A Laing distal myopathy-associated proline substitution in the β-myosin rod perturbs myosin cross-bridging activity.

ABSTRACT: Proline substitutions within the coiled-coil rod region of the β-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin-myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractil

SUBMITTER: Buvoli M 

PROVIDER: S-EPMC11060730 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature