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

ABSTRACT: Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Deregulation of expression of ECC genes is concomitant with sexual m

SUBMITTER: Marchioretti C 

PROVIDER: S-EPMC9902403 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature