ArticleActa neuropathologica2016
Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet.
Article in Acta neuropathologica, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 87 citations in OpenAlex.
- Androgen receptor imprints satellite cell stemness and preserves their reservoir for lifelong regeneration and optimal repair.Science advances · 2026Article
- PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA.JCI insight · 2026Article
- Clinical Significance of Plasma Sphingosine-1-Phosphate Decline in Progression of Spinal and Bulbar Muscular Atrophy.Journal of clinical neurology (Seoul, Korea) · 2026Article
- Cerebral Ischemia-Reperfusion Injury: Unraveling the Mitophagy-Oxidative Stress Axis for Neuroprotective Strategies.International journal of molecular sciences · 2026Review
- 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 synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy.JCI insight · 2025Article
- N-acetylaspartate promotes glycolytic-to-oxidative fiber-type switch and resistance to atrophic stimuli in myotubes.Cell death & disease · 2024Article
- Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Differentially disrupted spinal cord and muscle energy metabolism in spinal and bulbar muscular atrophy.JCI insight · 2024Article
- Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy.Journal of cachexia, sarcopenia and muscle · 2024Article
- Angiogenic potential of skeletal muscle derived extracellular vesicles differs between oxidative and glycolytic muscle tissue in mice.Scientific reports · 2023Article
- Article
- Androgen receptor coordinates muscle metabolic and contractile functions.Journal of cachexia, sarcopenia and muscle · 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
- LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice.Nature communications · 2023Article
- The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases.Journal of personalized medicine · 2022Review
- 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
2 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors at 7 institutions in 2 countries.
Funding
Abstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients.
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