A Murinized Bimagrumab Analogue Increases Skeletal Muscle Mass and Improves Cardiometabolic Remodelling in Experimental Hypertrophic Cardiomyopathy.

Abstract

BACKGROUND: Hypertrophic cardiomyopathy (HCM) involves left ventricular hypertrophy and metabolic dysfunction. Given the role of skeletal muscle in systemic metabolism, we investigated whether activin type II receptor inhibition with CDD866, a murinized bimagrumab analogue that induces skeletal muscle hypertrophy, improves physical performance and cardiometabolic remodelling in established HCM. METHODS: Twenty-four-week-old male mice harbouring the cardiac myosin R403Q mutation received CDD866 or isotype antibody (20 mg/kg subcutaneously every 3 days) for 4 weeks; wild-type (WT) littermates received isotype antibody. Assessments included body composition, muscle imaging and histology, grip strength, treadmill exercise, glucose tolerance, echocardiography, cardiac histopathology, myocardial substrate oxidation by 13C nuclear magnetic resonance in isolated beating hearts and cardiac transcriptomics and proteomics. Values are mean ± SEM. RESULTS: Compared with R403Q placebo, CDD866 increased lean mass (22.5 ± 0.6 vs. 18.7 ± 0.5 g; p < 0.001), grip strength (135.3 ± 3.4 vs. 99.9 ± 4.3 cN; p < 0.0001) and treadmill distance (99.8 ± 1.7 vs. 77.2 ± 3.2 m; p < 0.0001). Hindlimb muscle volume increased by 24 ± 8% (p < 0.05), and individual muscle weights increased by 44%-87% (all p < 0.0001). CDD866 reduced total left ventricular wall thickness (1.80 ± 0.03 vs. 1.98 ± 0.03 mm; p < 0.001) and improved E/A ratio (1.31 ± 0.04 vs. 0.99 ± 0.04; p < 0.001) and early diastolic mitral annular velocity (18.6 ± 0.7 vs. 14.0 ± 0.7 mm/s; p < 0.01). Cardiomyocyte cross-sectional area and myocardial fibrosis decreased by 32 ± 6% (p < 0.0001) and 69 ± 31% (p < 0.01), respectively. Glucose tolerance was impaired in R403Q mice versus WT (p < 0.01), with a nonsignificant reduction in AUC following CDD866 (p = 0.223). CDD866 increased the fractional contribution of fatty acids to myocardial oxidative metabolism (0.66 ± 0.02 vs. 0.38 ± 0.05; p < 0.01) and reduced 13C-lactate output (15.3 ± 2.5 vs. 40.2 ± 3.8 nmol/min; p < 0.001). Consistent with these measurements, cardiac RNA-seq GSEA showed HCM-associated suppression and CDD866-associated enrichment of fatty acid oxidation, pyruvate metabolism, the tricarboxylic acid cycle, oxidative phosphorylation, ATP synthesis and branched-chain amino acid catabolism (all FDR q < 0.05). Integrated transcriptomic and proteomic upstream regulator predictions provided an exploratory regulatory context for these metabolic findings. CONCLUSIONS: CDD866 increased skeletal muscle mass and performance alongside improvements in cardiac remodelling, diastolic function and myocardial metabolism in established experimental HCM. Activin receptor inhibition offers a promising therapeutic avenue for HCM.

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