Key result
PRKAG2 R299Q impairs early cardiac function independent of glycogen storage, driven by enhanced AMPKγ2-myosin binding.
Why the study?
Although PRKAG2 variants cause hypertrophic cardiomyopathy and conduction disturbances via glycogen storage, many phenotypes remain unexplained, prompting investigation into how they induce hypertrophy and electrical changes during early cardiogenesis.
The PRKAG2 R299Q variant alters cardiac excitability and contractility during early development independent of glycogen accumulation, driven by an enhanced interaction between AMPKγ2 and myosin.
PRKAG2 effects on cardiogenesis precede glycogen accumulation via myosin; hypothesis-generating for myosin-targeted therapies pending human studies.
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 cDNA (Tg R299Q ) under a myocardium-specific promoter, and examined cardiac electrophysiology, contractile function, and cytoarchitecture during cardiogenesis and in adult hearts. RESULTS: Tg R299Q 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 postfertilization, Tg R299Q hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca 2+ transient durations. We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the Tg R299Q hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in Tg R299Q . 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 + /Ca 2+ exchanger) inhibition increased Ca 2+ duration and diastolic Ca 2+ in transgenic zebrafish expressing wild-type Prkag2 cDNA but not Tg R299Q hearts, indicating reduced free cytosolic Ca 2+ for NCX-mediated extrusion in Tg R299Q . These findings suggest that enhanced AMPKγ2-myosin interaction may promote myofilament Ca 2 + retention, thereby prolonging Ca 2 + transient duration and action potential duration in the mutant. Notably, the myosin inhibitor mavacamten reduced AMPKγ2-myosin interaction in Tg R299Q hearts, and both mavacamten and vmhcl knockdown rescued the early electrophysiological abnormalities. CONCLUSIONS: The PRKAG2 variant altered cardiac excitability, contractility, and Ca 2+ 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.
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Ge et al. (2026) studied Hypertrophic cardiomyopathy. Prkag2 R299Q variant vs. Wild-type Prkag2 was evaluated on Cardiac electrophysiology and contractile function. The PRKAG2 R299Q variant altered cardiac excitability, contractility, and calcium handling during cardiogenesis independent of glycogen accumulation, driven by enhanced AMPKγ2-myosin interaction.
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