scholarly journals Muscle‐specific sirtuin1 gain‐of‐function ameliorates skeletal muscle atrophy in a pre‐clinical mouse model of cerebral ischemic stroke

2020 ◽  
Vol 2 (7) ◽  
pp. 387-397
Author(s):  
Kiril Tuntevski ◽  
Ameena Hajira ◽  
Austin Nichols ◽  
Stephen E. Alway ◽  
Junaith S. Mohamed
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Gain Of Function ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

scholarly journals Transcriptome Analysis of Skeletal Muscle Reveals Altered Proteolytic and Neuromuscular Junction Associated Gene Expressions in a Mouse Model of Cerebral Ischemic Stroke

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 726
Author(s):  
Peter J. Ferrandi ◽  
Mohammad Moshahid Khan ◽  
Hector G. Paez ◽  
Christopher R. Pitzer ◽  
Stephen E. Alway ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Neuromuscular Junction ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Altered Expression ◽  
Post Stroke ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that induces muscle wasting and weakness, which predominantly contribute to functional disability in stroke patients. Currently, no pharmacological drug is available to treat post-stroke muscle morbidities as the mechanisms underlying post-stroke muscle wasting remain poorly understood. To understand the stroke-mediated molecular changes occurring at the transcriptional level in skeletal muscle, the gene expression profiles and enrichment pathways were explored in a mouse model of cerebral ischemic stroke via high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq revealed that the elevated muscle atrophy observed in response to stroke was associated with the altered expression of genes involved in proteolysis, cell cycle, extracellular matrix remodeling, and the neuromuscular junction (NMJ). These data suggest that stroke primarily targets muscle protein degradation and NMJ pathway proteins to induce muscle atrophy. Collectively, we for the first time have found a novel genome-wide transcriptome signature of post-stroke skeletal muscle in mice. Our study will provide critical information to further elucidate specific gene(s) and pathway(s) that can be targeted to mitigate accountable for post-stroke muscle atrophy and related weakness.

scholarly journals Molecular Mechanisms of Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Junaith Mohamed ◽  
Mohammad Khan ◽  
Peter Ferrandi ◽  
Hector Paez ◽  
Christopher Pitzer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Abstract P806: Sirtuin1 Plays a Critical Role in Reversing Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Junaith S Mohamed ◽  
Peter J Ferrandi ◽  
Paez G Hector ◽  
Christopher R Pitzer ◽  
Stephen E Alway
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Rna Seq ◽  
Stroke Patients ◽  
Post Stroke ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that severely induces muscle wasting and weakness, which contributes more to the long-term functional disability in stroke patients than any other disease. Currently, no approved pharmacological drug is available to treat stroke-induced muscle loss. Rehabilitative therapy is the only available option to improve muscle function in stroke patients. However, higher muscle fatigability and lower muscle strength from extensive muscle wasting in post-stroke patients provide poor rehabilitative outcomes. As a result, about two-thirds of stroke survivors persist in a state of insufficient recovery and experience physical disability that drastically reduces their health and quality of life. The major challenge in the drug discovery effort for treating post-stroke muscle wasting is the lack of our understanding of the molecular and/or cellular mechanisms that underlie the muscle wasting in stroke. To understand the molecular origin of stroke-induced muscle atrophy, gene expression profiling and associated biological pathway enrichment studies were performed in a mouse model of cerebral ischemic stroke using high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq data revealed that the elevated atrophy in skeletal muscle observed in response to stroke was primairly associated with the altered expression of genes involved in the muscle protein degradation pathway. Further analysis of RNA-seq data identified Sirtuin1 (SirT1) as a critical protein that plays a significant role in regulating post-stroke muscle mass. SirT1 gain-of-function in skeletal muscle significantly reversed stroke-induced muscle atrophy via inhibiting the activation of the ubiquitin proteasomal pathway and restoring autophagy function. Collectively, this study identified suppression of SirT1as a novel mechanism by which stroke induces muscle atrophy.

scholarly journals Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0129686 ◽  
Author(s):  
Giulia Maria Camerino ◽  
Jean-François Desaphy ◽  
Michela De Bellis ◽  
Roberta Francesca Capogrosso ◽  
Anna Cozzoli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Biology ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Functional Evaluation ◽  
Muscle Disuse

scholarly journals Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 325 ◽  
Author(s):  
Mathilde Chivet ◽  
Caterina Marchioretti ◽  
Marco Pirazzini ◽  
Diana Piol ◽  
Chiara Scaramuzzino ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Androgen Receptor ◽  
Muscle Atrophy ◽  
Fiber Type ◽  
Sodium Dodecyl ◽  
Premature Death ◽  
Motor Dysfunction ◽  
Skeletal Muscle Atrophy ◽  
Muscle Pathology ◽  
Gain Of Function

Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.

scholarly journals Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1824 ◽  
Author(s):  
Lilia A. Koza ◽  
Aimee N. Winter ◽  
Jessica Holsopple ◽  
Angela N. Baybayon-Grandgeorge ◽  
Claudia Pena ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Protocatechuic Acid ◽  
Neuromuscular Junctions ◽  
Disease Onset ◽  
Skeletal Muscle Atrophy ◽  
Therapeutic Effects ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.

Molecular Mechanisms of Skeletal Muscle Atrophy in a Mouse Model of Cerebral Ischemia

Stroke ◽  
2015 ◽  
Vol 46 (6) ◽  
pp. 1673-1680 ◽  
Author(s):  
Marine Maud Desgeorges ◽  
Xavier Devillard ◽  
Jérome Toutain ◽  
Didier Divoux ◽  
Josiane Castells ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cerebral Ischemia ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy
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