Myosin ATPase Inhibition Relieves the Energetic Burden in Skeletal Myofibres of Patients With Heart Failure With Reduced Ejection Fraction

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) affects millions worldwide and is characterized by chronic cardiac dysfunction, impaired perfusion, altered skeletal muscle energetics, and, thus, exercise intolerance. Efficient therapeutic strategies reducing the burden of the impaired muscle metabolism in HFrEF are currently lacking. Hence, in the present study, we sought to determine whether myosin dynamics and its important role in ATP consumption can constitute a potent biochemical target to optimize skeletal muscle energy usage in HFrEF. METHODS: We used skeletal muscle tissue from 11 human patients with HFrEF and 10 controls with comparable age, sex, and body mass index. We isolated individual myofibres and incubated them ex vivo with varying concentrations of a myosin inhibitor, mavacamten. We then performed 2'-(or-3')-O-(N-Methylanthraniloyl) adenosine 5'-triphosphate chase experiments, together with LC/MS-based proteomics profiling. RESULTS: We observed a distinct regulation of acetyl-lysine sites and higher myosin energy consumption in resting muscle fibers from patients with HFrEF than in controls. When exposed to mavacamten, we found a dose-dependent reduction in myosin ATP consumption in myofibres of patients with HFrEF, reversing the pathological over-consumption. CONCLUSIONS: Skeletal muscle myosin becomes inefficient in HFrEF. Pharmacological inhibition of myosin ATPase activity offers an inventive strategy to lower muscle energy demand and potentially address metabolic disturbances in HFrEF.