ArticleActa neuropathologica2020
MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease.
Article in Acta neuropathologica, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 33 citations in OpenAlex.
- PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA.JCI insight · 2026Article
- Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis.Human molecular genetics · 2025Article
- Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.Acta neuropathologica · 2024Article
- Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy.Journal of cachexia, sarcopenia and muscle · 2024Article
- Simple and efficient differentiation of human iPSCs into contractible skeletal muscles for muscular disease modeling.Scientific reports · 2023Article
- Gene Structure, Expression and Function Analysis ofInternational journal of molecular sciences · 2023Article
- Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Article
- Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial CaNature communications · 2023Article
- Atrophic skeletal muscle fibre-derived small extracellular vesicle miR-690 inhibits satellite cell differentiation during ageing.Journal of cachexia, sarcopenia and muscle · 2022Article
- Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b.International journal of molecular sciences · 2022Article
- Neuromuscular junction pathology is correlated with differential motor unit vulnerability in spinal and bulbar muscular atrophy.Acta neuropathologica communications · 2022Article
- Review
- AR cooperates with SMAD4 to maintain skeletal muscle homeostasis.Acta neuropathologica · 2022Article
- Article
- The role of ubiquitination in spinal and bulbar muscular atrophy.Frontiers in molecular neuroscience · 2022Review
- Article
- Clenbuterol-sensitive delayed outward potassium currents in a cell model of spinal and bulbar muscular atrophy.Pflugers Archiv : European journal of physiology · 2021Article
- Molecular Mechanisms of Skeletal Muscle Hypertrophy.Journal of neuromuscular diseases · 2021Review
- Molecular Mechanisms Underlying Muscle Wasting in Huntington's Disease.International journal of molecular sciences · 2020Review
- Decreased Myocyte Enhancer Factor 2 Levels in the Hippocampus of Huntington's Disease Mice Are Related to Cognitive Dysfunction.Molecular neurobiology · 2020Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
Abstract
Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders.
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