- Mavacamten is a small molecule inhibitor of myosin ATPase activity, used in hypertrophic cardiomyopathies, which targets myocardial hypercontractility by reducing the number of myosin heads in a disordered relaxed configuration in favor of a predominantly super-relaxed state as in normal muscle.
- Mouse models carrying the MYH7 mutation most common in distal Laing myopathy display muscle hypercontractility and severe fatigue. Study of the muscle of these mice or of individuals with Laing myopathy shows a disordered relaxed state of the preponderant myosin heads, leading to overconsumption of ATP.
- Administration of MYK-581, a myosin inhibitor analogous to mavacamten, restored the physiological ratio of disordered relaxed configuration to super-relaxed state of the myosin heads, and improved the endurance and running ability of the mice.
A Laing distal myopathy-associated proline substitution in the β-myosin rod perturbs myosin cross-bridging activity. Buvoli M, Wilson GC, Buvoli A et al. J Clin Invest. 2024 May 1;134(9):e172599.
A therapeutic leap: how myosin inhibitors moved from cardiac interventions to skeletal muscle myopathy solutions. Bogomolovas J, Chen J. J Clin Invest. 2024 May 1;134(9):e179958
