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1
Hyatt, Hayden W., and Scott K. Powers. "Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity." Antioxidants 10, no. 4 (April 11, 2021): 588. http://dx.doi.org/10.3390/antiox10040588.
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Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.
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Man, William D. C., Paul Kemp, John Moxham, and Michael I. Polkey. "Exercise and muscle dysfunction in COPD: implications for pulmonary rehabilitation." Clinical Science 117, no. 8 (August 24, 2009): 281–91. http://dx.doi.org/10.1042/cs20080660.
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Skeletal muscle dysfunction in COPD (chronic obstructive pulmonary disease) patients, particularly of the quadriceps, is of clinical interest because it not only influences the symptoms that limit exercise, but may also contribute directly to poor exercise performance and health status, increased healthcare utilization, and mortality. Furthermore, unlike the largely irreversible impairment of the COPD lung, skeletal muscles represent a potential site to improve patients' level of function and quality of life. However, despite expanding knowledge of potential contributing factors and greater understanding of molecular mechanisms of muscle wasting, only one intervention has been shown to be effective in reversing COPD muscle dysfunction, namely exercise training. Pulmonary rehabilitation, an intervention based on individually tailored exercise training, has emerged as arguably the most effective non-pharmacological intervention in improving exercise capacity and health status in COPD patients. The present review describes the effects of chronic exercise training on skeletal muscles and, in particular, focuses on the known effects of pulmonary rehabilitation on the quadriceps muscle in COPD. We also describe the current methods to augment the effects of pulmonary rehabilitation and speculate how greater knowledge of the molecular pathways of skeletal muscle wasting may aid the development of novel pharmaceutical agents.
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Ignatieva, Elena, Natalia Smolina, Anna Kostareva, and Renata Dmitrieva. "Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype." International Journal of Molecular Sciences 22, no. 14 (July 8, 2021): 7349. http://dx.doi.org/10.3390/ijms22147349.
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Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.
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Man, William D. C., Paul Kemp, John Moxham, and Michael I. Polkey. "Skeletal muscle dysfunction in COPD: clinical and laboratory observations." Clinical Science 117, no. 7 (August 17, 2009): 251–64. http://dx.doi.org/10.1042/cs20080659.
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COPD (chronic obstructive pulmonary disease), although primarily a disease of the lungs, exhibits secondary systemic manifestations. The skeletal muscles are of particular interest because their function (or dysfunction) not only influences the symptoms that limit exercise, but may contribute directly to poor exercise performance. Furthermore, skeletal muscle weakness is of great clinical importance in COPD as it is recognized to contribute independently to poor health status, increased healthcare utilization and even mortality. The present review describes the current knowledge of the structural and functional abnormalities of skeletal muscles in COPD and the possible aetiological factors. Increasing knowledge of the molecular pathways of muscle wasting will lead to the development of new therapeutic agents and strategies to combat COPD muscle dysfunction.
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Conte, Elena, Elena Bresciani, Laura Rizzi, Ornella Cappellari, Annamaria De Luca, Antonio Torsello, and Antonella Liantonio. "Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies." International Journal of Molecular Sciences 21, no. 4 (February 13, 2020): 1242. http://dx.doi.org/10.3390/ijms21041242.
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Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function.
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Ábrigo, Johanna, Alvaro A. Elorza, Claudia A. Riedel, Cristian Vilos, Felipe Simon, Daniel Cabrera, Lisbell Estrada, and Claudio Cabello-Verrugio. "Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–17. http://dx.doi.org/10.1155/2018/2063179.
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Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.
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Hardee, Justin P., Ryan N. Montalvo, and James A. Carson. "Linking Cancer Cachexia-Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/8018197.
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Cancer cachexia, a wasting syndrome characterized by skeletal muscle depletion, contributes to increased patient morbidity and mortality. While the intricate balance between protein synthesis and breakdown regulates skeletal muscle mass, the suppression of basal protein synthesis may not account for the severe wasting induced by cancer. Therefore, recent research has shifted to the regulation of “anabolic resistance,” which is the impaired ability of nutrition and exercise to stimulate protein synthesis. Emerging evidence suggests that oxidative metabolism can regulate both basal and induced muscle protein synthesis. While disrupted protein turnover and oxidative metabolism in cachectic muscle have been examined independently, evidence suggests a linkage between these processes for the regulation of cancer-induced wasting. The primary objective of this review is to highlight the connection between dysfunctional oxidative metabolism and cancer-induced anabolic resistance in skeletal muscle. First, we review oxidative metabolism regulation of muscle protein synthesis. Second, we describe cancer-induced alterations in the response to an anabolic stimulus. Finally, we review a role for exercise to inhibit cancer-induced anabolic suppression and mitochondrial dysfunction.
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Furrer, Regula, and Christoph Handschin. "Muscle Wasting Diseases: Novel Targets and Treatments." Annual Review of Pharmacology and Toxicology 59, no. 1 (January 6, 2019): 315–39. http://dx.doi.org/10.1146/annurev-pharmtox-010818-021041.
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Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases.
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Silva, Kleiton Augusto Santos, Thaysa Ghiarone, Kathy Schreiber, DeAna Grant, Tommi White, Madlyn I. Frisard, Sergiy Sukhanov, Bysani Chandrasekar, Patrice Delafontaine, and Tadashi Yoshida. "Angiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscle." Journal of Applied Physiology 126, no. 6 (June 1, 2019): 1550–62. http://dx.doi.org/10.1152/japplphysiol.00898.2018.
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Angiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5′-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels.
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Leduc-Gaudet, Jean-Philippe, Dominique Mayaki, Olivier Reynaud, Felipe E. Broering, Tomer J. Chaffer, Sabah N. A. Hussain, and Gilles Gouspillou. "Parkin Overexpression Attenuates Sepsis-Induced Muscle Wasting." Cells 9, no. 6 (June 11, 2020): 1454. http://dx.doi.org/10.3390/cells9061454.
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Sepsis elicits skeletal muscle weakness and fiber atrophy. The accumulation of injured mitochondria and depressed mitochondrial functions are considered as important triggers of sepsis-induced muscle atrophy. It is unclear whether mitochondrial dysfunctions in septic muscles are due to the inadequate activation of quality control processes. We hypothesized that overexpressing Parkin, a protein responsible for the recycling of dysfunctional mitochondria by the autophagy pathway (mitophagy), would confer protection against sepsis-induced muscle atrophy by improving mitochondrial quality and content. Parkin was overexpressed for four weeks in the limb muscles of four-week old mice using intramuscular injections of adeno-associated viruses (AAVs). The cecal ligation and perforation (CLP) procedure was used to induce sepsis. Sham operated animals were used as controls. All animals were studied for 48 h post CLP. Sepsis resulted in major body weight loss and myofiber atrophy. Parkin overexpression prevented myofiber atrophy in CLP mice. Quantitative two-dimensional transmission electron microscopy revealed that sepsis is associated with the accumulation of enlarged and complex mitochondria, an effect which was attenuated by Parkin overexpression. Parkin overexpression also prevented a sepsis-induced decrease in the content of mitochondrial subunits of NADH dehydrogenase and cytochrome C oxidase. We conclude that Parkin overexpression prevents sepsis-induced skeletal muscle atrophy, likely by improving mitochondrial quality and contents.
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Demos-Davies, Kimberly M., Bradley S. Ferguson, Maria A. Cavasin, Jennifer H. Mahaffey, Sarah M. Williams, Jessica I. Spiltoir, Katherine B. Schuetze, et al. "HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling." American Journal of Physiology-Heart and Circulatory Physiology 307, no. 2 (July 15, 2014): H252—H258. http://dx.doi.org/10.1152/ajpheart.00149.2014.
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Little is known about the function of the cytoplasmic histone deacetylase HDAC6 in striated muscle. Here, we addressed the role of HDAC6 in cardiac and skeletal muscle remodeling induced by the peptide hormone angiotensin II (ANG II), which plays a central role in blood pressure control, heart failure, and associated skeletal muscle wasting. Comparable with wild-type (WT) mice, HDAC6 null mice developed cardiac hypertrophy and fibrosis in response to ANG II. However, whereas WT mice developed systolic dysfunction upon treatment with ANG II, cardiac function was maintained in HDAC6 null mice treated with ANG II for up to 8 wk. The cardioprotective effect of HDAC6 deletion was mimicked in WT mice treated with the small molecule HDAC6 inhibitor tubastatin A. HDAC6 null mice also exhibited improved left ventricular function in the setting of pressure overload mediated by transverse aortic constriction. HDAC6 inhibition appeared to preserve systolic function, in part, by enhancing cooperativity of myofibrillar force generation. Finally, we show that HDAC6 null mice are resistant to skeletal muscle wasting mediated by chronic ANG-II signaling. These findings define novel roles for HDAC6 in striated muscle and suggest potential for HDAC6-selective inhibitors for the treatment of cardiac dysfunction and muscle wasting in patients with heart failure.
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Blackwell, Thomas A., Igor Cervenka, Bhuwan Khatri, Jacob L. Brown, Megan E. Rosa-Caldwell, David E. Lee, Richard A. Perry, et al. "Transcriptomic analysis of the development of skeletal muscle atrophy in cancer-cachexia in tumor-bearing mice." Physiological Genomics 50, no. 12 (December 1, 2018): 1071–82. http://dx.doi.org/10.1152/physiolgenomics.00061.2018.
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Cancer-cachexia (CC) is a wasting condition directly responsible for 20–40% of cancer-related deaths. The mechanisms controlling development of CC-induced muscle wasting are not fully elucidated. Most investigations focus on the postcachectic state and do not examine progression of the condition. We recently demonstrated mitochondrial degenerations precede muscle wasting in time course progression of CC. However, the extent of muscle perturbations before wasting in CC is unknown. Therefore, we performed global gene expression analysis in CC-induced muscle wasting to enhance understanding of intramuscular perturbations across the development of CC. Lewis lung carcinoma (LLC) was injected into the hind-flank of C57BL6/J mice at 8 wk of age with tumor allowed to develop for 1, 2, 3, or 4 wk and compared with PBS-injected control. Muscle wasting was evident at 4 wk LLC. RNA sequencing of gastrocnemius muscle samples showed widespread alterations in LLC compared with PBS animals with largest differences seen in 4 wk LLC, suggesting extensive transcriptomic alterations concurrent to muscle wasting. Commonly altered pathways included: mitochondrial dysfunction and protein ubiquitination, along with other less studied processes in this condition regulating transcription/translation and cytoskeletal structure. Current findings present novel evidence of transcriptomic shifts and altered cellular pathways in CC-induced muscle wasting.
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Adams, Volker, Victoria Gußen, Sergey Zozulya, André Cruz, Anselmo Moriscot, Axel Linke, and Siegfried Labeit. "Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy." Cells 9, no. 10 (October 11, 2020): 2272. http://dx.doi.org/10.3390/cells9102272.
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Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13–23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction.
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Maestraggi, Quentin, Benjamin Lebas, Raphaël Clere-Jehl, Pierre-Olivier Ludes, Thiên-Nga Chamaraux-Tran, Francis Schneider, Pierre Diemunsch, Bernard Geny, and Julien Pottecher. "Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/7897325.
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Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called “cytopathic hypoxia,” perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system (“immunoparalysis”) translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.
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Puthucheary, Zudin, Stephen Harridge, and Nicholas Hart. "Skeletal muscle dysfunction in critical care: Wasting, weakness, and rehabilitation strategies." Critical Care Medicine 38 (October 2010): S676—S682. http://dx.doi.org/10.1097/ccm.0b013e3181f2458d.
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Daou, Hélène N. "Exercise as an anti-inflammatory therapy for cancer cachexia: a focus on interleukin-6 regulation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 318, no. 2 (February 1, 2020): R296—R310. http://dx.doi.org/10.1152/ajpregu.00147.2019.
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Cancer cachexia is a complicated disorder of extreme, progressive skeletal muscle wasting. It is directed by metabolic alterations and systemic inflammation dysregulation. Numerous studies have demonstrated that increased systemic inflammation promotes this type of cachexia and have suggested that cytokines are implicated in the skeletal muscle loss. Exercise is firmly established as an anti-inflammatory therapy that can attenuate or even reverse the process of muscle wasting in cancer cachexia. The interleukin IL-6 is generally considered to be a key player in the development of the microenvironment of malignancy; it promotes tumor growth and metastasis by acting as a bridge between chronic inflammation and cancerous tissue and it also induces skeletal muscle atrophy and protein breakdown. Paradoxically, a beneficial role for IL-6 has also been identified recently, and that is its status as a “founding member” of the myokine class of proteins. Skeletal muscle is an important source of circulating IL-6 in people who participate in exercise training. IL-6 acts as an anti-inflammatory myokine by inhibiting TNFα and improving glucose uptake through the stimulation of AMPK signaling. This review discusses the action of IL-6 in skeletal muscle tissue dysfunction and the role of IL-6 as an “exercise factor” that modulates the immune system. This review also sheds light on the main considerations related to the treatment of muscle wasting in cancer cachexia.
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Beltrà, Marc, Fabrizio Pin, Riccardo Ballarò, Paola Costelli, and Fabio Penna. "Mitochondrial Dysfunction in Cancer Cachexia: Impact on Muscle Health and Regeneration." Cells 10, no. 11 (November 12, 2021): 3150. http://dx.doi.org/10.3390/cells10113150.
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Cancer cachexia is a frequently neglected debilitating syndrome that, beyond representing a primary cause of death and cancer therapy failure, negatively impacts on patients’ quality of life. Given the complexity of its multisystemic pathogenesis, affecting several organs beyond the skeletal muscle, defining an effective therapeutic approach has failed so far. Revamped attention of the scientific community working on cancer cachexia has focused on mitochondrial alterations occurring in the skeletal muscle as potential triggers of the complex metabolic derangements, eventually leading to hypercatabolism and tissue wasting. Mitochondrial dysfunction may be simplistically viewed as a cause of energy failure, thus inducing protein catabolism as a compensatory mechanism; however, other peculiar cachexia features may depend on mitochondria. On the one side, chemotherapy also impacts on muscle mitochondrial function while, on the other side, muscle-impaired regeneration may result from insufficient energy production from damaged mitochondria. Boosting mitochondrial function could thus improve the energetic status and chemotherapy tolerance, and relieve the myogenic process in cancer cachexia. In the present work, a focused review of the available literature on mitochondrial dysfunction in cancer cachexia is presented along with preliminary data dissecting the potential role of stimulating mitochondrial biogenesis via PGC-1α overexpression in distinct aspects of cancer-induced muscle wasting.
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Aquila, Giorgio, Andrea David Re Cecconi, Jeffrey J. Brault, Oscar Corli, and Rosanna Piccirillo. "Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia." Cells 9, no. 12 (November 24, 2020): 2536. http://dx.doi.org/10.3390/cells9122536.
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Cancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our understanding of the mechanisms contributing to muscle wasting during cancer has markedly increased. Both inflammation and oxidative stress (OS) alter anabolic and catabolic signaling pathways mostly culminating with muscle depletion. Several preclinical studies have emphasized the beneficial roles of several classes of nutraceuticals and modes of physical exercise, but their efficacy in CC patients remains scant. The route of nutraceutical administration is critical to increase its bioavailability and achieve the desired anti-cachexia effects. Accumulating evidence suggests that a single therapy may not be enough, and a bimodal intervention (nutraceuticals plus exercise) may be a more effective treatment for CC. This review focuses on the current state of the field on the role of inflammation and OS in the pathogenesis of muscle atrophy during CC, and how nutraceuticals and physical activity may act synergistically to limit muscle wasting and dysfunction.
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Kaneki, Masao, Masayuki Kobayashi, Shingo Kasamatsu, Shingo Yasuhara, and Shohei Shinozaki. "840 Myostatin Deficiency Inhibits Muscle Wasting and Improves Bacterial Clearance and Survival in Septic Mice." Journal of Burn Care & Research 41, Supplement_1 (March 2020): S259—S260. http://dx.doi.org/10.1093/jbcr/iraa024.413.
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Abstract Introduction Sepsis is a leading cause of the mortality of burn patients. Muscle wasting is a major complication of sepsis and burn injury and negatively affects clinical outcomes of patients with sepsis and burn injury. Myostatin (MSTN) is a myokine that causes muscle atrophy by activating the activin type 2 receptor (ActRII) pathway and myostatin deficiency increases skeletal muscle mass. However, a role of myostatin in critical illness (e.g., sepsis, burn injury)-induced muscle wasting has not yet been investigated. Moreover, a role of muscle wasting in immune suppression and mortality in sepsis is unknown. Methods Sepsis was induced by cecum ligation and puncture (CLP) in male MSTN-deficient mice at 8 weeks of age and age- and body weight (BW)-matched wild type (WT) mice. Survival was monitored for 14 days. Bacterial clearance was evaluated at 16 h after CLP by measuring bacterial load in the peritoneal cavity and circulation. The weight of gastrocnemius (GC), tibialis anterior (TA) and soleus (SOL) muscle and cross-sectional areas of GC were measured before and at 14 days after CLP. To evaluate neutrophil organ infiltration, myeloperoxidase (MPO) activity was measured in the liver and kidney at 16 h after CLP. To evaluate liver dysfunction, acute kidney injury and inflammatory response, plasma levels of AST, ALT, NGAL and high mobility group box 1 (HMGB1) were measured at 16 h after CLP. Protein expression of Murf-1 and Atrogin-1, key players in muscle wasting, and ActRIIB was evaluated in GC muscle by immunoblotting at 3 days and 16 h after CLP, respectively. Results MSTN deficiency increased skeletal muscle mass and inhibited sepsis-induced muscle wasting compared with BW-matched WT mice. Sepsis-induced increase in Murf-1, but not Atrogin-1, expression in muscle was attenuated by MSTN deficiency. CLP increased protein expression of ActRIIB in muscle. Moreover, MSTN deficiency reduced mortality of septic mice compared with age- and BW-matched WT mice. MSTN deficiency improved bacterial clearance and ameliorated increases in MPO activity in the liver and kidney and plasma concentrations of AST, ALT, NGAL and HMGB1 in septic mice. Conclusions Our data showed that MSTN deficiency inhibited muscle wasting and improved bacterial clearance and survival in septic mice. These data indicate that MSTN plays an important role in sepsis-induced muscle wasting. Moreover, our findings suggest that muscle wasting may not be just a complication of sepsis but a driver of sepsis development contributing to mortality of septic mice. This study also raises the possibility that muscle wasting and/or activation of the MSTN-ActRII pathway may exacerbate sepsis-induced immune dysfunction. Applicability of Research to Practice Our study identifies the MSTN-ActRII pathway as a novel, potential molecular target to ameliorate muscle wasting and improve survival of septic burned patients.
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Shemesh, Adi, Yichen Wang, Yingjuan Yang, Gong-She Yang, Danielle E. Johnson, Jonathan M. Backer, Jeffrey E. Pessin, and Haihong Zong. "Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 307, no. 10 (November 15, 2014): R1251—R1259. http://dx.doi.org/10.1152/ajpregu.00212.2014.
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Pompe disease is due to a deficiency in acid-α-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog l-leucyl-l-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.
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Spaulding, HR, C. Ballmann, JC Quindry, MB Hudson, and JT Selsby. "Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models." JRSM Cardiovascular Disease 8 (January 2019): 204800401987958. http://dx.doi.org/10.1177/2048004019879581.
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Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.
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Basic, Vladimir T., Elsa Tadele, Ali Ateia Elmabsout, Hongwei Yao, Irfan Rahman, Allan Sirsjö, and Samy M. Abdel-Halim. "Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 6 (September 15, 2012): L519—L527. http://dx.doi.org/10.1152/ajplung.00007.2012.
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Cigarette smoke (CS) is a well-established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting, remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance, a mouse model of CS exposure was used. The 129/SvJ mice were exposed to CS for 6 mo, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared with controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1), and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading toward impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area, and decreased exercise tolerance.
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Feige, Jerome. "Nutritional Strategies to Counteract Mitochondrial Dysfunction and NAD+ Deficiency in Human Sarcopenia." Innovation in Aging 4, Supplement_1 (December 1, 2020): 764–65. http://dx.doi.org/10.1093/geroni/igaa057.2760.
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Abstract The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. We compared genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men of different ethnicity. Individuals with sarcopenia demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low PGC-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced bioenergetic activity, and NAD+ deficiency in sarcopenic muscle. Our results point to mitochondrial homeostasis as a key mediator of pathological muscle aging. Novel nutritional solutions enhancing muscle strength and performance by enhancing mitochondrial function are being tested clinically and will be reviewed. These include activating mitophagy with Urolithin A or restoring NAD+ levels via tryptophane/kynurenine or with nicotinamide riboside.
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Brzeszczyńska, Joanna, Filip Brzeszczyński, David F. Hamilton, Robin McGregor, and A. Hamish R. W. Simpson. "Role of microRNA in muscle regeneration and diseases related to muscle dysfunction in atrophy, cachexia, osteoporosis, and osteoarthritis." Bone & Joint Research 9, no. 11 (November 1, 2020): 798–807. http://dx.doi.org/10.1302/2046-3758.911.bjr-2020-0178.r1.
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MicroRNAs (miRNAs) are a class of small non-coding RNAs that have emerged as potential predictive, prognostic, and therapeutic biomarkers, relevant to many pathophysiological conditions including limb immobilization, osteoarthritis, sarcopenia, and cachexia. Impaired musculoskeletal homeostasis leads to distinct muscle atrophies. Understanding miRNA involvement in the molecular mechanisms underpinning conditions such as muscle wasting may be critical to developing new strategies to improve patient management. MicroRNAs are powerful post-transcriptional regulators of gene expression in muscle and, importantly, are also detectable in the circulation. MicroRNAs are established modulators of muscle satellite stem cell activation, proliferation, and differentiation, however, there have been limited human studies that investigate miRNAs in muscle wasting. This narrative review summarizes the current knowledge as to the role of miRNAs in the skeletal muscle differentiation and atrophy, synthesizing the findings of published data. Cite this article: Bone Joint Res 2020;9(11):798–807.
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Pereira, Marcelo G., Vanessa A. Voltarelli, Gabriel C. Tobias, Lara de Souza, Gabriela S. Borges, Ailma O. Paixão, Ney R. de Almeida, et al. "Aerobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2α Modulation." Cancers 14, no. 1 (December 22, 2021): 28. http://dx.doi.org/10.3390/cancers14010028.
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Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-α. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2α activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia.
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Roy, Anirban, and Ashok Kumar. "ER Stress and Unfolded Protein Response in Cancer Cachexia." Cancers 11, no. 12 (December 3, 2019): 1929. http://dx.doi.org/10.3390/cancers11121929.
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Cancer cachexia is a devastating syndrome characterized by unintentional weight loss attributed to extensive skeletal muscle wasting. The pathogenesis of cachexia is multifactorial because of complex interactions of tumor and host factors. The irreversible wasting syndrome has been ascribed to systemic inflammation, insulin resistance, dysfunctional mitochondria, oxidative stress, and heightened activation of ubiquitin-proteasome system and macroautophagy. Accumulating evidence suggests that deviant regulation of an array of signaling pathways engenders cancer cachexia where the human body is sustained in an incessant self-consuming catabolic state. Recent studies have further suggested that several components of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) are activated in skeletal muscle of animal models and muscle biopsies of cachectic cancer patients. However, the exact role of ER stress and the individual arms of the UPR in the regulation of skeletal muscle mass in various catabolic states including cancer has just begun to be elucidated. This review provides a succinct overview of emerging roles of ER stress and the UPR in cancer-induced skeletal muscle wasting.
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Lena, Alessia, Markus S. Anker, and Jochen Springer. "Muscle Wasting and Sarcopenia in Heart Failure—The Current State of Science." International Journal of Molecular Sciences 21, no. 18 (September 8, 2020): 6549. http://dx.doi.org/10.3390/ijms21186549.
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Sarcopenia is primarily characterized by skeletal muscle disturbances such as loss of muscle mass, quality, strength, and physical performance. It is commonly seen in elderly patients with chronic diseases. The prevalence of sarcopenia in chronic heart failure (HF) patients amounts to up to 20% and may progress into cardiac cachexia. Muscle wasting is a strong predictor of frailty and reduced survival in HF patients. Despite many different techniques and clinical tests, there is still no broadly available gold standard for the diagnosis of sarcopenia. Resistance exercise and nutritional supplementation represent the currently most used strategies against wasting disorders. Ongoing research is investigating skeletal muscle mitochondrial dysfunction as a new possible target for pharmacological compounds. Novel agents such as synthetic ghrelin and selective androgen receptor modulators (SARMs) seem promising in counteracting muscle abnormalities but their effectiveness in HF patients has not been assessed yet. In the last decades, many advances have been accomplished but sarcopenia remains an underdiagnosed pathology and more efforts are needed to find an efficacious therapeutic plan. The purpose of this review is to illustrate the current knowledge in terms of pathogenesis, diagnosis, and treatment of sarcopenia in order to provide a better understanding of wasting disorders occurring in chronic heart failure.
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Wiggs, Michael P., Anna G. Beaudry, and Michelle L. Law. "Cardiac Remodeling in Cancer-Induced Cachexia: Functional, Structural, and Metabolic Contributors." Cells 11, no. 12 (June 15, 2022): 1931. http://dx.doi.org/10.3390/cells11121931.
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Cancer cachexia is a syndrome of progressive weight loss and muscle wasting occurring in many advanced cancer patients. Cachexia significantly impairs quality of life and increases mortality. Cardiac atrophy and dysfunction have been observed in patients with cachexia, which may contribute to cachexia pathophysiology. However, relative to skeletal muscle, little research has been carried out to understand the mechanisms of cardiomyopathy in cachexia. Here, we review what is known clinically about the cardiac changes occurring in cachexia, followed by further discussion of underlying physiological and molecular mechanisms contributing to cachexia-induced cardiomyopathy. Impaired cardiac contractility and relaxation may be explained by a complex interplay of significant heart muscle atrophy and metabolic remodeling, including mitochondrial dysfunction. Because cardiac muscle has fundamental differences compared to skeletal muscle, understanding cardiac-specific effects of cachexia may bring light to unique therapeutic targets and ultimately improve clinical management for patients with cancer cachexia.
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Mirzoev, Timur M., Kristina A. Sharlo, and Boris S. Shenkman. "The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions." International Journal of Molecular Sciences 22, no. 10 (May 11, 2021): 5081. http://dx.doi.org/10.3390/ijms22105081.
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Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, and contributes to an individual’s quality of life. Prolonged muscle inactivity/disuse (due to limb immobilization, mechanical ventilation, bedrest, spaceflight) represents one of the typical causes, leading to the loss of muscle mass and function. This disuse-induced muscle loss primarily results from repressed protein synthesis and increased proteolysis. Further, prolonged disuse results in slow-to-fast fiber-type transition, mitochondrial dysfunction and reduced oxidative capacity. Glycogen synthase kinase 3β (GSK-3β) is a key enzyme standing at the crossroads of various signaling pathways regulating a wide range of cellular processes. This review discusses various important roles of GSK-3β in the regulation of protein turnover, myosin phenotype, and oxidative capacity in skeletal muscles under disuse/unloading conditions and subsequent recovery. According to its vital functions, GSK-3β may represent a perspective therapeutic target in the treatment of muscle wasting induced by chronic disuse, aging, and a number of diseases.
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Fonseca, Guilherme Wesley Peixoto da, Jerneja Farkas, Eva Dora, Stephan von Haehling, and Mitja Lainscak. "Cancer Cachexia and Related Metabolic Dysfunction." International Journal of Molecular Sciences 21, no. 7 (March 27, 2020): 2321. http://dx.doi.org/10.3390/ijms21072321.
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Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer—dependent on the underlying type of cancer—and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.
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Russo, Cristina, Maria Stella Valle, Antonino Casabona, Lucia Spicuzza, Gianluca Sambataro, and Lucia Malaguarnera. "Vitamin D Impacts on Skeletal Muscle Dysfunction in Patients with COPD Promoting Mitochondrial Health." Biomedicines 10, no. 4 (April 14, 2022): 898. http://dx.doi.org/10.3390/biomedicines10040898.
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Skeletal muscle dysfunction is frequently associated with chronic obstructive pulmonary disease (COPD), which is characterized by a permanent airflow limitation, with a worsening respiratory disorder during disease evolution. In COPD, the pathophysiological changes related to the chronic inflammatory state affect oxidant–antioxidant balance, which is one of the main mechanisms accompanying extra-pulmonary comorbidity such as muscle wasting. Muscle impairment is characterized by alterations on muscle fiber architecture, contractile protein integrity, and mitochondrial dysfunction. Exogenous and endogenous sources of reactive oxygen species (ROS) are present in COPD pathology. One of the endogenous sources of ROS is represented by mitochondria. Evidence demonstrated that vitamin D plays a crucial role for the maintenance of skeletal muscle health. Vitamin D deficiency affects oxidative stress and mitochondrial function influencing disease course through an effect on muscle function in COPD patients. This review will focus on vitamin-D-linked mechanisms that could modulate and ameliorate the damage response to free radicals in muscle fibers, evaluating vitamin D supplementation with enough potent effect to contrast mitochondrial impairment, but which avoids potential severe side effects.
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Romagnoli, Cecilia, Teresa Iantomasi, and Maria Luisa Brandi. "Available In Vitro Models for Human Satellite Cells from Skeletal Muscle." International Journal of Molecular Sciences 22, no. 24 (December 8, 2021): 13221. http://dx.doi.org/10.3390/ijms222413221.
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Skeletal muscle accounts for almost 40% of the total adult human body mass. This tissue is essential for structural and mechanical functions such as posture, locomotion, and breathing, and it is endowed with an extraordinary ability to adapt to physiological changes associated with growth and physical exercise, as well as tissue damage. Moreover, skeletal muscle is the most age-sensitive tissue in mammals. Due to aging, but also to several diseases, muscle wasting occurs with a loss of muscle mass and functionality, resulting from disuse atrophy and defective muscle regeneration, associated with dysfunction of satellite cells, which are the cells responsible for maintaining and repairing adult muscle. The most established cell lines commonly used to study muscle homeostasis come from rodents, but there is a need to study skeletal muscle using human models, which, due to ethical implications, consist primarily of in vitro culture, which is the only alternative way to vertebrate model organisms. This review will survey in vitro 2D/3D models of human satellite cells to assess skeletal muscle biology for pre-clinical investigations and future directions.
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Nakazawa, Harumasa, Lai Ping Wong, Laura Shelton, Ruslan Sadreyev, and Masao Kaneki. "Farnesysltransferase Inhibitor Prevents Burn Injury-Induced Metabolome Changes in Muscle." Metabolites 12, no. 9 (August 27, 2022): 800. http://dx.doi.org/10.3390/metabo12090800.
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Burn injury remains a significant public health issue worldwide. Metabolic derangements are a major complication of burn injury and negatively affect the clinical outcomes of severely burned patients. These metabolic aberrations include muscle wasting, hypermetabolism, hyperglycemia, hyperlactatemia, insulin resistance, and mitochondrial dysfunction. However, little is known about the impact of burn injury on the metabolome profile in skeletal muscle. We have previously shown that farnesyltransferase inhibitor (FTI) reverses burn injury-induced insulin resistance, mitochondrial dysfunction, and the Warburg effect in mouse skeletal muscle. To evaluate metabolome composition, targeted quantitative analysis was performed using capillary electrophoresis mass spectrometry in mouse skeletal muscle. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and hierarchical cluster analysis demonstrated that burn injury induced a global change in metabolome composition. FTI treatment almost completely prevented burn injury-induced alterations in metabolite levels. Pathway analysis revealed that the pathways most affected by burn injury were purine, glutathione, β-alanine, glycine, serine, and threonine metabolism. Burn injury induced a suppressed oxidized to reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio as well as oxidative stress and adenosine triphosphate (ATP) depletion, all of which were reversed by FTI. Moreover, our data raise the possibility that burn injury may lead to increased glutaminolysis and reductive carboxylation in mouse skeletal muscle.
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Quadrilatero, Joe, Stephen E. Alway, and Esther E. Dupont-Versteegden. "Skeletal muscle apoptotic response to physical activity: potential mechanisms for protection." Applied Physiology, Nutrition, and Metabolism 36, no. 5 (October 2011): 608–17. http://dx.doi.org/10.1139/h11-064.
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Apoptosis is a highly conserved type of cell death that plays a critical role in tissue homeostasis and disease-associated processes. Skeletal muscle is unique with respect to apoptotic processes, given its multinucleated morphology and its apoptosis-associated differences related to muscle and (or) fiber type as well as mitochondrial content and (or) subtype. Elevated apoptotic signaling has been reported in skeletal muscle during aging, stress-induced states, and disease; a phenomenon that plays a role in muscle dysfunction, degradation, and atrophy. Exercise is a strong physiological stimulus that can influence a number of extracellular and intracellular signaling pathways, which may directly or indirectly influence apoptotic processes in skeletal muscle. In general, acute strenuous and eccentric exercise are associated with a proapoptotic phenotype and increased DNA fragmentation (a hallmark of apoptosis), whereas regular exercise training or activity is associated with an antiapoptotic environment and reduced DNA fragmentation in skeletal muscle. Interestingly, the protective effect of regular activity on skeletal muscle apoptotic processes has been observed in healthy, aged, stress-induced, and diseased rodent models. Several mechanisms for this protective response have been proposed, including altered anti- and proapoptotic protein expression, increased mitochondrial biogenesis and improved mitochondrial function, and reduced reactive oxygen species generation and (or) enhanced antioxidant status. Given the current literature, we propose that regular physical activity may represent an effective strategy to decrease apoptotic signaling, and possibly muscle wasting and dysfunction, during aging and disease.
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Nakajima, Shibasaki, Sawaguchi, Haruyama, Kaneda, Nakajima, Hasegawa, et al. "Growth Differentiation Factor-15 (GDF-15) is a Biomarker of Muscle Wasting and Renal Dysfunction in Preoperative Cardiovascular Surgery Patients." Journal of Clinical Medicine 8, no. 10 (October 1, 2019): 1576. http://dx.doi.org/10.3390/jcm8101576.
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Frailty and sarcopenia increase the risk of complications and mortality when invasive treatment such as cardiac surgery is performed. Growth differentiation factor-15 (GDF-15) involves various pathophysiological conditions including renal dysfunction, heart failure and cachexia. We investigated the pathophysiological roles of preoperative GDF-15 levels in cardiovascular surgery patients. Preoperative skeletal muscle index (SMI) determined by bioelectrical impedance analysis, hand-grip strength, 4 m gait speed, and anterior thigh muscle thickness (TMth) measured by echocardiography were assessed in 72 patients (average age 69.9 years) who underwent cardiovascular surgery. The preoperative serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay. Circulating GDF-15 level was correlated with age, brain natriuretic peptide, and estimated glomerular filtration rate (eGFR). It was also negatively correlated with SMI, hand-grip strength, and anterior TMth. In multivariate analysis, eGFR and anterior TMth were the independent determinants of GDF-15 concentration even after adjusting for age, sex, and body mass index. Alternatively, the GDF-15 level was an independent determinant of eGFR and anterior TMth. We concluded that preoperative GDF-15 levels reflect muscle wasting as well as renal dysfunction in preoperative cardiovascular surgery patients. GDF-15 may be a novel biomarker for identify high-risk patients with muscle wasting and renal dysfunction before cardiovascular surgery.
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Minderis, Petras, Indrė Libnickienė, and Aivaras Ratkevičius. "MUSCLE WASTING AFTER 48 HOURS OF FOOD DEPRIVATION DIFFERS BETWEEN MOUSE STRAINS AND IS PROMOTED BY MYOSTATIN DYSFUNCTION." Baltic Journal of Sport and Health Sciences 2, no. 101 (2016): 53–60. http://dx.doi.org/10.33607/bjshs.v2i101.56.
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Background. Genetic factors play an important role in determining muscle mass. Indeed, myostatin dysfunction is associated with a pronounced muscle hypertrophy. The aim of our study was to test the hypothesis that starvation induced muscle wasting differs between BEH+/+ and C57BL/6J strains of mice and myostatin dysfunction prevents muscle wasting in BEH strain. Methods. 18-week-old males of C57BL/6J, BEH+/+ and BEH were subjected to 48 h food deprivation (FD). C57BL/6J mice were representatives of classic mouse strain. BEH mice which differ from BEH+/+ mice by Compact mutation in the Mstn gene represented a model for myostatin dysfunction. All mice were divided into experimental and control groups. The control groups consisted of mice fed ad libitum. Seven mice were studied in each group. Mice were weighed before as well as 24 h and 48 h after FD which was followed by dissection and weighing of the hindlimb skeletal muscle. Results. BEH and BEH+/+ mice showed a similar (16.9 ± 1.4% vs. 19.3 ± 2.4%, p > .05) loss of body mass while loss of body mass in C57BL/6J mice was the greatest (24.8 ± 1.9%, p < .001) after FD. The loss of muscle mass was significant in both BEH (p < .001) and C57BL/6J (p < .01) mice, but it was below the level of significance (p > .05) in BEH+/+ mice. Conclusions. Myostatin dysfunction promotes muscle atrophy after FD. During short periods of FD, BEH+/+ mice are more resistant to body and muscle loss compared to C57BL/6J mice.
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Ballarò, Riccardo, Patrizia Lopalco, Valentina Audrito, Marc Beltrà, Fabrizio Pin, Roberto Angelini, Paola Costelli, et al. "Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia." Cancers 13, no. 4 (February 18, 2021): 850. http://dx.doi.org/10.3390/cancers13040850.
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Objective: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. Methods: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. Results: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. Conclusions: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.
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Rezuş, Elena, Alexandra Burlui, Anca Cardoneanu, Ciprian Rezuş, Cătălin Codreanu, Mirela Pârvu, Gabriela Rusu Zota, and Bogdan Ionel Tamba. "Inactivity and Skeletal Muscle Metabolism: A Vicious Cycle in Old Age." International Journal of Molecular Sciences 21, no. 2 (January 16, 2020): 592. http://dx.doi.org/10.3390/ijms21020592.
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Aging is an inevitable and gradually progressive process affecting all organs and systems. The musculoskeletal system makes no exception, elderly exhibit an increased risk of sarcopenia (low muscle mass),dynapenia (declining muscle strength), and subsequent disability. Whereas in recent years the subject of skeletal muscle metabolic decline in the elderly has been gathering interest amongst researchers, as well as medical professionals, there are many challenges yet to be solved in order to counteract the effects of aging on muscle function efficiently. Noteworthy, it has been shown that aging individuals exhibit a decline in skeletal muscle metabolism, a phenomenon which may be linked to a number of predisposing (risk) factors such as telomere attrition, epigenetic changes, mitochondrial dysfunction, sedentary behavior (leading to body composition alterations), age-related low-grade systemic inflammation (inflammaging), hormonal imbalance, as well as a hypoproteic diet (unable to counterbalance the repercussions of the age-related increase in skeletal muscle catabolism). The present review aims to discuss the relationship between old age and muscle wasting in an effort to highlight the modifications in skeletal muscle metabolism associated with aging and physical activity.
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Heo, Ji-Won, and Sung-Eun Kim. "Comparative Transcriptomic Profiling of Organs Associated With Metabolic Dysfunction in Cancer-Induced Cachexia." Current Developments in Nutrition 5, Supplement_2 (June 2021): 501. http://dx.doi.org/10.1093/cdn/nzab041_016.
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Abstract Objectives Approximately 50–80% of cancer patients suffer from cachexia represented by weight loss mainly due to loss of skeletal muscle. Cancer-induced cachexia is a complex metabolic syndrome associated with not only systemic inflammation but also perturbations to energy metabolism. In this study, we profiled gene expression patterns of different organs in CT-26 tumor bearing mice in order to understand metabolic dysfunction in cancer cachexia. Methods The transcriptomic profiles of skeletal muscle, adipose tissue, and liver of CT26-tumor bearing mice were generated using SurePrint G3 Mouse Gene Expression 8 × 60 K v2 (Agilent, Inc.). Functional and network analyses were performed using Gene Set Enrichment Analysis and Ingenuity Pathway Analysis (QIAGEN). Results We identified 299, 508, and 1,311 genes differentially regulated in skeletal muscle, adipose tissue, and liver, respectively. In the skeletal muscle, lipid biosynthetic process and mitochondrial electron transport were negatively regulated and network involved in glutamine metabolism was up-regulated. In adipose tissue, tricarboxylic acid cycle was down-regulated and lipid metabolism was associated with several genes including Thrsp, Plvap, and Sphk1. In the liver, regulation of gluconeogenesis was down-regulated, while production of lactic acid and uptake of D-glucose were related with H6pd and Pkm whose expression was up-regulated during cancer cachexia. Furthermore, the top network matched by genes commonly up-regulated in all organs included Bcl3, Csf2rb, Fcgr2a, and Lilrb3, which are known to be associated with inflammation and muscle wasting. Conclusions Our data suggest that skeletal muscle, adipose tissue, and liver present distinct gene expression profiles associated with inflammation and energy metabolism and several genes up-regulated in all organs might be candidate biomarkers for the prevention and early detection of cancer cachexia. Funding Sources This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education.
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Mofarrahi, Mahroo, Ioanna Sigala, Theodoros Vassilokopoulos, Sharon Harel, Yeting Guo, Richard Debigare, Francois Maltais, and Sabah N. A. Hussain. "Angiogenesis-related factors in skeletal muscles of COPD patients: roles of angiopoietin-2." Journal of Applied Physiology 114, no. 9 (May 1, 2013): 1309–18. http://dx.doi.org/10.1152/japplphysiol.00954.2012.
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The role of angiogenesis factors in skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD) is unknown. The first objective of this study was to assess various pro- and antiangiogenic factor and receptor expressions in the vastus lateralis muscles of control subjects and COPD patients. Preliminary inquiries revealed that angiopoietin-2 (ANGPT2) is overexpressed in limb muscles of COPD patients. ANGPT2 promotes skeletal satellite cell survival and differentiation. Factors that are involved in regulating muscle ANGPT2 production are unknown. The second objective of this study was to evaluate how oxidants and proinflammatory cytokines influence muscle-derived ANGPT2 expression. Angiogenic gene expressions in human vastus lateralis biopsies were quantified with low-density real-time PCR arrays. ANGPT2 mRNA expressions in cultured skeletal myoblasts were quantified in response to proinflammatory cytokine and H2O2 exposure. Ten proangiogenesis genes, including ANGPT2, were significantly upregulated in the vastus lateralis muscles of COPD patients. ANGPT2 mRNA levels correlated negatively with forced expiratory volume in 1 s and positively with muscle wasting. Immunoblotting confirmed that ANGPT2 protein levels were significantly greater in muscles of COPD patients compared with control subjects. ANGPT2 expression was induced by interferon-γ and -β and by hydrogen peroxide, but not by tumor necrosis factor. We conclude that upregulation of ANGPT2 expression in vastus lateralis muscles of COPD patients is likely due to oxidative stress and represents a positive adaptive response aimed at facilitating myogenesis and angiogenesis.
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Klaude, Maria, Katarina Fredriksson, Inga Tjäder, Folke Hammarqvist, Bo Ahlman, Olav Rooyackers, and Jan Wernerman. "Proteasome proteolytic activity in skeletal muscle is increased in patients with sepsis." Clinical Science 112, no. 9 (April 2, 2007): 499–506. http://dx.doi.org/10.1042/cs20060265.
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Patients with sepsis in the ICU (intensive care unit) are characterized by skeletal muscle wasting. This leads to muscle dysfunction that also influences the respiratory capacity, resulting in prolonged mechanical ventilation. Catabolic conditions are associated with a general activation of the ubiquitin–proteasome pathway in skeletal muscle. The aim of the present study was to measure the proteasome proteolytic activity in both respiratory and leg muscles from ICU patients with sepsis and, in addition, to assess the variation of proteasome activity between individuals and between duplicate leg muscle biopsy specimens. When compared with a control group (n=10), patients with sepsis (n=10) had a 30% (P<0.05) and 45% (P<0.05) higher proteasome activity in the respiratory and leg muscles respectively. In a second experiment, ICU patients with sepsis (n=17) had a 55% (P<0.01) higher proteasome activity in the leg muscle compared with a control group (n=10). The inter-individual scatter of proteasome activity was larger between the patients with sepsis than the controls. We also observed a substantial intra-individual difference in activity between duplicate biopsies in several of the subjects. In conclusion, the proteolytic activity of the proteasome was higher in skeletal muscle from patients with sepsis and multiple organ failure compared with healthy controls. It was shown for the first time that respiratory and leg muscles were affected similarly. Furthermore, the variation in proteasome activity between individuals was more pronounced in the ICU patients for both muscle types, whereas the intra-individual variation between biopsies was similar for ICU patients and controls.
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Su, Zhen, Janet D. Klein, Jie Du, Harold A. Franch, Liping Zhang, Faten Hassounah, Matthew B. Hudson, and Xiaonan H. Wang. "Chronic kidney disease induces autophagy leading to dysfunction of mitochondria in skeletal muscle." American Journal of Physiology-Renal Physiology 312, no. 6 (June 1, 2017): F1128—F1140. http://dx.doi.org/10.1152/ajprenal.00600.2016.
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Chronic kidney disease (CKD) causes loss of lean body mass by multiple mechanisms. This study examines whether autophagy-mediated proteolysis contributes to CKD-induced muscle wasting. We tested autophagy in the muscle of CKD mice with plantaris muscle overloading to mimic resistance exercise or with acupuncture plus low-frequency electrical stimulation (Acu/LFES) treatment. In CKD muscle, Bnip3, Beclin-1, and LC3II mRNAs and proteins were increased compared with those in control muscle, indicating autophagosome-lysosome formation induction. Acu/LFES suppressed the CKD-induced upregulation of autophagy. However, overloading increased autophagy-related proteins in normal and CKD muscle. Serum from uremic mice induces autophagy formation but did not increase the myosin degradation or actin break down in cultured muscle satellite cells. We examined mitochondrial biogenesis, copy number, and ATP production in cultured myotubes, and found all three aspects to be decreased by uremic serum. Inhibition of autophagy partially reversed this decline in cultured myotubes. In CKD mice, the mitochondrial copy number, biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), and mitochondrial fusion marker Mitofusin-2 (Mfn2) are decreased. Both muscle overloading and Acu/LFES increased mitochondrial copy number, and reversed the CKD-induced decreases in PGC-1α, TFAM, and Mfn2. We conclude that the autophagy is activated in the muscle of CKD mice. However, myofibrillar protein is not directly broken down through autophagy. Instead, CKD-induced upregulation of autophagy leads to dysfunction of mitochondria and decrease of ATP production.
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Neto Silva, Ivo, José Alberto Duarte, Aurélie Perret, Nicolas Dousse, Hannah Wozniak, Bernardo Bollen Pinto, Raphaël Giraud, and Karim Bendjelid. "Diaphragm dysfunction and peripheral muscle wasting in septic shock patients: Exploring their relationship over time using ultrasound technology (the MUSiShock protocol)." PLOS ONE 17, no. 3 (March 28, 2022): e0266174. http://dx.doi.org/10.1371/journal.pone.0266174.
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Background Intensive Care Unit (ICU) patients are known to lose muscle mass and function during ICU stay. Ultrasonography (US) application for the assessment of the skeletal muscle is a promising tool and might help detecting muscle changes and thus several dysfunctions during early stages of ICU stay. MUSiShock is a research project aiming to investigate structure and function of diaphragm and peripheral muscles using ultrasound techniques in septic shock patients, and to assess their relevance in several clinical outcomes such as the weaning process. Methods and design This is a research protocol from an observational prospective cohort study. We plan to assess eighty-four septic shock patients during their ICU stay at the following time-points: at 24 hours of ICU admission, then daily until day 5, then weekly, at extubation time and at ICU discharge. At each time-point, we will measure the quadriceps rectus femoris and diaphragm muscles, using innovative US muscle markers such as Shear-Wave Elastography (SWE). In parallel, the Medical Research Council (MRC) sum score for muscle testing and the Airway occlusion pressure (P0.1) will also be collected. We will describe the association between SWE assessment and other US markers for each muscle. The association between the changes in both diaphragm and rectus femoris US markers over time will be explored as well; finally, the analysis of a combined model of one diaphragm US marker and one limb muscle US marker to predict weaning success/failure will be tested. Discussion By using muscle ultrasound at both diaphragm and limb levels, MUSiShock aims to improve knowledge in the early detection of muscle dysfunction and weakness, and their relationship with muscle strength and MV weaning, in critically ill patients. A better anticipation of these short-term muscle structure and function outcomes may allow clinicians to rapidly implement measures to counteract it. Trial registration ClinicalTrials.gov, NCT04550143. Registered on 16 September 2020.
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Tintignac, Lionel A., Hans-Rudolf Brenner, and Markus A. Rüegg. "Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting." Physiological Reviews 95, no. 3 (July 2015): 809–52. http://dx.doi.org/10.1152/physrev.00033.2014.
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The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibers. It is designed to reliably convert the action potential from the presynaptic motor neuron into the contraction of the postsynaptic muscle fiber. Diseases that affect the neuromuscular junction may cause failure of this conversion and result in loss of ambulation and respiration. The loss of motor input also causes muscle wasting as muscle mass is constantly adapted to contractile needs by the balancing of protein synthesis and protein degradation. Finally, neuromuscular activity and muscle mass have a major impact on metabolic properties of the organisms. This review discusses the mechanisms involved in the development and maintenance of the neuromuscular junction, the consequences of and the mechanisms involved in its dysfunction, and its role in maintaining muscle mass during aging. As life expectancy is increasing, loss of muscle mass during aging, called sarcopenia, has emerged as a field of high medical need. Interestingly, aging is also accompanied by structural changes at the neuromuscular junction, suggesting that the mechanisms involved in neuromuscular junction maintenance might be disturbed during aging. In addition, there is now evidence that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia.
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Campelj, Dean G., Cara A. Timpani, Aaron C. Petersen, Alan Hayes, Craig A. Goodman, and Emma Rybalka. "The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction." Cancers 12, no. 12 (December 17, 2020): 3810. http://dx.doi.org/10.3390/cancers12123810.
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Chemotherapy-induced muscle wasting and dysfunction is a contributing factor to cachexia alongside cancer and increases the risk of morbidity and mortality. Here, we investigate the effects of the chemotherapeutic agent irinotecan (IRI) on skeletal muscle mass and function and whether BGP-15 (a poly-(ADP-ribose) polymerase-1 (PARP-1) inhibitor and heat shock protein co-inducer) adjuvant therapy could protect against IRI-induced skeletal myopathy. Healthy 6-week-old male Balb/C mice (n = 24; 8/group) were treated with six intraperitoneal injections of either vehicle, IRI (30 mg/kg) or BGP-15 adjuvant therapy (IRI+BGP; 15 mg/kg) over two weeks. IRI reduced lean and tibialis anterior mass, which were attenuated by IRI+BGP treatment. Remarkably, IRI reduced muscle protein synthesis, while IRI+BGP reduced protein synthesis further. These changes occurred in the absence of a change in crude markers of mammalian/mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) signaling and protein degradation. Interestingly, the cytoskeletal protein dystrophin was reduced in both IRI- and IRI+BGP-treated mice, while IRI+BGP treatment also decreased β-dystroglycan, suggesting significant remodeling of the cytoskeleton. IRI reduced absolute force production of the soleus and extensor digitorum longus (EDL) muscles, while IRI+BGP rescued absolute force production of the soleus and strongly trended to rescue force output of the EDL (p = 0.06), which was associated with improvements in mass. During the fatiguing stimulation, IRI+BGP-treated EDL muscles were somewhat susceptible to rupture at the musculotendinous junction, likely due to BGP-15’s capacity to maintain the rate of force development within a weakened environment characterized by significant structural remodeling. Our paradoxical data highlight that BGP-15 has some therapeutic advantage by attenuating IRI-induced skeletal myopathy; however, its effects on the remodeling of the cytoskeleton and extracellular matrix, which appear to make fast-twitch muscles more prone to tearing during contraction, could suggest the induction of muscular dystrophy and, thus, require further characterization.
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Barreiro, Esther, Ester Puig-Vilanova, Anna Salazar-Degracia, Sergi Pascual-Guardia, Carme Casadevall, and Joaquim Gea. "The phosphodiesterase-4 inhibitor roflumilast reverts proteolysis in skeletal muscle cells of patients with COPD cachexia." Journal of Applied Physiology 125, no. 2 (August 1, 2018): 287–303. http://dx.doi.org/10.1152/japplphysiol.00798.2017.
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Peripheral muscle weakness and mass loss are characteristic features in severe chronic obstructive pulmonary disease (COPD). We hypothesized that the phosphodiesterase (PDE)-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 μM roflumilast N-oxide (RNO) for three time cohorts (1, 6, and 24 h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting. In COPD patients at 6 h RNO treatment, myotube tyrosine release, total protein ubiquitination, and tripartite motif-containing protein 32 levels were significantly lower than healthy controls, whereas at 24 h RNO treatment, myotube myosin heavy chain ( MyHC) -I and MyHC-IIx expression levels were upregulated in both patients and controls. In the 6-h RNO cohort, in patients and controls, myotube expression of nuclear factor (erythroid-derived 2)-like 2 ( NRF2) and its downstream antioxidants sirtuin-1, FGF-inducible 14, and insulin-like growth factor-1 was upregulated, whereas that of myocyte-specific enhancer factor 2C, myogenic differentiation, myogenin, myostatin, atrogin-1, and muscle RING-finger protein-1 was downregulated. In myotubes of severe COPD patients with cachexia, roflumilast-induced cAMP signaling exerts beneficial effects by targeting muscle protein breakdown (tyrosine release), along with reduced expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In both patients and controls, roflumilast also favored antioxidant defense through upregulation of the NRF2 pathway and that of the histone deacetylase sirtuin-1, whereas it improved the expression of slow- and fast-twitch myosin isoforms. These findings show that muscle dysfunction and wasting may be targeted by roflumilast-induced cAMP signaling in COPD. These results have potential therapeutic implications, as this PDE-4 inhibitor is currently available for the treatment of systemic inflammation and exacerbations in patients with severe COPD. NEW & NOTEWORTHY In myotubes of cachectic chronic obstructive pulmonary disease (COPD) patients, cAMP signaling exerted beneficial effects by targeting muscle proteolysis and reducing gene expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In myotubes of patients and controls, roflumilast also favored antioxidant defense through upregulation of the nuclear factor (erythroid-derived 2)-like 2 pathway, of sirtuin-1, and of gene expression of slow- and fast-twitch isoforms. These findings have potential clinical implications for the treatment of muscle wasting in patients with COPD and cachexia.
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Supinski, G. S., J. Vanags, and L. A. Callahan. "Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 6 (June 2009): L994—L1001. http://dx.doi.org/10.1152/ajplung.90404.2008.
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Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system is activated in skeletal muscle in sepsis, and it has been postulated that this degradative pathway is responsible for inducing skeletal muscle weakness and wasting. The objective of this study was to determine if administration of proteasomal inhibitors (MG132, epoxomicin, bortezomib) can prevent sepsis-induced diaphragm weakness. Rats were given either 1) saline (0.5 ml ip), 2) endotoxin (12 mg/kg ip), 3) endotoxin plus MG132 (2.5 mg/kg), 4) endotoxin plus epoxomicin (1 μmol/kg), or 5) endotoxin plus bortezomib (0.05 mg/kg). Animals were killed either 48 or 96 h after injections, and assessments were made of diaphragm proteolysis, force-frequency relationships, mass, protein content, and caspase activation. Endotoxin increased proteolysis ( P <0.001). MG132, epoxomicin, and bortezomib each prevented the endotoxin-induced increase in proteolysis ( P <0.01). Endotoxin induced severe reductions in diaphragm force generation by 48 h ( P <0.01); none of the proteasomal inhibitors prevented loss of force. Endotoxin induced significant reductions in diaphragm mass and protein content by 96 h ( P <0.01); neither MG132 nor epoxomicin prevented loss of mass or protein, but bortezomib attenuated the reduction in protein content ( P <0.05). Endotoxin increased diaphragm caspase-3 activity ( P <0.01); caspase-3 activity remained high when either MG132, epoxomicin, or bortezomib were given. These data suggest proteasomal inhibitors are not an adequate treatment to prevent endotoxin-induced diaphragmatic dysfunction.
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Liu, Yuqing, Xiao Bi, Yumei Zhang, Yingdeng Wang, and Wei Ding. "Mitochondrial dysfunction/NLRP3 inflammasome axis contributes to angiotensin II-induced skeletal muscle wasting via PPAR-γ." Laboratory Investigation 100, no. 5 (December 19, 2019): 712–26. http://dx.doi.org/10.1038/s41374-019-0355-1.
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Clark, Yvonne Y., Loren E. Wold, Laura A. Szalacha, and Donna O. McCarthy. "Ubiquinol Reduces Muscle Wasting but Not Fatigue in Tumor-Bearing Mice." Biological Research For Nursing 17, no. 3 (September 16, 2014): 321–29. http://dx.doi.org/10.1177/1099800414543822.
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Purpose:Fatigue is the most common and distressing symptom reported by cancer patients during and after treatment. Tumor growth increases oxidative stress and cytokine production, which causes skeletal muscle wasting and cardiac dysfunction. The purpose of this study was to determine whether treatment with the antioxidant ubiquinol improves muscle mass, cardiac function, and behavioral measures of fatigue in tumor-bearing mice.Method:Adult female mice were inoculated with colon26 tumor cells. Half the control and tumor-bearing mice were administered ubiquinol (500 mg/kg/day) in their drinking water. Voluntary wheel running (i.e., voluntary running activity [VRA]) and grip strength were measured at Days 0, 8, 14, and 17 of tumor growth. Cardiac function was measured using echocardiography on Day 18 or 19. Biomarkers of inflammation, protein degradation, and oxidative stress were measured in serum and heart and gastrocnemius tissue.Results:VRA and grip strength progressively declined in tumor-bearing mice. Muscle mass and myocardial diastolic function were decreased, and expression of proinflammatory cytokines was increased in serum and muscle and heart tissue on Day 19 of tumor growth. Oxidative stress was present only in the heart, while biomarkers of protein degradation were increased only in the gastrocnemius muscle. Ubiquinol increased muscle mass in the tumor-bearing and control animals but had no effect on the expression of biomarkers of inflammation, protein degradation, or oxidative stress or on behavioral measures of fatigue.
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Park, Sang Hee, Dong Seon Kim, Jieun Oh, Jeong-Ho Geum, Jung-Eun Kim, Su-Young Choi, Ji Hye Kim, and Jae Youl Cho. "Matricaria chamomilla (Chamomile) Ameliorates Muscle Atrophy in Mice by Targeting Protein Catalytic Pathways, Myogenesis, and Mitochondrial Dysfunction." American Journal of Chinese Medicine 49, no. 06 (January 2021): 1493–514. http://dx.doi.org/10.1142/s0192415x21500701.
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Muscle atrophy, or loss of skeletal muscle, is caused by aging, malnutrition, immobility through injury, or diseases such as cancer. Chamomile (Matricaria chamomilla L.) contains various active components, including flavonoids, sesquiterpenes, polyacetylenes, and coumarins, and is used in various herbal medicines in the European Pharmacopoeia. In this study, we investigated the effects of ethanol extract of chamomile [Formula: see text](MC) on muscle wasting and its mechanism of action. Mice with dexamethasone (DEX)-induced muscle atrophy were orally administered MC (100, 200, and 300 mg/kg) for 4 weeks. Micro-computed tomography analysis showed that MC (200 and 300 mg/kg) significantly recovered DEX-induced loss of muscle volume, density, and weight and MC-treated DEX-induced mice also showed increased moving distance and grip strength. MC suppressed the mRNA level of muscle RING finger 1 (MuRF1) while increasing the expression of mitochondrial transcription factor A (TFAM), MyoD, and Myogenin-1. We found 25 peaks in MC samples through HPLC analysis and identified 6 peaks by comparison with a profile of standard compounds: chlorogenic acid (CGA), luteolin-7-O-glucoside (L7G), patulitrin, apigenin-7-O-glucoside (A7G), herniarin, and (E)-tonghaosu. Of these components, the gene expression of MyoD was significantly augmented by patulitrin, herniarin, CGA, and L7G in C2C12 cells, while Myogenin-1 gene expression was increased by A7G, patulitrin, herniarin, CGA, and L7G. Moreover, TFAM gene expression and phosphorylation of AKT were increased by all six ingredients. Based on our results, we suggest MC for use as a supplement or remedy for muscle wasting, including cachexia and sarcopenia.