestrin with the other lumenal ER proteins. Moreover, the calsequestrin-rich elements were enriched also in the receptor for inositol 1,4,5-trisphosphate, the second messenger that induces Ca2+ release from intracellular stores. These results document the previously hypothesized molecular heterogeneity of the smooth muscle endomembrane system, particularly in relation to the rapid storage and release of Ca2+.
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Rose, Adam J., Jacob Jeppesen, Bente Kiens, and Erik A. Richter. "Effects of contraction on localization of GLUT4 and v-SNARE isoforms in rat skeletal muscle." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 297, no. 5 (November 2009): R1228—R1237. http://dx.doi.org/10.1152/ajpregu.00258.2009.
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In skeletal muscle, contractions increase glucose uptake due to a translocation of GLUT4 glucose transporters from intracellular storage sites to the surface membrane. Vesicle-associated membrane proteins (VAMPs) are believed to play an important role in docking and fusion of the GLUT4 transporters at the surface membrane. However, knowledge about which VAMP isoforms colocalize with GLUT4 vesicles in mature skeletal muscle and whether they translocate during muscle contractions is incomplete. The aim of the present study was to further identify VAMP isoforms, which are associated with GLUT4 vesicles and examine which VAMP isoforms translocate to surface membranes in skeletal muscles undergoing contractions. VAMP2, VAMP3, VAMP5, and VAMP7 were enriched in immunoprecipitated GLUT4 vesicles. In response to 20 min of in situ contractions, there was a redistribution of GLUT4 (+64 ± 13%), transferrin receptor (TfR; +75 ± 22%), and insulin-regulated aminopeptidase (IRAP; +70 ± 13%) to fractions enriched in heavy membranes away from low-density membranes (−32 ± 7%; −18 ± 12%; −33 ± 9%; respectively), when compared with the resting contralateral muscle. Similarly, there was a redistribution of VAMP2 (+240 ± 40%), VAMP5 (+79 ± 9%), and VAMP7 (+79 ± 29%), but not VAMP3, to fractions enriched in heavy membranes away from low-density membranes (−49 ± 10%, −54 ± 9%, −14 ± 11%, respectively) in contracted vs. resting muscle. In summary, VAMP2, VAMP3, VAMP5, and VAMP7 coimmunoprecipitate with intracellular GLUT4 vesicles in muscle, and VAMP2, VAMP5, VAMP7, but not VAMP3, translocate to the cell surface membranes similar to GLUT4, TfR, and IRAP in response to muscle contractions. These findings suggest that VAMP2, VAMP5, and VAMP7 may be involved in translocation of GLUT4 during muscle contractions.
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Eisenberg, B. R. "Adaptability of ultrastructure in the mammalian muscle." Journal of Experimental Biology 115, no. 1 (March 1, 1985): 55–68. http://dx.doi.org/10.1242/jeb.115.1.55.
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All the skeletal muscle fibres taken from an adult mammal do not look alike. The structural differences are a result of adaptations which allow gradations in mechanical output to be achieved. The anatomy is described and the amounts of the subcellular components are measured by stereological techniques from electron micrographs. A population of normal, adult fibres is classified by the Z-line width, by the amounts of the mitochondria, T-system and terminal cisternae (TC), and by the isoforms of contractile proteins present. Classification of fibres by some of these ultrastructural components gives clusters named fast-twitch and slow-twitch types, but classification by other components gives a continuum of overlapping properties. Transformation from the fast- to the slow-twitch type or vice versa follows a specific alteration in the use of the fibre. The mechanical demand on the fibre is modified by changing the frequency of stimulation in the nerve with an implanted electrode. The time course of the changes in subcellular composition in the fibre during adaptation is followed for many weeks. Changes in the membrane systems begin within hours and are complete in days. Changes in the contractile proteins and metabolic systems begin in days and are complete in weeks. During these transitional phases of adaptation the fibres have an unusual complement of components never seen in a normal adult fibre. Extreme alterations, such as myofibril disassembly or supranormal amounts of mitochondria also result during some adaptive transitions. The aberrant appearance in the transitional fibres may be a result of doing the required mechanical work with a less than optimal set of proteins. At the end of the fibre type transformation, the fibre ultrastructure is indistinguishable from normal.
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Pancaroglu, Raika, and Filip Van Petegem. "Calcium Channelopathies: Structural Insights into Disorders of the Muscle Excitation–Contraction Complex." Annual Review of Genetics 52, no. 1 (November 23, 2018): 373–96. http://dx.doi.org/10.1146/annurev-genet-120417-031311.
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Ion channels are membrane proteins responsible for the passage of ions down their electrochemical gradients and across biological membranes. In this, they generate and shape action potentials and provide secondary messengers for various signaling pathways. They are often part of larger complexes containing auxiliary subunits and regulatory proteins. Channelopathies arise from mutations in the genes encoding ion channels or their associated proteins. Recent advances in cryo-electron microscopy have resulted in an explosion of ion channel structures in multiple states, generating a wealth of new information on channelopathies. Disease-associated mutations fall into different categories, interfering with ion permeation, protein folding, voltage sensing, ligand and protein binding, and allosteric modulation of channel gating. Prime examples of these are Ca2+-selective channels expressed in myocytes, for which multiple structures in distinct conformational states have recently been uncovered. We discuss the latest insights into these calcium channelopathies from a structural viewpoint.
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Croissant, Coralie, Romain Carmeille, Charlotte Brévart, and Anthony Bouter. "Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies." International Journal of Molecular Sciences 22, no. 10 (May 17, 2021): 5276. http://dx.doi.org/10.3390/ijms22105276.
Full textAbstract:
Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.
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Babiychuk, Eduard B., and Annette Draeger. "Annexins in Cell Membrane Dynamics." Journal of Cell Biology 150, no. 5 (September 4, 2000): 1113–24. http://dx.doi.org/10.1083/jcb.150.5.1113.
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The sarcolemma of smooth muscle cells is composed of alternating stiff actin-binding, and flexible caveolar domains. In addition to these stable macrodomains, the plasma membrane contains dynamic glycosphingolipid- and cholesterol-enriched microdomains, which act as sorting posts for specific proteins and are involved in membrane trafficking and signal transduction. We demonstrate that these lipid rafts are neither periodically organized nor exclusively confined to the actin attachment sites or caveolar regions. Changes in the Ca2+ concentration that are affected during smooth muscle contraction lead to important structural rearrangements within the sarcolemma, which can be attributed to members of the annexin protein family. We show that the associations of annexins II, V, and VI with smooth muscle microsomal membranes exhibit a high degree of Ca2+ sensitivity, and that the extraction of annexins II and VI by detergent is prevented by elevated Ca2+ concentrations. Annexin VI participates in the formation of a reversible, membrane–cytoskeleton complex (Babiychuk, E.B., R.J. Palstra, J. Schaller, U. Kämpfer, and A. Draeger. 1999. J. Biol. Chem. 274:35191–35195). Annexin II promotes the Ca2+-dependent association of lipid raft microdomains, whereas annexin V interacts with glycerophospholipid microcompartments. These interactions bring about a new configuration of membrane-bound constituents, with potentially important consequences for signaling events and Ca2+ flux.
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Gosens, Reinoud, Gerald L. Stelmack, Gordon Dueck, Mark M. Mutawe, Martha Hinton, Karol D. McNeill, Angela Paulson, et al. "Caveolae facilitate muscarinic receptor-mediated intracellular Ca2+ mobilization and contraction in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 6 (December 2007): L1406—L1418. http://dx.doi.org/10.1152/ajplung.00312.2007.
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Contractile responses of airway smooth muscle (ASM) determine airway resistance in health and disease. Caveolae microdomains in the plasma membrane are marked by caveolin proteins and are abundant in contractile smooth muscle in association with nanospaces involved in Ca2+ homeostasis. Caveolin-1 can modulate localization and activity of signaling proteins, including trimeric G proteins, via a scaffolding domain. We investigated the role of caveolae in contraction and intracellular Ca2+ ([Ca2+]i) mobilization of ASM induced by the physiological muscarinic receptor agonist, acetylcholine (ACh). Human and canine ASM tissues and cells predominantly express caveolin-1. Muscarinic M3 receptors (M3R) and Gαq/11 cofractionate with caveolin-1-rich membranes of ASM tissue. Caveolae disruption with β-cyclodextrin in canine tracheal strips reduced sensitivity but not maximum isometric force induced by ACh. In fura-2-loaded canine and human ASM cells, exposure to methyl-β-cyclodextrin (mβCD) reduced sensitivity but not maximum [Ca2+]i induced by ACh. In contrast, both parameters were reduced for the partial muscarinic agonist, pilocarpine. Fluorescence microscopy revealed that mβCD disrupted the colocalization of caveolae-1 and M3R, but [ N-methyl-3H]scopolamine receptor-binding assay revealed no effect on muscarinic receptor availability or affinity. To dissect the role of caveolin-1 in ACh-induced [Ca2+]i flux, we disrupted its binding to signaling proteins using either a cell-permeable caveolin-1 scaffolding domain peptide mimetic or by small interfering RNA knockdown. Similar to the effects of mβCD, direct targeting of caveolin-1 reduced sensitivity to ACh, but maximum [Ca2+]i mobilization was unaffected. These results indicate caveolae and caveolin-1 facilitate [Ca2+]i mobilization leading to ASM contraction induced by submaximal concentrations of ACh.
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Goodyear, L. J., M. F. Hirshman, R. J. Smith, and E. S. Horton. "Glucose transporter number, activity, and isoform content in plasma membranes of red and white skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 261, no. 5 (November 1, 1991): E556—E561. http://dx.doi.org/10.1152/ajpendo.1991.261.5.e556.
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The fiber type composition of a skeletal muscle is an important determinant of its ability to take up glucose. Although numerous factors may account for this phenomenon, we have hypothesized that fiber type differences in glucose transporter number, isoform content, and/or intrinsic activity play an important role. Skeletal muscle plasma membranes were prepared from red and white gastrocnemius muscle from male Sprague-Dawley rats that were either exercised on a treadmill (1 h, 20 m/min, 10% grade), injected with 20 U insulin, or remained sedentary. In sedentary rats, plasma membrane glucose transporter number (cytochalasin B binding) was 2.4-fold greater in red compared with white muscle. Exercise and insulin both increased glucose transporter number by 40% in red muscle and twofold in white muscle. Maximal velocity of glucose transport (Vmax) was 2-fold greater in red compared with white muscle, whereas exercise and insulin increased Vmax by 2.3-fold in red muscle and 3.6-fold in white muscle. Glucose transporter turnover number, a measure of the average intrinsic activity of transporters in the plasma membrane, was not different between red and white muscle and increased 80–90% with exercise and insulin in both red and white muscle. Both GLUT-1 and GLUT-4 isoform content were greater in red than white muscle. These results suggest that fiber type differences in rates of glucose uptake in resting, insulin-stimulated, and contraction-stimulated skeletal muscle may be due to differences in the number but not the intrinsic activity of glucose transporter proteins.
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Oba, T., M. Koshita, and M. Yamaguchi. "H2O2 modulates twitch tension and increases Po of Ca2+ release channel in frog skeletal muscle." American Journal of Physiology-Cell Physiology 271, no. 3 (September 1, 1996): C810—C818. http://dx.doi.org/10.1152/ajpcell.1996.271.3.c810.
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The effect of H2O2 was examined to elucidate the basis of muscle injury after exercise. Exposure of single fibers to 1.5-6 mM H2O2 led to twitch potentiation followed by a marked decrease. Then, fibers contracted spontaneously. BAY K 8644 augmented twitch potentiation and slowed the decay of twitches. In 5 mM dithiothreitol (DTT), twitch potentiation and spontaneous contraction were not observed on H2O2 addition. Cytoplasmic application of 1.5-3 mM H2O2 to heavy sarcoplasmic reticulum (SR) vesicles incorporated into planar lipid bilayers increased the open probability of Ca2+ release channels, an effect reversed by DTT. We investigated oxidation of sulfhydryl groups on proteins in SR membrane by H2O2 with N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimide. Pretreatment of light and heavy SR membranes with 1.5 mM H2O2 exponentially increased fluorescence intensity. The time constant of the intensity increase was increased markedly only in heavy SR in solution containing 50 microM cytoplasmic Ca2+, so Ca2+ release was associated with protein oxidation by H2O2. Thus extracellular H2O2 probably acts by oxidizing sulfhydryls of proteins at two distinct sites: the dihydropyridine receptors, oxidation of which elicits potentiation and subsequent inhibition of twitches, and Ca2+ release channels, whose oxidation elicits spontaneous contraction, resulting in muscle dysfunction.
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Protasi, Feliciano, Clara Franzini-Armstrong, and Paul D. Allen. "Role of Ryanodine Receptors in the Assembly of Calcium Release Units in Skeletal Muscle." Journal of Cell Biology 140, no. 4 (February 23, 1998): 831–42. http://dx.doi.org/10.1083/jcb.140.4.831.
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Abstract. In muscle cells, excitation–contraction (e–c) coupling is mediated by “calcium release units,” junctions between the sarcoplasmic reticulum (SR) and exterior membranes. Two proteins, which face each other, are known to functionally interact in those structures: the ryanodine receptors (RyRs), or SR calcium release channels, and the dihydropyridine receptors (DHPRs), or L-type calcium channels of exterior membranes. In skeletal muscle, DHPRs form tetrads, groups of four receptors, and tetrads are organized in arrays that face arrays of feet (or RyRs). Triadin is a protein of the SR located at the SR–exterior membrane junctions, whose role is not known. We have structurally characterized calcium release units in a skeletal muscle cell line (1B5) lacking Ry1R. Using immunohistochemistry and freeze-fracture electron microscopy, we find that DHPR and triadin are clustered in foci in differentiating 1B5 cells. Thin section electron microscopy reveals numerous SR–exterior membrane junctions lacking foot structures (dyspedic). These results suggest that components other than Ry1Rs are responsible for targeting DHPRs and triadin to junctional regions. However, DHPRs in 1B5 cells are not grouped into tetrads as in normal skeletal muscle cells suggesting that anchoring to Ry1Rs is necessary for positioning DHPRs into ordered arrays of tetrads. This hypothesis is confirmed by finding a “restoration of tetrads” in junctional domains of surface membranes after transfection of 1B5 cells with cDNA encoding for Ry1R.
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Protasi, Feliciano, Laura Pietrangelo, and Simona Boncompagni. "Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing." International Journal of Molecular Sciences 22, no. 12 (June 8, 2021): 6195. http://dx.doi.org/10.3390/ijms22126195.
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Proper skeletal muscle function is controlled by intracellular Ca2+ concentration and by efficient production of energy (ATP), which, in turn, depend on: (a) the release and re-uptake of Ca2+ from sarcoplasmic-reticulum (SR) during excitation–contraction (EC) coupling, which controls the contraction and relaxation of sarcomeres; (b) the uptake of Ca2+ into the mitochondrial matrix, which stimulates aerobic ATP production; and finally (c) the entry of Ca2+ from the extracellular space via store-operated Ca2+ entry (SOCE), a mechanism that is important to limit/delay muscle fatigue. Abnormalities in Ca2+ handling underlie many physio-pathological conditions, including dysfunction in ageing. The specific focus of this review is to discuss the importance of the proper architecture of organelles and membrane systems involved in the mechanisms introduced above for the correct skeletal muscle function. We reviewed the existing literature about EC coupling, mitochondrial Ca2+ uptake, SOCE and about the structural membranes and organelles deputed to those functions and finally, we summarized the data collected in different, but complementary, projects studying changes caused by denervation and ageing to the structure and positioning of those organelles: a. denervation of muscle fibers—an event that contributes, to some degree, to muscle loss in ageing (known as sarcopenia)—causes misplacement and damage: (i) of membrane structures involved in EC coupling (calcium release units, CRUs) and (ii) of the mitochondrial network; b. sedentary ageing causes partial disarray/damage of CRUs and of calcium entry units (CEUs, structures involved in SOCE) and loss/misplacement of mitochondria; c. functional electrical stimulation (FES) and regular exercise promote the rescue/maintenance of the proper architecture of CRUs, CEUs, and of mitochondria in both denervation and ageing. All these structural changes were accompanied by related functional changes, i.e., loss/decay in function caused by denervation and ageing, and improved function following FES or exercise. These data suggest that the integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity); modifications in the architecture of these intracellular membrane systems may contribute to muscle dysfunction in ageing and sarcopenia.
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Liu, Xujie, Suya Wang, Xiaoling Guo, Yifei Li, Roza Ogurlu, Fujian Lu, Maksymilian Prondzynski, et al. "Increased Reactive Oxygen Species–Mediated Ca 2+ /Calmodulin-Dependent Protein Kinase II Activation Contributes to Calcium Handling Abnormalities and Impaired Contraction in Barth Syndrome." Circulation 143, no. 19 (May 11, 2021): 1894–911. http://dx.doi.org/10.1161/circulationaha.120.048698.
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Background: Mutations in tafazzin ( TAZ ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. Methods: We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac-specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells and cardiac-specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca 2+ handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca 2+ handling and contractility. Results: A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias, including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared with wild-type controls, BTHS-induced pluripotent stem cell–derived cardiomyocytes had increased diastolic Ca 2+ and decreased Ca 2+ transient amplitude. BTHS-induced pluripotent stem cell–derived cardiomyocytes had higher levels of mitochondrial and cellular reactive oxygen species than wild-type controls, which activated CaMKII (Ca 2+ /calmodulin-dependent protein kinase II). Activated CaMKII phosphorylated the RYR2 (ryanodine receptor 2) on serine 2814, increasing Ca 2+ leak through RYR2. Inhibition of this reactive oxygen species–CaMKII–RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca 2+ handling in BTHS-induced pluripotent stem cell–derived cardiomyocytes and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca 2+ and decreased Ca 2+ transient amplitude. These abnormalities were ameliorated by Ca 2+ /calmodulin-dependent protein kinase II or reactive oxygen species inhibition. Conclusions: This study identified a molecular pathway that links TAZ mutation with abnormal Ca 2+ handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial reactive oxygen species production.
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Hardie, D. Grahame. "Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism." Proceedings of the Nutrition Society 70, no. 1 (November 11, 2010): 92–99. http://dx.doi.org/10.1017/s0029665110003915.
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The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP:ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-of-rapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished.
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Sakihara, Chie, William J. Perkins, David O. Warner, and Keith A. Jones. "Anesthetics Inhibit Acetylcholine-promoted Guanine Nucleotide Exchange of Heterotrimeric G Proteins of Airway Smooth Muscle." Anesthesiology 101, no. 1 (July 1, 2004): 120–26. http://dx.doi.org/10.1097/00000542-200407000-00019.
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Background Anesthetics inhibit airway smooth muscle contraction in part by a direct effect on the smooth muscle cell. This study tested the hypothesis that the anesthetics halothane and hexanol, which both relax airway smooth muscle in vitro, inhibit acetylcholine-promoted nucleotide exchange at the alpha subunit of the Gq/11 heterotrimeric G protein (Galphaq/11; i.e., they inhibit muscarinic receptor-Galphaq/11 coupling). Methods The effect of halothane (0.38 +/- 0.02 mm) and hexanol (10 mm) on basal and acetylcholine-stimulated Galphaq/11 guanosine nucleotide exchange was determined in membranes prepared from porcine tracheal smooth muscle. The nonhydrolyzable, radioactive form of guanosine-5'-triphosphate, [S]GTPgammaS, was used as the reporter for Galphaq/11 subunit dissociation from the membrane to soluble fraction, which was immunoprecipitated with rabbit polyclonal anti-Galphaq/11 antiserum. Results Acetylcholine caused a significant time- and concentration-dependent increase in the magnitude of Galphaq/11 nucleotide exchange compared with basal values (i.e., without acetylcholine), reaching a maximal difference at 100 microm (35.9 +/-2.9 vs. 9.8 +/-1.2 fmol/mg protein, respectively). Whereas neither anesthetic had an effect on basal Galphaq/11 nucleotide exchange, both halothane and hexanol significantly inhibited the increase in Galphaq/11 nucleotide exchange produced by 30 microm acetylcholine (by 59% and 68%, respectively). Conclusions Halothane and hexanol interact with the receptor-heterotrimeric G-protein complex in a manner that prevents acetylcholine-promoted exchange of guanosine-5(')-triphosphate for guanosine-5'-diphosphate at Galphaq/11. These data are consistent with the ability of anesthetics to interfere with cellular processes mediated by heterotrimeric G proteins in many cells, including effects on muscarinic receptor-G-protein regulation of airway smooth muscle contraction.
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Block, B. A., T. Imagawa, K. P. Campbell, and C. Franzini-Armstrong. "Structural evidence for direct interaction between the molecular components of the transverse tubule/sarcoplasmic reticulum junction in skeletal muscle." Journal of Cell Biology 107, no. 6 (December 1, 1988): 2587–600. http://dx.doi.org/10.1083/jcb.107.6.2587.
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The architecture of the junctional sarcoplasmic reticulum (SR) and transverse tubule (T tubule) membranes and the morphology of the two major proteins isolated from these membranes, the ryanodine receptor (or foot protein) and the dihydropyridine receptor, have been examined in detail. Evidence for a direct interaction between the foot protein and a protein component of the junctional T tubule membrane is presented. Comparisons between freeze-fracture images of the junctional SR and rotary-shadowed images of isolated triads and of the isolated foot protein, show that the foot protein has two domains. One is the large hydrophilic foot which spans the junctional gap and is composed of four subunits. The other is a hydrophobic domain which presumably forms the SR Ca2+-release channel and which also has a fourfold symmetry. Freeze-fracture images of the junctional T tubule membranes demonstrate the presence of diamond-shaped clusters of particles that correspond exactly in position to the subunits of the feet protein. These results suggest the presence of a large junctional complex spanning the two junctional membranes and intervening gap. This junctional complex is an ideal candidate for a mechanical coupling hypothesis of excitation-contraction coupling at the triadic junction.
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Pörtner, H. O. "Physiological basis of temperature-dependent biogeography: trade-offs in muscle design and performance in polar ectotherms." Journal of Experimental Biology 205, no. 15 (August 1, 2002): 2217–30. http://dx.doi.org/10.1242/jeb.205.15.2217.
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SUMMARYPolar, especially Antarctic, oceans host ectothermic fish and invertebrates characterized by low-to-moderate levels of motor activity; maximum performance is reduced compared with that in warmer habitats. The present review attempts to identify the trade-offs involved in adaptation to cold in the light of progress in the physiology of thermal tolerance. Recent evidence suggests that oxygen limitations and a decrease in aerobic scope are the first indications of tolerance limits at both low and high temperature extremes. The cold-induced reduction in aerobic capacity is compensated for at the cellular level by elevated mitochondrial densities, accompanied by molecular and membrane adjustments for the maintenance of muscle function. Particularly in the muscle of pelagic Antarctic fish, among notothenioids, the mitochondrial volume densities are among the highest known for vertebrates and are associated with cold compensation of aerobic metabolic pathways, a reduction in anaerobic scope, rapid recovery from exhaustive exercise and enhanced lipid stores as well as a preference for lipid catabolism characterized by high energy efficiency at high levels of ambient oxygen supply. Significant anaerobic capacity is still found at the very low end of the activity spectrum, e.g. among benthic eelpout (Zoarcideae).In contrast to the cold-adapted eurytherms of the Arctic, polar (especially Antarctic) stenotherms minimize standard metabolic rate and, as a precondition, the aerobic capacity per milligram of mitochondrial protein,thereby minimizing oxygen demand. Cost reductions are supported by the downregulation of the cost and flexibility of acid—base regulation. At maintained factorial scopes, the reduction in standard metabolic rate will cause net aerobic scope to be lower than in temperate species. Loss of contractile myofilaments and, thereby, force results from space constraints due to excessive mitochondrial proliferation. On a continuum between low and moderately high levels of muscular activity, polar fish have developed characteristics of aerobic metabolism equivalent to those of high-performance swimmers in warmer waters. However, they only reach low performance levels despite taking aerobic design to an extreme.
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Melzer, Werner. "No voltage change at skeletal muscle SR membrane during Ca2+ release—just Mermaids on acid." Journal of General Physiology 150, no. 8 (July 3, 2018): 1055–58. http://dx.doi.org/10.1085/jgp.201812084.
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Calcium ions control multiple physiological functions by binding to extracellular and intracellular targets. One of the best-studied Ca2+-dependent functions is contraction of smooth and striated muscle tissue, which results from Ca2+ ligation to calmodulin and troponin C, respectively. Ca2+ signaling typically involves flux of the ion across membranes via specifically gated channel proteins. Because calcium ions are charged, they possess the ability to generate changes in the respective transmembrane voltage. Ca2+-dependent voltage alterations of the surface membrane are easily measured using microelectrodes. A well-known example is the characteristic plateau phase of the action potential in cardiac ventricular cells that results from the opening of voltage-gated L-type Ca2+ channels. Ca2+ ions are also released from intracellular storage compartments in many cells, but these membranes are not accessible to direct voltage recording with microelectrodes. In muscle, for example, release of Ca2+ from the sarcoplasmic reticulum (SR) to the myoplasm constitutes a flux that is considerably larger than the entry flux from the extracellular space. Whether this flux is accompanied by a voltage change across the SR membrane is an obvious question of mechanistic importance and has been the subject of many investigations. Because the tiny spaces enclosed by the SR membrane are inaccessible to microelectrodes, alternative methods have to be applied. In a study by Sanchez et al. (2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812035) in this issue, modern confocal light microscopy and genetically encoded voltage probes targeted to the SR were applied in a new approach to search for changes in the membrane potential of the SR during Ca2+ release.
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Murthy, M. S. R., and S. V. Pande. "Characterization of a solubilized malonyl-CoA-sensitive carnitine palmitoyltransferase from the mitochondrial outer membrane as a protein distinct from the malonyl-CoA-insensitive carnitine palmitoyltransferase of the inner membrane." Biochemical Journal 268, no. 3 (June 15, 1990): 599–604. http://dx.doi.org/10.1042/bj2680599.
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By using octyl glucoside in the presence of glycerol, it is possible to obtain a solubilized malonyl-CoA-sensitive carnitine palmitoyltransferase (CPTo) from the outer membranes of rat liver mitochondria. H.p.l.c. on hydroxyapatite column has now allowed a clear separation of the CPTo from the malonyl-CoA-insensitive CPT activity of the inner membranes (CPTi). The separated CPTo activity showed inhibition by low micromolar concentrations of malonyl-CoA, 2-tetradecylglycidyl-CoA and etomoxir-CoA. On solubilization and fractionation, the CPTo rapidly lost activity, unlike the relatively stable CPTi activity. Reconstitution into asolectin liposomes enhanced the activity and the malonyl-CoA-sensitivity of the CPTo fractions, whereas it had no such effect on the activity or malonyl-CoA insensitivity of the CPTi fractions. A polyclonal antibody raised against the malonyl-CoA-insensitive enzyme, purified from the inner membranes, precipitated the CPTi activity, but showed no reactivity with the CPTo fractions. In Western blots, the above antibody did not react with any polypeptide of the CPTo fractions. Incubation of the outer-membrane preparations with [3H]etomoxir, in the presence of ATP and CoA, led to labelling of a 90 kDa polypeptide that in the above hydroxyapatite chromatography was eluted in the same region as the CPTo. No such polypeptide labelling was seen in the CPTi fractions. With heart and skeletal-muscle mitochondria, the correspondingly labelled polypeptide was of about 86 kDa. These results show that the CPTo and CPTi are distinct proteins, that a subunit of 90 kDa for liver and 86 kDa for muscle constitutes a component of their respective CPTo systems, and that the 66 kDa subunit of the CPTi does not constitute a part of the CPTo system.
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Tang, Kechun, Teresa Pasqua, Angshuman Biswas, Sumana Mahata, Jennifer Tang, Alisa Tang, Gautam K. Bandyopadhyay, et al. "Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice." Journal of Endocrinology 232, no. 2 (February 2017): 137–53. http://dx.doi.org/10.1530/joe-16-0370.
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Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifnγ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. As CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage.
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González-Andrés, Paula, Laura Fernández-Peña, Carlos Díez-Poza, Carlos Villalobos, Lucía Nuñez, and Asunción Barbero. "Marine Heterocyclic Compounds That Modulate Intracellular Calcium Signals: Chemistry and Synthesis Approaches." Marine Drugs 19, no. 2 (January 31, 2021): 78. http://dx.doi.org/10.3390/md19020078.
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Intracellular Ca2+ plays a pivotal role in the control of a large series of cell functions in all types of cells, from neurotransmitter release and muscle contraction to gene expression, cell proliferation and cell death. Ca2+ is transported through specific channels and transporters in the plasma membrane and subcellular organelles such as the endoplasmic reticulum and mitochondria. Therefore, dysregulation of intracellular Ca2+ homeostasis may lead to cell dysfunction and disease. Accordingly, chemical compounds from natural origin and/or synthesis targeting directly or indirectly these channels and proteins may be of interest for the treatment of cell dysfunction and disease. In this review, we show an overview of a group of marine drugs that, from the structural point of view, contain one or various heterocyclic units in their core structure, and from the biological side, they have a direct influence on the transport of calcium in the cell. The marine compounds covered in this review are divided into three groups, which correspond with their direct biological activity, such as compounds with a direct influence in the calcium channel, compounds with a direct effect on the cytoskeleton and drugs with an effect on cancer cell proliferation. For each target, we describe its bioactive properties and synthetic approaches. The wide variety of chemical structures compiled in this review and their significant medical properties may attract the attention of many different researchers.
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Berridge, M. J. "Regulation of ion channels by inositol trisphosphate and diacylglycerol." Journal of Experimental Biology 124, no. 1 (September 1, 1986): 323–35. http://dx.doi.org/10.1242/jeb.124.1.323.
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Calcium-mobilizing receptors function to regulate ion channels located not only in the plasma membrane but also across the membranes of intracellular organelles, particularly the endoplasmic reticulum. A characteristic feature of such receptors is that they stimulate the hydrolysis of an inositol lipid to generate a pair of second messengers. Diacylglycerol remains within the plasma membrane where it activates protein kinase C leading to the phosphorylation of proteins some of which may regulate specific ionic channels, such as the calcium-dependent potassium channel or the Na+/H+ exchanger which regulates intracellular pH. The inositol trisphosphate (Ins 1,4,5P3) released to the cytosol functions as a second messenger to release calcium from the endoplasmic reticulum. The Ins 1,4,5P3 acts on a specific receptor to enhance the passive efflux of calcium while having no effect on the active calcium pump. There are indications that this Ins 1,4,5P3-induced release of calcium from an internal membrane store might provide an explanation of excitation-contraction coupling in skeletal muscle. Skinned skeletal muscle cells can be induced to contract by adding Ins 1,4,5P3. Mobilization of calcium from intracellular reservoirs by Ins 1,4,5P3 may thus prove to be a ubiquitous and fundamental mechanism for regulating cellular activity.
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Stenoien, David L., Tatyana V. Knyushko, Monica P. Londono, Lee K. Opresko, M. Uljana Mayer, Scott T. Brady, Thomas C. Squier, and Diana J. Bigelow. "Cellular trafficking of phospholamban and formation of functional sarcoplasmic reticulum during myocyte differentiation." American Journal of Physiology-Cell Physiology 292, no. 6 (June 2007): C2084—C2094. http://dx.doi.org/10.1152/ajpcell.00523.2006.
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Phospholamban (PLB) associates with the Ca2+-ATPase in sarcoplasmic reticulum (SR) membranes to permit the modulation of contraction in response to β-adrenergic signaling. To understand how coordinated changes in the abundance and intracellular trafficking of PLB and the Ca2+-ATPase contribute to the maturation of functional muscle, we measured changes in abundance, location, and turnover of endogenous and tagged proteins in myoblasts and during their differentiation. We found that PLB is constitutively expressed in both myoblasts and differentiated myotubes, whereas abundance increases of the Ca2+-ATPase coincide with the formation of differentiated myotubes. We observed that PLB is primarily present in highly mobile vesicular structures outside the endoplasmic reticulum, irrespective of the expression of the Ca2+-ATPase, indicating that PLB targeting is regulated through vesicle trafficking. Moreover, using pulse-chase methods, we observed that in myoblasts, PLB is trafficked through directed transport through the Golgi to the plasma membrane before endosome-mediated internalization. The observed trafficking of PLB to the plasma membrane suggests an important role for PLB during muscle differentiation, which is distinct from its previously recognized role in the regulation of the Ca2+-ATPase.