Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle

Abstract

Polyglutamine (polyQ)-expanded androgen receptor (AR) causes spinobulbar muscular atrophy. Skeletal muscle is a primary site of polyQ-expanded AR toxicity, however it remains to be established what the early pathological processes are and how they unfold during disease progression. Using transgenic, knock-in SBMA mice and patient-derived muscle biopsies, we show that polyQ-expanded AR alters the generation of intrinsic muscle force prior to denervation. The pattern of expression of genes encoding key components of the excitation-contraction coupling (ECC) machinery is altered in the muscles of presymptomatic mice and patients. Altered mitochondrial respiration is another early event followed by stimulus-dependent accumulation of calcium into mitochondria during disease onset and structural organization alterations of the muscle triad. Surgical castration and AR silencing prevented early pathological processes. These observations show that androgen-dependent deregulations of ECC and defective mitochondrial respiration are early but reversible events followed by altered muscle force, contraction dynamics, and calcium dyshomeostasis.