The expansion of polyglutamine within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). Skeletal muscles are a primary site of toxicity; however, our current understanding of the early pathological processes and how they evolve during disease progression remains limited.
Using transgenic and knock-in mouse models as well as patient-derived muscle biopsies, we demonstrate that presymptomatic SBMA mice develop a respiratory defect associated with the dysregulated expression of genes involved in excitation–contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These events are followed by stimulus-dependent calcium accumulation in mitochondria and structural disorganization of muscle triads.
The dysregulation of ECC gene expression coincides with sexual maturity and elevated serum androgen levels. Consistent with the androgen-dependent nature of these alterations, both surgical castration and AR silencing alleviate early and late pathological processes.
Overall, these findings reveal that ECC dysregulation and impaired mitochondrial respiration are early but reversible events, which precede muscle weakness, calcium dyshomeostasis, and disruption of triad architecture.
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