Abstract 4367510: Increased Skeletal Muscle Mass Normalizes Cardiac Metabolic Pathways and Attenuates Left Ventricular Hypertrophy and Diastolic Dysfunction in Hypertrophic Cardiomyopathy

Background: Emerging evidence shows that key features of HCM—left-ventricular hypertrophy (LVH), diastolic dysfunction, and impaired cardiac energetics—are linked to systemic metabolic derangements such as insulin resistance. Because skeletal muscle mediates ~80% of post-prandial glucose disposal and ~25% of basal metabolic rate, even modest increases in muscle mass can markedly enhance whole-body insulin sensitivity. Moreover, dysregulated branched-chain amino acid (BCAA) catabolism yields intermediates that blunt insulin signaling and drive pathological cardiac growth, placing BCAA metabolism at the nexus of HCM and systemic insulin resistance. Hypothesis: Pharmacologically induced skeletal-muscle hypertrophy—achieved by myostatin/activin blockade with the murine anti-ActRII antibody CDD866—increases muscle demand for glucose and BCAAs, thereby reducing insulin resistance, restoring cardiac metabolic flexibility, and ameliorating established HCM features. Methods: Male R403Q-HCM mice (24 wk) received CDD866 or isotype control (20 mg/kg s.c. q3d) for 4 wk. End-point tests included echoMRI body composition, skeletal-muscle weights, echocardiography, oral glucose tolerance test (oGTT), grip strength, exercise tolerance test, and LV transcriptomics. Results: CDD866 produced robust muscle hypertrophy (+20% lean mass; body weight +12%; individual muscles +44–87%) and lowered oGTT AUC, indicating improved insulin sensitivity. LVH was reduced (LV wall thickness −9%), diastolic indices improved (E/A and Em ↑), and cardiac gene expression reverted toward WT with up-regulation of fatty-acid oxidation, BCAA catabolism, and mitochondrial oxidative pathways. Functional capacity increased (grip strength +35%, treadmill endurance +29%). Conclusions: Pharmacologic myostatin/activin blockade enlarges skeletal muscle, improves insulin sensitivity, restores cardiac metabolic flexibility, reduces LV hypertrophy, and enhances diastolic function in established HCM. Augmenting muscle mass therefore emerges as a promising adjunct therapy for HCM, especially in insulin-resistant states.