Cardiac myosin inhibitor improves skeletal muscle contractility in Laing myopathy

• 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 mutationModification soudaine et transmissible du matériel génétique. Elle peut être spontanée ou induite par des agents dits » mutagènes » (radiations, produits toxiques,…). 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 ATPmolécule représentant la principale forme d’énergie immédiatement utilisable par la cellule pour son fonctionnement..
• 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