Cardiac and skeletal actin substrates uniquely tune cardiac myosin strain-dependent mechanics.

ABSTRACT: Cardiac ventricular myosin (?mys) translates actin by transducing ATP free energy into mechanical work during muscle contraction. Unitary ?mys translation of actin is the step-size. In vitro and in vivo ?mys regulates contractile force and velocity autonomously by remixing three different step-sizes with adaptive stepping frequencies. Cardiac and skeletal actin isoforms have a specific 1 : 4 stoichiometry in normal adult human ventriculum. Human adults with inheritable hypertrophic cardiomyopathy (HCM) upregulate skeletal actin in ventriculum probably compensating the diseased muscle's inability to meet demand by adjusting ?mys force-velocity characteristics. ?mys force-velocity characteristics were compared for skeletal versus cardiac actin substrates using ensemble in vitro motility and single myosin assays. Two competing myosin strain-sensitive mechanisms regulate step-size choices dividing single ?mys mechanics into low- and high-force regimes. The actin isoforms alter myosin strain-sensitive regulation such that onset of the high-force regime, where a short step-size is a large or major contributor, is offset to higher loads probably by the unique cardiac essential light chain (ELC) N-terminus/cardiac actin contact at Glu6/Ser358. It modifies ?mys force-velocity by stabilizing the ELC N-terminus/cardiac actin association. Uneven onset of the high-force regime for skeletal versus cardiac actin modulates force-velocity characteristics as skeletal/cardiac actin fractional content increases in diseased muscle.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC6282072 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature