Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Giorgetti E

PROVIDER: S-EPMC5076565 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Giorgetti Elisa E Yu Zhigang Z Chua Jason P JP Shimamura Ryosuke R Zhao Lili L Zhu Fan F Venneti Sriram S Pennuto Maria M Guan Yuanfang Y Hung Gene G Lieberman Andrew P AP

Cell reports 20160901 1

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 carbohydra ...[more]

PMID: 27681426

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Project description:BackgroundAndrogens are anabolic steroid hormones that exert their function by binding to the androgen receptor (AR). We have previously established that AR deficiency in limb muscles impairs sarcomere myofibrillar organization and decreases muscle strength in male mice. However, despite numerous studies performed in men and rodents, the signalling pathways controlled by androgens via their receptor in skeletal muscles remain poorly understood.MethodsMale ARskm-/y (n = 7-12) and female ARskm-/- mice (n = 9), in which AR is selectively ablated in myofibres of musculoskeletal tissue, and male AR(i)skm-/y , in which AR is selectively ablated in post-mitotic skeletal muscle myofibres (n = 6), were generated. Longitudinal monitoring of body weight, blood glucose, insulin, lipids and lipoproteins was performed, alongside metabolomic analyses. Glucose metabolism was evaluated in C2C12 cells treated with 5α-dihydrotestosterone (DHT) and the anti-androgen flutamide (n = 6). Histological analyses on macroscopic and ultrastructural levels of longitudinal and transversal muscle sections were conducted. The transcriptome of gastrocnemius muscles from control and ARskm-/y mice was analysed at the age of 9 weeks (P < 0.05, 2138 differentially expressed genes) and validated by RT-qPCR analysis. The AR (4691 peaks with false discovery rate [FDR] < 0.1) and H3K4me2 (47 225 peaks with FDR < 0.05) cistromes in limb muscles were determined in 11-week-old wild-type mice.ResultsWe show that disrupting the androgen/AR axis impairs in vivo glycolytic activity and fastens the development of type 2 diabetes in male, but not in female mice. In agreement, treatment with DHT increases glycolysis in C2C12 myotubes by 30%, whereas flutamide has an opposite effect. Fatty acids are less efficiently metabolized in skeletal muscles of ARskm-/y mice and accumulate in cytoplasm, despite increased transcript levels of genes encoding key enzymes of beta-oxidation and mitochondrial content. Impaired glucose and fatty acid metabolism in AR-deficient muscle fibres is associated with 30% increased lysine and branched-chain amino acid catabolism, decreased polyamine biosynthesis and disrupted glutamate transamination. This metabolic switch generates ammonia (2-fold increase) and oxidative stress (30% increased H2 O2 levels), which impacts mitochondrial functions and causes necrosis in <1% fibres. We unravel that AR directly activates the transcription of genes involved in glycolysis, oxidative metabolism and muscle contraction.ConclusionsOur study provides important insights into diseases caused by impaired AR function in musculoskeletal system and delivers a deeper understanding of skeletal muscle pathophysiological dynamics that is instrumental to develop effective treatment for muscle disorders.

Project description:The factors that underpin heterogeneity in muscle hypertrophy following resistance exercise training (RET) remain largely unknown. We examined circulating hormones, intramuscular hormones, and intramuscular hormone-related variables in resistance-trained men before and after 12 weeks of RET. Backward elimination and principal component regression evaluated the statistical significance of proposed circulating anabolic hormones (e.g., testosterone, free testosterone, dehydroepiandrosterone, dihydrotestosterone, insulin-like growth factor-1, free insulin-like growth factor-1, luteinizing hormone, and growth hormone) and RET-induced changes in muscle mass (n = 49). Immunoblots and immunoassays were used to evaluate intramuscular free testosterone levels, dihydrotestosterone levels, 5?-reductase expression, and androgen receptor content in the highest- (HIR; n = 10) and lowest- (LOR; n = 10) responders to the 12 weeks of RET. No hormone measured before exercise, after exercise, pre-intervention, or post-intervention was consistently significant or consistently selected in the final model for the change in: type 1 cross sectional area (CSA), type 2 CSA, or fat- and bone-free mass (LBM). Principal component analysis did not result in large dimension reduction and principal component regression was no more effective than unadjusted regression analyses. No hormone measured in the blood or muscle was different between HIR and LOR. The steroidogenic enzyme 5?-reductase increased following RET in the HIR (P < 0.01) but not the LOR (P = 0.32). Androgen receptor content was unchanged with RET but was higher at all times in HIR. Unlike intramuscular free testosterone, dihydrotestosterone, or 5?-reductase, there was a linear relationship between androgen receptor content and change in LBM (P < 0.01), type 1 CSA (P < 0.05), and type 2 CSA (P < 0.01) both pre- and post-intervention. These results indicate that intramuscular androgen receptor content, but neither circulating nor intramuscular hormones (or the enzymes regulating their intramuscular production), influence skeletal muscle hypertrophy following RET in previously trained young men.

Dataset Information

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

Publications

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

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