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

Giorgetti, E.; Zhang, Yu; Chua, Jason P.; Shimamura, Ryosuke; Zhao, Lili; Zhu, Fan; Venneti, Sriram; Pennuto, Maria; Guan, Yuanfang; Hung, Gene; Lieberman, Andrew P.

doi:10.1016/j.celrep.2016.08.084

Cited by 47 publications

(82 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AR100Q mice showed progressive body weight loss starting from 8 weeks of age (p = 0.0001) ( Figure 1D), and deterioration of motor function assessed by rotarod and hanging wire tasks, starting from week 12 (p = 0.002) and week 11 (p = 0.0001), respectively ( Figure 1E). AR100Q mice developed atrophy of glycolytic muscles, resulting in 25-to-50% weight loss of quadriceps, gastrocnemius, TA, and EDL, but not soleus, by 8 weeks of age, consistent with previous findings (Figure 1F) (14,30). By nicotinamide adenine dinucleotide (NADH) staining we found a significant (p = 0.0001) glycolytic-to-oxidative fiber-type switch in 8-week-old AR100Q mice, as previously described in SBMA knock-in mice and patients ( Figure 1G) (26,30).…”

Section: Supplementary Figures 3 and 4a-d) Formation Of Muscle Intrasupporting

confidence: 91%

“…Several of these symptoms are found in SBMA patients (27,(70)(71)(72), and deleterious effects of chronic low-intensity endurance exercise were reported in SBMA mice (14). Our findings that CASQ1 expression is regulated by AR signaling and is reduced before onset of atrophy and motor dysfunction in SBMA mice suggest a role for this key ECC gene in pathological processes occurring in SBMA.…”

Section: Discussionsupporting

confidence: 50%

“…Males are affected because they have high levels of circulating testosterone in the serum (10). Neuromuscular phenotype, sex-dependency, metabolic alterations and peripheral symptoms are well recapitulated in transgenic and knock-in mouse models of disease (11)(12)(13)(14). Mechanistically, the mild signs of androgen insensitivity and endocrine abnormalities implicate partial AR loss of function (LOF) underlying disease pathogenesis (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…Pharmacologic intervention to either silence polyQ-expanded AR expression with antisense oligonucleotides (ASOs) in peripheral tissues, specially skeletal muscle (34), or to promote its degradation and stimulate muscle hypertrophy with the insulin-like growth factor 1 and the beta-agonist clenbuterol (35,36) ameliorated disease manifestations, including metabolic defects in muscle (14). These observations further support the idea that not only the MN, but also the skeletal muscle is central to disease and represents a key target-tissue for therapy development.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

Chivet

Marchioretti

Pirazzini

et al. 2019

Preprint

View full text Add to dashboard Cite

Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine (polyQ) expansions in the androgen receptor (AR) gene. Although clinical and experimental evidence highlight a primary role for skeletal muscle in the onset, progression, and outcome of disease, the pathophysiological and molecular processes underlying SBMA muscle atrophy are poorly understood. Here we show that polyQ-expanded AR alters intrinsic muscle force generation before denervation. Reduced muscle force was associated with a switch in fiber-type composition, disrupted muscle striation, altered calcium (Ca ++ ) dynamics in response to muscle contraction, and aberrant expression of excitation-contraction coupling (ECC) machinery genes in transgenic, knock-in and inducible SBMA mice and patients. Importantly, treatment to suppress polyQ-expanded AR toxicity restored ECC gene expression back to normal. Suppression of AR activation by surgical castration elicited similar ECC gene expression changes in normal mice, suggesting that AR regulates the expression of these genes in physiological conditions. Bioinformatic analysis revealed the presence of androgen-responsive elements on several genes involved in muscle function and homeostasis, and experimental evidence showed AR-dependent regulation of expression and promoter occupancy of the most up-regulated gene from transcriptomic analysis in SBMA muscle, i.e. sarcolipin, a key ECC gene. These observations reveal an unpredicted role for AR in the regulation of expression of genes involved in muscle contraction and Ca ++ dynamics, a level of muscle function regulation that is disrupted in SBMA muscle, yet restored by pharmacologic treatment.

show abstract

Section: Supplementary Figures 3 and 4a-d) Formation Of Muscle Intrasupporting

confidence: 91%

Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

Chivet

Marchioretti

Pirazzini

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…As a result, a major focus of the field has been on either preventing synthesis of mutant proteins using antisense oligonucleotides (Lieberman et al, 2014; Sahashi et al, 2015; Giorgetti et al, 2016) or enhancing degradation by leveraging the endogenous cellular machinery (Sittler et al, 2001; Adachi et al, 2003, 2007; Tokui et al, 2009; Wang et al, 2013; Silva-Fernandes et al, 2014). The latter approach highlights the importance of ongoing research into the pathways that disaggregate, ubiquitinate, deubiquitinate, and degrade mutant proteins.…”

Section: Discussionmentioning

confidence: 99%

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Nath

Lieberman

2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression. As a result, a vast body of research has focused on eliminating the mutant protein to broadly prevent downstream toxicity, either by silencing mutant protein expression or leveraging the endogenous protein quality control machinery. In the latter approach, a focus has been placed on four critical components of mutant protein degradation that are active in the nucleus, a key site of toxicity: disaggregation, ubiquitination, deubiquitination, and proteasomal activity. These machineries have unique functional components, but work together as a cellular defense system that can be successfully leveraged to alleviate disease phenotypes in several models of polyglutamine toxicity. This review will highlight recent advances in understanding both the potential and role of these components of the protein quality control machinery in polyglutamine disease pathophysiology.

show abstract

Androgen receptor coordinates muscle metabolic and contractile functions

Ghaibour

Schuh

Souali-Crespo

et al. 2023

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

Background Androgens 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. Methods Male 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. Results We 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 H2O2 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. Conclusions Our 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.

show abstract

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

Cited by 47 publications

References 49 publications

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

Polyglutamine-expanded androgen receptor disrupts muscle triad, calcium dynamics and the excitation-contraction coupling gene expression program

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Androgen receptor coordinates muscle metabolic and contractile functions

Contact Info

Product

Resources

About