Abstract Body: Introduction: Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an adult-onset neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor. SBMA patients exhibit muscle atrophy and metabolic disorders, such as non-alcoholic fatty liver disease, diabetes, and hypertension, which can affect cardiac function. Some patients have Brugada’s syndrome, increasing the risk of sudden cardiac death. It remains unclear whether these arrhythmias are driven by hypertension or arises from intrinsic defects in cardiomyocytes.

Hypothesis: We hypothesized that human induced pluripotent stem cells (iPSCs) bearing a polyglutamine expansion in the androgen receptor can reveal the molecular basis of arrhythmia when differentiated to cardiomyocytes.

Methods: This study uses human iPSCs to model SBMA. We differentiated iPSCs derived from an individual with SBMA and isogenic controls where the polyglutamine tract was CRISPR-corrected to a normal repeat length. Because the androgen receptor is a steroid hormone receptor, we treated iPSC-cardiomyocytes with 5α-dihydrotestosterone, a potent metabolite of testosterone, from Days 21-30 of differentiation. We performed immunostaining, calcium imaging, and molecular profiling of healthy and diseased iPSC-cardiomycytes.

Results: Morphological analysis revealed differences in cell size and nuclear size in SBMA iPSC-cardiomyocytes compared to healthy controls. Calcium imaging revealed a higher frequency of arrhythmia in SBMA iPSC-cardiomyocytes, underscoring the cell-autonomous origin of cardiac complications. Through western blot analysis, we identified a previously uncharacterized AR isoform encoded by exon 1 and exon 8.

Conclusions: Our findings suggest that the polyglutamine expansion in AR induces arrhythmia in SBMA cardiomyocytes, emphasizing the importance of cardiac care for SBMA patients.