Circulation research · 2026
AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin.
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Ge Qianyun, Saha Kusumika, Burch Micah L, Battista Willow H, Kc Ashmita, Homilius Max, Victorio Rachelle A, Quan Dajun, Huang Hsiang-Ling, Hazel Joseph M, Williams Alex, Pan Emily, Chinthalapudi Krishna, Heissler Sarah M, MacRae Calum A, Zhu Wandi
Аннотация
BACKGROUND: Variants in PRKAG2 cause hypertrophic cardiomyopathy and conduction disturbances. Although prior studies associated PRKAG2-related hypertrophy with increased glycogen storage, many hypertrophic cardiomyopathy phenotypes remain unexplained. We aimed to uncover how PRKAG2 variants induce myocyte hypertrophy and electrical changes during early cardiac development.
METHODS: We generated transgenic zebrafish expressing wild-type or pathogenic variant Prkag2 under a myocardium-specific promoter, Tg(cmcl2:Prkag2WT) (TgWT) and Tg(cmcl2: Prkag2R299Q) (TgR299Q), respectively, and examined cardiac electrophysiology, contractile function, and cytoarchitecture during cardiogenesis and in adult hearts.
RESULTS: TgR299Q fish showed hypertrophic cardiomyocytes and progressive contractile abnormalities, recapitulating human hypertrophic cardiomyopathy phenotypes. Cardiomyocyte glycogen was elevated in adult but not embryonic hearts. Despite the absence of glycogen accumulation at 6 days post-fertilization, TgR299Q hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca2+ transient durations, compared to TgWT and wild-type (Tübingen/AB [TuAB]). We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the TgR299Q hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in TgR299Q. Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament. NCX (Na+/Ca2+ exchanger) inhibition increased Ca2+ duration and diastolic Ca2+ in TgWT but not TgR299Q hearts, indicating reduced free cytosolic Ca2+ for NCX-mediated extrusion in TgR299Q. These findings suggest that enhanced AMPKγ2-myosin interaction may promote myofilament Ca2+ retention, thereby prolonging Ca2+ transient duration and action potential duration in the mutant. Notably, the myosin inhibitor mavacamten reduced AMPKγ2-myosin interaction in TgR299Q hearts, and both mavacamten and vmhcl knockdown rescued the early electrophysiological abnormalities.
CONCLUSIONS: The PRKAG2 variant altered cardiac excitability, contractility, and Ca2+ handling during cardiogenesis, independent of glycogen accumulation. Enhanced interactions between AMPKγ2 and myosin contributed to these early changes. Our study revealed a novel link between cellular energy sensing and contractile machinery, with therapeutic potential for modulating contractile function in cardiomyopathies.
METHODS: We generated transgenic zebrafish expressing wild-type or pathogenic variant Prkag2 under a myocardium-specific promoter, Tg(cmcl2:Prkag2WT) (TgWT) and Tg(cmcl2: Prkag2R299Q) (TgR299Q), respectively, and examined cardiac electrophysiology, contractile function, and cytoarchitecture during cardiogenesis and in adult hearts.
RESULTS: TgR299Q fish showed hypertrophic cardiomyocytes and progressive contractile abnormalities, recapitulating human hypertrophic cardiomyopathy phenotypes. Cardiomyocyte glycogen was elevated in adult but not embryonic hearts. Despite the absence of glycogen accumulation at 6 days post-fertilization, TgR299Q hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca2+ transient durations, compared to TgWT and wild-type (Tübingen/AB [TuAB]). We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the TgR299Q hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in TgR299Q. Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament. NCX (Na+/Ca2+ exchanger) inhibition increased Ca2+ duration and diastolic Ca2+ in TgWT but not TgR299Q hearts, indicating reduced free cytosolic Ca2+ for NCX-mediated extrusion in TgR299Q. These findings suggest that enhanced AMPKγ2-myosin interaction may promote myofilament Ca2+ retention, thereby prolonging Ca2+ transient duration and action potential duration in the mutant. Notably, the myosin inhibitor mavacamten reduced AMPKγ2-myosin interaction in TgR299Q hearts, and both mavacamten and vmhcl knockdown rescued the early electrophysiological abnormalities.
CONCLUSIONS: The PRKAG2 variant altered cardiac excitability, contractility, and Ca2+ handling during cardiogenesis, independent of glycogen accumulation. Enhanced interactions between AMPKγ2 and myosin contributed to these early changes. Our study revealed a novel link between cellular energy sensing and contractile machinery, with therapeutic potential for modulating contractile function in cardiomyopathies.