Open AccessImpact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics
Author(s) -
Gerrie P. Farman,
Priya Muthu,
Katarzyna Kaźmierczak,
Danuta SzczesnaCordary,
Jeffrey R. Moore
Publication year - 2014
Publication title -
journal of applied physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.253
H-Index - 229
eISSN - 8750-7587
pISSN - 1522-1601
DOI - 10.1152/japplphysiol.00798.2014
Subject(s) - hypertrophic cardiomyopathy , molecular mechanics , myosin , bridge (graph theory) , rlc circuit , cardiomyopathy , medicine , cardiology , chemistry , physics , biology , microbiology and biotechnology , molecular dynamics , heart failure , computational chemistry , quantum mechanics , voltage , capacitor
Familial hypertrophic cardiomyopathy (HCM) is associated with mutations in sarcomeric proteins, including the myosin regulatory light chain (RLC). Here we studied the impact of three HCM mutations located in the NH2 terminus of the RLC on the molecular mechanism of β-myosin heavy chain (MHC) cross-bridge mechanics using the in vitro motility assay. To generate mutant β-myosin, native RLC was depleted from porcine cardiac MHC and reconstituted with mutant (A13T, F18L, and E22K) or wild-type (WT) human cardiac RLC. We characterized the mutant myosin force and motion generation capability in the presence of a frictional load. Compared with WT, all three mutants exhibited reductions in maximal actin filament velocity when tested under low or no frictional load. The actin-activated ATPase showed no significant difference between WT and HCM-mutant-reconstituted myosins. The decrease in velocity has been attributed to a significantly increased duty cycle, as was measured by the dependence of actin sliding velocity on myosin surface density, for all three mutant myosins. These results demonstrate a mutation-induced alteration in acto-myosin interactions that may contribute to the pathogenesis of HCM.