Key result
Testosterone worsens Brugada syndrome phenotypes by reducing Nav1.5 and INa via autophagy activation.
Why the study?
Men are more likely than women to have Brugada syndrome, prompting investigation into the underlying mechanisms by which testosterone affects the electrophysiology of Brugada syndrome cardiomyocytes.
Does 100 nM testosterone treatment affect Nav1.5 expression and sodium current (INa) in human iPSC-derived cardiomyocytes harboring an SCN5A p.Ala1050Thr variant?
Does 100 nM testosterone treatment affect Nav1.5 expression and sodium current (INa) in human iPSC-derived cardiomyocytes harboring an SCN5A p.Ala1050Thr variant?
This preclinical study demonstrates that testosterone exacerbates the Brugada syndrome cellular phenotype in SCN5A-mutant human iPSC-derived cardiomyocytes by activating AMPK/mTOR-mediated autophagy, providing a potential mechanistic explanation for the male predominance in Brugada syndrome.
Testosterone effects in BrS hiPSC-CMs are hypothesis-generating; leaves open whether androgen modulation influences clinical penetrance or risk.
Background and Aims Men are more likely to suffer from Brugada syndrome (BrS) than women. The aim of this study is to explore the underlying mechanisms by which testosterone affects the electrophysiology of BrS cardiomyocytes. Methods Human induced pluripotent stem cell (hiPSC) lines generated from fibroblasts of a BrS patient harboring a pathogenic variant (p.Ala1050Thr) in SCN5A (abbreviated as BrS) and one healthy donor (abbreviated as WT) and a site-corrected (using CRISPR/Cas9) hiPSC line (abbreviated as isogenic) were used for differentiation into cardiomyocytes (hiPSC-CMs). Western blot and patch clamp analyses were carried out. Results Treatment with 100 nM testosterone on BrS hiPSC-CMs led decrease in Nav1.5 expression, INa and Vmax of APs. The administration of the testosterone antagonist, flutamide, effectively prevented the effects induced by testosterone. Remarkably, testosterone failed to exert any significant impact on Nav1.5 expression and INa in both the WT and isogenic hiPSC-CMs. Further, the concurrent application of the autophagy inhibitor Bafilomycin A1 (BafA1) and testosterone resulted in an elevated expression of the autophagy marker LC3BII in BrS hiPSC-CMs, in contrast to the effect observed with BafA1 treatment alone. Additionally, the activation of autophagy through rapamycin led to an increase in the expression of Nav1.5 and INa within BrS hiPSC-CMs. Conversely, the inhibition of autophagy resulted in a decrease in the BrS phenotype, highlighting the pivotal role of autophagy modulation. testosterone treatment was found to increase phosphorylation levels of AMP-activated protein kinase (AMPK) but decrease the phosphorylation levels of mammalian target of rapamycin (mTOR) in BrS hiPSC-CMs. Furthermore, the inhibition of AMPK effectively mitigated the exacerbating effects of testosterone on the BrS phenotype. Conclusion Testosterone could exacerbate the BrS phenotype in hiPSC-CMs with SCN5A variants through activating autophagy signaling.
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Li et al. (2026) studied Brugada syndrome with SCN5A variant (n=2). Testosterone vs. WT and isogenic hiPSC-CMs, or co-treatment with flutamide/autophagy/AMPK modulators was evaluated on Nav1.5 expression, INa, Vmax of action potentials, and autophagy signaling markers (LC3BII, AMPK, mTOR). Testosterone (100 nM) decreased Nav1.5 expression, INa, and action potential Vmax in Brugada syndrome SCN5A-variant hiPSC-CMs via AMPK-mTOR autophagy activation, an effect prevented by flutamide.
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