Mavacamten facilitates myosin head ON ‐to‐ OFF transitions and shortens thin filament length in relaxed mouse skeletal muscle

The first-in-its-class cardiac drug mavacamten shifts myosin heads towards a structurally inactive position where they lay along the helical tracks of the thick filament. However, mavacamten is not completely specific to cardiac myosin and can also affect skeletal muscle myosin, an important consideration since mavacamten is administered orally and so will also be present in skeletal tissue. Indeed, emerging clinical reports indicate mavacamten-induced generalized skeletal myopathy in elderly patients. These findings raise important safety considerations for vulnerable populations, while also highlighting the drug's potential as a novel basic research tool to probe thick filament regulation and myosin head availability in skeletal muscle mechanics experiments. Using small-angle X-ray diffraction (MyoXRD), we tracked these structural changes in the thick filaments of relaxed muscle before and after mavacamten incubation and found that mavacamten treatment reduced the proportion of myosin heads in an active state but did not eliminate length-dependent structural changes in passive muscle that are linked to changes in contraction performance upon activation, demonstrating similar effects to those observed in cardiac muscle. These findings provide valuable insights for the potential use of mavacamten as a tool to study skeletal muscle contraction across striated muscle.