Year: 2026
Type: editorial
Abstract: Metabolic dysregulation is a hallmark of many cardiomyopathies, including hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, affecting approximately 1 in 500 individuals worldwide 1 .Despite advances in disease management, no curative therapy is currently available for protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2)-related HCM, highlighting the need to identify mechanisms and novel therapeutic targets to improve clinical outcomes in HCM patients.In this issue of Circulation Research, Ge et al 2 demonstrate that the pathogenic HCMassociated PRKAG2 R299Q variant induces cardiac electrical abnormalities beginning in early cardiogenesis, preceding the onset of excessive glycogen accumulation.Moreover, the authors demonstrate a direct interaction between AMP-activated protein kinase gamma-2 (AMPKγ2) and myosin, which is further enhanced by the PRKAG2 R299Q variant.Pharmacological inhibition of myosin with the FDA-approved cardiac myosin inhibitor mavacamten partially corrected the electrical abnormalities in PRKAG2 R299Q transgenic (Tg R299Q ) zebrafish.HCM is characterized by pathological thickening and stiffening of the ventricular myocardium.It is well known that HCM hearts exhibit metabolic dysfunction, including a switch from fatty acid oxidation toward greater reliance on glucose metabolism, accompanied by alterations in amino acid and ketone body metabolism 3 .In addition, in HCM, cardiac myosin shifts from the energy-conserving super-relaxed state to a more active conformation, leading to excessive cross-bridge formation, hypercontractility, and increased energy demand 4 .However, how metabolic remodeling is linked to the cardiac muscle phenotype, and whether it represents a cause or consequence of HCM, remains unclear.AMPK is a master regulator of cellular energy homeostasis, with its γ2 regulatory subunit encoded by the human PRKAG2 gene.The γ2 subunit contains nucleotide-
Source: Circulation Research
Institution: University of Colorado Anschutz
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7202408805