Upon androgen binding, the AR undergoes a conformational change that leads to nuclear translocation and activation, which are all necessary steps to induce toxicity, thus explaining the sex-dependent nature of SBMA 3. The AR is the main mediator of androgen signaling.
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The disease is androgen dependent, and full manifestations are exhibited in males. SBMA is a progressive late-onset disease characterized by the selective degeneration of lower motor neurons (MNs) and weakness, fasciculations, and atrophy of skeletal muscle 2. SBMA affects 2–5/100,000 subjects, which is probably an underestimation due to misdiagnosis and lack of disease-specific biomarkers. Spinobulbar muscular atrophy (SBMA, OMIM 313200), also known as Kennedy’s disease, is a genetic neuromuscular disease caused by the presence of over 37 expansions of a microsatellite CAG trinucleotide tandem repeat encoding a polyglutamine (polyQ) tract in exon 1 of the androgen receptor ( AR) gene 1. These observations show that ECC deregulation and defective mitochondrial respiration are early but reversible events followed by altered muscle force, calcium dyshomeostasis, and dismantling of triad structure. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes. Deregulation of expression of ECC genes is concomitant with sexual maturity and androgen raise in the serum. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. 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. 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.
Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Nature Communications volume 14, Article number: 602 ( 2023) Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca 2+ accumulation in spinobulbar muscular atrophy skeletal muscle
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