Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

Abstract

Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.

Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity

“…3A ). The SBMA model chosen for the study expresses the human AR transgene with 100 glutamine residues (AR100Q) and recapitulates the main features of the SBMA phenotype, with androgen-dependent muscle atrophy, reduced grip strength, denervation, and shortened survival, starting at 7 weeks of age ( 34 ). Notably, protein levels of monomeric human AR in the skeletal muscle and spinal cord of these mice are comparable to the wild type’s ( 34 ).…”

“…The SBMA model chosen for the study expresses the human AR transgene with 100 glutamine residues (AR100Q) and recapitulates the main features of the SBMA phenotype, with androgen-dependent muscle atrophy, reduced grip strength, denervation, and shortened survival, starting at 7 weeks of age ( 34 ). Notably, protein levels of monomeric human AR in the skeletal muscle and spinal cord of these mice are comparable to the wild type’s ( 34 ). On the basis of quantitative measures of body weight, we performed a statistical power analysis to establish the minimum number of mice required for each cohort in the trial (Cohen’s d effect size: 0.8; minimum sample size for each group: 10 mice).…”

Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

“…SBMA mouse muscle has been found to have disruption of neurotrophic factors such as brain derived growth factor (BDNF), suggesting a potential therapeutic role for growth factor support [24]. The alteration in SBMA mouse muscle is associated with glycolytic-to-oxidative fiber-type switching and mitochondrial dysfunction, and dependence on the age at which mutant AR is expressed [25]. The accumulation of toxic effects at early stages of the disease may indicate a need for intervention in patients at an early age.…”

Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients

“…Evidence suggests that muscle cells are primarily affected also in SBMA and are crucial components of the disease pathogenesis [ 36 , 37 , 38 , 39 , 40 ]. Indeed, silencing the peripheral mutant ARpolyQ expression in different SBMA mouse models resulted in prolonged survival, thereby providing evidence for a direct effect of ARpolyQ on muscle atrophy [ 12 , 41 ].…”