Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing

• Published in: Cell reports (Cambridge) Vol. 17; no. 1; pp. 125 - 136
• Main Authors: Giorgetti, Elisa, Yu, Zhigang, Chua, Jason P., Shimamura, Ryosuke, Zhao, Lili, Zhu, Fan, Venneti, Sriram, Pennuto, Maria, Guan, Yuanfang, Hung, Gene, Lieberman, Andrew P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.09.2016; Elsevier
• Subjects: Animals; antisense oligonucleotides; CAG/polyglutamine disease; Carbohydrate Metabolism - genetics; Citric Acid Cycle - genetics; Disease Models, Animal; exercise; Gene Expression Regulation; Gene Silencing; glycolysis; Glycolysis - genetics; Humans; metabolism; Mice; Mice, Transgenic; mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Muscle, Skeletal; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Muscular Atrophy, Spinal - therapy; Oligonucleotides, Antisense - pharmacology; Peptides - chemistry; Peptides - metabolism; Physical Conditioning, Animal; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; skeletal muscle; spinal and bulbar muscular atrophy; mitochondria; antisense oligonucleotides; glycolysis; spinal and bulbar muscular atrophy; exercise; metabolism; skeletal muscle; CAG/polyglutamine disease
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.08.084

Spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR). Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation. AR113Q muscle exhibits diminished glycolysis, altered mitochondria, and an impaired response to exercise. Strikingly, the expression of genes regulating muscle energy metabolism is rescued following peripheral polyQ AR gene silencing by antisense oligonucleotides (ASO), a therapeutic strategy that alleviates disease. Our data establish the occurrence of a metabolic imbalance in SBMA muscle triggered by peripheral expression of the polyQ AR and indicate that alterations in energy utilization contribute to non-neuronal disease manifestations. [Display omitted] •Decreased expression of carbohydrate metabolic genes characterizes AR113Q muscle•AR113Q skeletal muscle shows decreased glycolysis and altered mitochondria•Peripheral gene silencing by ASO rescues expression of muscle energy metabolism genes•Altered muscle energy utilization contributes to non-neuronal disease manifestations Spinal and bulbar muscular atrophy is a degenerative disorder of the neuromuscular system caused by the polyglutamine androgen receptor (polyQ AR). Giorgetti et al. report that mutant skeletal muscle exhibits alterations in energy metabolism and exercise performance as a consequence of peripheral expression of the polyQ AR.