Academic literature on the topic 'Muscular atrophy – Pathogenesis'

The spinal and bulbar muscular atrophy is a slowly progressive X-linked polysystemic disease associated with polyglutamine expansion in the androgen receptor gene. The mutant protein exhibits toxic properties towards neurons and myocytes. The main motor manifestations of the spinal and bulbar muscular atrophy are weakness, atrophy and fasciculation of the muscles of the limbs and bulbar group. Traditionally spinal and bulbar muscular atrophy belongs to the group of motor neuron diseases, but in recent years there is increasing evidence of a significant role of primary muscle pathology in the pathogenesis and clinical picture of this disease. This article provides a review of the literature on the pathogenesis, clinical manifestations and diagnosis of the spinal and bulbar muscular atrophy. We present a case report of the spinal and bulbar muscular atrophy with a clinical findings resembling metabolic myopathy.

Kennedy’s X-linked spinal and bulbar muscular atrophy is a rare hereditary lower motoneuron neurodegenerative disease, which is based on the genetic defect of the androgen receptor’s first exon (AR), characterized by an abnormal increase of CAG-repeats. This article describes a clinical case of a patient with complaints about low limb weakness, walking distance shortening to 400–500 meters, coordination disturbances, and moderate polyneuropathy. According to complaints, neurological examination and patient’s family history, a genetic study was performed confirming the proposed diagnosis. Following neurometabolic, vitamin, physical therapy, physiotherapy and acupuncture were performed and the patient’s physical activity increasing and intensity of symptoms reduction was achieved. The article also highlights the features of pathogenesis and the prospects for pathogenetic treatment of this disease.

Low levels of survival motor neuron (SMN) protein cause the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA), through mechanisms that are poorly defined. SMN protein is ubiquitously expressed, however the major pathological hallmarks of SMA are focused on the neuromuscular system, including a loss of lower motor neurons in the ventral horn of the spinal cord and atrophy of skeletal muscle. At present there is no cure for SMA. Most research to date has focused on examining how low levels of SMN lead to pathological changes in motor neurons, therefore the contribution of other tissues, for example muscle, remains unclear. In this thesis I have used proteomic techniques to identify intrinsic molecular changes in muscle of SMA mice that contribute to neuromuscular pathology in SMA. I demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomics data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. In addition robust up-regulation of VDAC2 and down-regulation of parvalbumin was confirmed in two mouse models of SMA as well as in patient muscle biopsies. Thus intrinsic pathology of skeletal muscle is an important event in SMA. I then used proteomics to identify individual proteins in skeletal muscle of SMA that report directly on disease status. Two proteins, GRP75 and calreticulin, showed increased expression levels over time in different muscles as well as in skin samples, a more accessible tissue for biopsies in patients. Preliminary results suggest that GRP75 and calreticulin can be detected and measured in SMA patient muscle biopsies. These results show that proteomics provides a powerful platform for biomarker identification in SMA, revealing GRP75 and calreticulin as peripherally accessible potential protein biomarkers capable of reporting on disease progression in muscle as well as in skin samples. Finally I identified a role for ubiquitin-dependent pathways in regulating neuromuscular pathology in SMA. Levels of ubiquitin-like modifier activating enzyme 1 (UBA1) were reduced in spinal cord and skeletal muscle tissue of SMA mice. Dysregulation of UBA1 and subsequently the ubiquitination pathways led to the accumulation of β-catenin. I show here that pharmacological inhibition of β-catenin robustly ameliorates neuromuscular pathology in animal models of SMA. Interestingly, downstream disruption of β-catenin was restricted to the neuromuscular system in SMA mice. Pharmacological inhibition of β-catenin failed to prevent systemic pathology in organs. Thus disruption of ubiquitin homeostasis, with downstream consequences for β-catenin signalling, contributes to the pathogenesis of SMA, thereby highlighting novel therapeutic targets for this disease.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by widespread loss of lower motor neurons from the spinal cord. Lower motor neuron degeneration leads to a progressive decline in motor development, manifesting as muscle atrophy and weakness. It is now well characterised that ubiquitin homeostasis is altered in SMA and that reduction of the ubiquitin-like modifier-activating enzyme 1 (UBA1) is central to this disruption. UBA1 is responsible for activating ubiquitin as the first step in the ubiquitin conjugation process, marking unwanted proteins for degradation by the proteasome. While it is known that therapies targeting UBA1 rescue neuromuscular phenotypes in SMA models, the mechanism by which UBA1 mediates neurodegeneration is unclear. In fact, very little is known about the function of UBA1 beyond its canonical role in the ubiquitin proteasome system. To better understand the role of UBA1 in motor neuron degeneration, a robust set of antibodies for both in vivo and in vitro work to study UBA1 have been identified. This enabled a novel characterisation of UBA1 distribution throughout disease progression in SMA spinal motor neurons to be performed, revealing that UBA1 reduction is an important pre-symptomatic molecular feature of SMA. To identify downstream targets of UBA1 critical for UBA1-mediated degeneration in SMA, label-free proteomics was performed on HEK293 cells after overexpression or knockdown of UBA1. The proteomics data was analysed across multiple platforms, including Biolayout, IPA and DAVID to identify UBA1-dependent pathways and demonstrated that modulation of UBA1 levels lead to disruption of key cellular pathways including translation elongation, nuclear transport, and tRNA synthetases. Validation of target proteins from these UBA1-dependent pathways identified that the tRNA synthetease GARS behaves in a UBA1-dependent manner across a range of model systems in vitro and in vivo. It was then identified that GARS expression is significantly dysregulated across a range of neuronal tissues in a mouse model of SMA. Interestingly, mutations in GARS cause Charcot-Marie-Tooth disease type 2D (CMT2D), an axonal neuropathy, in which a disruption to sensory neuron fate in dorsal root ganglia has recently been identified. In a mouse model of SMA we identified a phenotype consistent with that in the CMT2D mouse model and showed that disruption to sensory neuron fate is reversible and dependent on changes in UBA1 and GARS expression in SMA. In conclusion, modulation of UBA1 levels leads to disruption of key cellular pathways, with dysregulation of tRNA synthetases a prominent feature that is likely to play a role in the pathogenesis of SMA.

The androgen receptor (AR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. Mutations in the androgen receptor are associated with androgen insensitivity syndrome (AIS), and a neurodegenerative disease, spinal bulbar muscular atrophy (SBMA). Most of the mutations causing AIS are loss-of-function missense mutations whereas SBMA is caused by a gain-of-function polyglutamine expansion in the N-terminal domain of the protein. Characterization of AR mutations has led to a better understanding of structure-function relationships of the AR and serves as a prototype for steroid receptors mechanisms of action.
In the first paper, we examine the role of an AR mutation in causing mild androgen insensitivity syndrome. We found that this mutation conferred reduced transactivation by AR through impaired interactions with the AR coactivator, TIF2, and impaired homodimerization.
In the second paper, we investigate the role of the AR polyGln expansion mutation in SBMA pathogenesis. Recent evidence has implicated proteolytic degradation of polyGln-expanded proteins and their subsequent intracellular aggregation in polyGn-expanded disease pathogenesis. We examined the role and composition of aggregates using fluorescently-tagged AR and found that proteolysis need not be a prerequisite for aggregation and that aggregation is not necessary for poly-Gln-induced cellular toxicity.
Finally, we characterize the novel heterodimerization of AR and ERalpha. We determined that this direct interaction has functional implications for the transactivational properties of both receptors.

Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyGln) tract in the human androgen receptor (hAR). One mechanism by which polyGln-expanded proteins are believed to cause neuronotoxicity is through aberrant interaction(s) with, and possible sequestration of, critical cellular protein(s).
Our goal was to confirm and further characterize the interaction between hAR and cytochrome c oxidase subunit Vb (COXVb), a nuclear-encoded mitochondrial protein. We had previously isolated COXVb as an AR-interacting protein in a yeast two-hybrid search to identify candidates that interact with normal and polyGln-expanded AR. Using the mammalian two-hybrid system, we confirm that COXVb interacts with normal and mutant AR and demonstrate that the COXVb-normal AR interaction is stimulated by heat shock protein 70 (Hsp70). Also, BFP-tagged AR specifically co-localizes with cytoplasmic aggregates formed by GFP-labelled polyGln-expanded AR in androgen-treated cells.
Mitochondrial dysfunction may precede neuropathological findings in polyGln-expanded disorders and may thus represent an early event in neuronotoxicity. Interaction of COXVb and hAR, with subsequent sequestration of COXVb, may provide a mechanism for putative mitochondrial dysfunction in SBMA.

Spinal Muscular Atrophy (SMA) is caused by mutation or deletion of the Survival Motor Neuron 1 (SMN1), which encodes cell-ubiquitous SMN protein. Although classified as a neuromuscular disease, a range of systemic pathologies is reported in SMA patients. Despite a clear understanding of the genetics, the role of SMN protein in SMA pathogenesis is somewhat unclear, especially in tissues outside the CNS. Here, we describe failed liver development in response to reduced SMN levels, in a Taiwanese mouse model of severe SMA. Molecular analysis revealed significant changes in proteins involved in cell cycling and blood homeostasis including coagulation prior to motor neuron pathology. With SMN being directly associated with some of these proteins, this indicates primary liver pathology in SMA. Study of livers obtained from two other mouse models of SMA; severe SMNΔ7 and intermediate 2B, which have slightly higher SMN levels than Taiwanese SMA mice, also revealed significant overlapping pathologies, suggestive of high intrinsic susceptibility of the liver to SMN decrease. Proteomic study of pre-symptomatic 2B/- liver revealed significant perturbations in mitochondrial bioenergetics, which could account for metabolic defects in SMA patients. Vascular changes can be observed in mouse models of SMA and even skeletal muscle of severe SMA patients. Although Taiwanese SMA liver showed no morphological changes to its vasculature, it does have impairments in several key vascular signaling molecules, including VEGF and Tie-2. Furthermore, we report for the first time significant vascular changes in a zebrafish model of SMA, that could be associated with defective neuronal-vascular signaling and is supported by preliminary findings in the Taiwanese SMA retina. This thesis uncovers perturbations in several clinically relevant signalling pathways directly linked to SMN decrease, independent of the motor neurone pathology. Taken together this work emphasises the importance of a systemic therapy in SMA.

Spinal muscular atrophy (SMA) is the leading genetic cause of death of young children. It is an autosomal recessive disease caused by the mutation and/or the deletion within the ubiquitously expressed survival motor neuron 1 (SMN1) gene. SMA pathology is characterized by spinal cord motor neuron degeneration, neuromuscular junction (NMJ) defects and muscular atrophy. Upon disease onset, SMA patients progressively become paralyzed and in the most severe cases, they die due to respiratory complications. Over the years, it has become clear that SMN is a multi-functional protein with important roles in small nuclear ribonucleoprotein (snRNP) assembly, RNA metabolism, axonal outgrowth and pathfinding, mRNA transport as well as in the functional development of NMJs, skeletal muscle and cardiac muscle. However, it remains unclear which of these functions, and the respective perturbed molecular pathways, dictate SMA pathogenesis. Here, we have established Smn-depleted PC12 cells and an intermediate SMA mouse model to characterize a role for Smn in the regulation of actin cytoskeleton dynamics. We find that Smn depletion results in the increased expression of profilin IIa and active RhoA (RhoA-GTP) as well as the decreased expression of plastin 3 and Cdc42. Importantly, the inhibition of rho-kinase (ROCK), a direct downstream regulator of RhoA, significantly increased the lifespan of SMA mice and shows beneficial potential as a therapeutic strategy for SMA. In an addition, we have uncovered a muscle- and motor neuron-independent role for SMN in the regulation of pancreatic development and glucose metabolism in SMA mice and type 1 SMA patients. This finding highlights the importance of combining a glucose tolerance assessment of SMA patients with their existing clinical care management. Thus, our work has uncovered two novel and equally important roles for the SMN protein, both of which contribute significantly to SMA pathogenesis.

L’atròfia muscular espinal (AME) és una malaltia neuromuscular causada per mutació o deleció en el gen SMN1, que codifica per la proteïna ubiqua SMN (de l’anglès survival motor neuron). L’AME es caracteritza per atròfia muscular i degeneració de les motoneurones (MN) de la medul·la espinal. Els esdeveniments moleculars que causen la vulnerabilitat específica de les MN amb nivells baixos de proteïna SMN encara no es coneixen. La via de l’NF-κB (nuclear factor-κB) ha destacat recentment ja que sembla jugar un paper cabdal en la supervivència de les MN i en les malalties neurodegeneratives. Els factors de transcripció NF-κB regulen gens relacionats amb molts processos cel·lulars. En aquest treball hem analitzat la capacitat dels membres de la via de l’NF-κB de regular la proteïna Smn i el seu possible rol en la patogènesi de l’AME. L’activació de la via de l’NF-κB està associada a la fosforilació de l’IKKα/IKKβ i la translocació nuclear del factor RelA/p50 (via canònica) o la fosforilació de l’homodímer d’IKKα i la translocació nuclear del factor RelB/p52 (via no canònica). La inhibició de diferents membres d’aquestes vies (tant la canònica com la no canònica) usant la metodologia de transducció amb lentivirus amb shRNA en cultius primaris de MN embrionàries aïllades de ratolí hem demostrat que una reducció selectiva del factor RelA provoca una reducció de la proteïna Smn, mentre que una reducció del factor RelB no té cap efecte en els nivells de l’Smn. En el nostre model cel·lular, la reducció dels nivells de l’IKKα o l’IKKβ provoca un efecte oposat en l’Smn. Mitjançant la tècnica de la RT-PCR hem observat que la transducció de les MN amb l’shIKKβ provoca un augment dels nivells de l’mRNA de Smn, mentre que la transducció amb l’shIKKα o l’shRelA no modifica l’expressió de Smn. El doble knockdown de l’IKKα i l’IKKβ a les MN mostra una reducció de l’Smn. El knockdown selectiu de l’IKKα o l’IKKβ presenta una reducció de la fosforilació del RelA, es coneix que aquesta fosforilació en permet l’alliberament del seu inhibidor al citosol i en facilita la translocació nuclear. També la proteïna CREB, un dels factors de transcripció coneguts de l’Smn, disminueix amb la transducció de les MN amb els shIKKα o amb l’IKKα i l’IKKβ alhora, així com amb l’shRelA. Ara bé, les motoneurones amb l’shIKKβ mostren una reducció de la fosforilació de RelA però un augment dels nivells de CREB. La transducció de les MN amb l’shCREB disminueix els nivells de l’Smn recolzant el paper regulador de CREB en l’Smn. Hem observat una reducció de l’IKKα, l’IKKβ i de la fosforilació de RelA amb la transducció de les MN amb l’shSmn i en les MN del model murí sever de l’AME. Els nostres resultats mostren l’habilitat de la via canònica de l’NF-κB de regular els nivells de l’Smn i que aquesta via també es troba alterada en les MN deficients en la proteïna Smn. En conjunt, aquestes observacions suggereixen que la via de l’NF-κB pot tenir un rol en la patogènesi i ser, a la vegada, una possible diana terapèutica per l’AME.
La Atrofia Muscular Espinal (SMA) es un trastorno neuromuscular causado por la mutación o deleción del gen SMN1, el cual codifica para la proteína que se expresa ubicuamente SMN (del inglés Survival Motor Neuron). La AME se caracteriza por atrofia muscular y degeneración de las motoneuronas de la médula espinal (MN). Los eventos moleculares detrás de la vulnerabilidad selectiva de las MN con niveles bajos de la proteína SMN se desconocen. La vía del factor nuclear-kB (NF-kB) ha sido implicada recientemente en la supervivencia de las MNs, así como en trastornos neurodegenerativos. Los factores de transcripción NF-kB regulan genes relacionados con varios procesos celulares. En este trabajo hemos analizado la capacidad de los miembros de la vía del NF-κB de regular la proteína SMN y su posible rol en la patogénesis del AME. La activación de la vía del NF-κB está asociada a la fosforilación de IKKα / IKKβ y la translocación nuclear del factor RelA/ p50 (vía canónica) o la fosforilación del homodímero de IKKα y la translocación nuclear del factor RelB / p52 (vía no canónica). Hemos realizado la inhibición de diferentes miembros de estas vías (tanto la canónica como la no canónica) usando la metodología de shRNA, y la transducción mediante el uso de lentivirus, en cultivos primarios de MN embrionarias aisladas de ratón. Hemos demostrado que una reducción selectiva del factor RelA provoca una reducción de la proteína SMN, mientras que una reducción del factor RelB no tiene ningún efecto en los niveles de la SMN. En nuestro modelo celular, la reducción de las proteínas IKKα o IKKβ mostró efectos opuestos sobre la proteína Smn. Mediante la técnica de PCR, hemos observado que la transducción de las MN con el shIKKβ provoca un aumento de los niveles de mRNA de SMN, mientras que la transducción con el shIKKα o el shRelA no cambian los niveles de RNA de SMN. El doble knockdown de IKKα e IKKβ en las MN muestra una reducción de SMN. El knockdown selectivo de IKKα o IKKβ presenta una reducción de la fosforilación del RelA, esta fosforilación permite la liberación de su inhibidor en el citosol y facilita la translocación nuclear. La proteína CREB, uno de los factores de transcripción conocidos para SMN, disminuye con la transducción de las MN con shIKKα o con IKKα e IKKβ a la vez, así como con shRelA. Ahora bien, las motoneuronas transducidas con shIKKβ muestran una reducción de la fosforilación de RelA pero un aumento de los niveles de la proteína CREB. La transducción de las MN con el shCREB disminuyó los niveles de la proteína SMN apoyando el papel regulador de CREB sobre SMN.
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by mutation or loss in SMN1 gene, encoding the ubiquitously expressed Survival Motor Neuron (SMN) protein. SMA is characterized by muscle atrophy, and spinal cord motoneurons (MNs) degeneration. The molecular events behind the selective vulnerability of these MNs to low level of SMN protein are still unknown. The nuclear factor-κB (NF-κB) pathway has recently been emerged having a vital role related to MN survival, and in neurodegenerative disorders. The NF-κB transcription factors regulate genes related to several cellular processes. In the present work, we have analyzed the ability of NF-κB pathway members to regulate Smn and their possible role in SMA pathogenesis. The NF-κB pathway activation is associated with IKKα/IKKβ phosphorylation, and RelA/p50 nuclear translocation (canonical) or IKKα homodimer phosphorylation, and RelB/p52 nuclear translocation (non-canonical). The inhibition of different protein members of both canonical, and non-canonical pathways using shRNA lentiviral transduction methodology in a primary culture of isolated embryonic spinal cord MNs reveals that the selective reduction of RelA induced the reduction of Smn whereas RelB protein reduction had no effect on Smn. In our culture system, reduction of IKKα or IKKβ proteins showed opposite effects on Smn. RT-PCR studies indicate that the shIKKβ-transduced MNs showed increased Smn mRNA levels, whereas it was not observed changes in Smn mRNA in the case of shIKKα- or shRelA-transduced MNs. The double knock-down of IKKα and IKKβ in MNs showed Smn reduction. The knockdown of IKKα and/or IKKβ showed a decrease in RelA phosphorylation, where the phosphorylation of RelA enable RelA/p50 release from its inhibitor in the cytoplasm and facilitates their nuclear translocation. Also, the CREB, one of the transcription factors for Smn was decreased in shIKKα, or in shIKKα- plus IKKβ-transduced MNs, and as well as in shRelA-transduced MNs. But, the shIKKβ MNs exhibited reduced p-RelA but increased CREB level. The shCREB-transduced MNs decreased Smn level, authenticating the regulatory role of CREB on Smn. We observed a reduction in IKKα, IKKβ and p-RelA levels in shSmn-tranduced MNs, and in MNs from a severe type SMA mouse model. Our results show the ability of NF-κB canonical pathway to regulate Smn level and, conversely, this pathway is also altered in Smn-deficient MNs. Together, these observations suggest that the NF-κB pathway has a role in SMA pathogenesis, and could be a therapeutic target for SMA.

Spinal muscular Atrophy (SMA) is caused by reduced levels of the SMN protein. In humans this is caused by loss of SMN1 and retention of SMN2. The challenge in modelling SMA, in either tissue culture cells or animals, is first to obtain the desired SMN levels equivalent to what is observed in SMA. Various models of SMA in tissue culture cells, invertebrates, and mammals have been created have been developed. The targets of SMN reduction that are most relevant for the pathogenesis of SMA and how the phenotype of SMA can be modified independent of SMN levels are two important questions that remain unanswered. Here the current in vitro and in vivo models of SMA are summarized.

Sarcopenia is one of geriatric syndromes, characterized by decreased muscle mass accompanied by decreased muscle strength and/or performance. It is more prevalent with increase in age, and the prevalence depends on the criteria applied and the characteristic of the elderly. Sarcopenia has a higher risk of morbidity and mortality in elderly patients. The definition criteria of sarcopenia are still controversial, but diagnostic criteria from the Asian Working Group for Sarcopenia and the European Working Group on Sarcopenia in Older People (EWGSOP) are the most used criteria for clinical practice. Pathogenesis sarcopenia involved a multifactorial process and is divided into intrinsic and extrinsic factors. Risk factors for sarcopenia include constitutional factors, aging, lifestyle, changes in body condition, and chronic diseases. Based on that, sarcopenia is divided into primary and secondary sarcopenia. There are three stage of sarcopenia, which are pre-sarcopenia, sarcopenia, and severe sarcopenia. Nutrition and exercise are the two main pillars to manage sarcopenia.