Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics

Gerrie P. Farman, Priya Muthu, Katarzyna Kazmierczak, Danuta Szczesna-Cordary, Jeffrey R. Moore

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1471-1477
Number of pages7
JournalJournal of applied physiology (Bethesda, Md. : 1985)
Volume117
Issue number12
DOIs
StatePublished - Dec 15 2014

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Familial Hypertrophic Cardiomyopathy
Myosin Light Chains
Myosins
Mechanics
Mutation
Hypertrophic Cardiomyopathy
Myosin Heavy Chains
pioglitazone
Cardiac Myosins
Light
Actin Cytoskeleton
Actins
Swine

Keywords

  • cardiac ventricular myosin
  • hypertrophic cardiomyopathy
  • in vitro motility
  • myosin regulatory light chain

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics. / Farman, Gerrie P.; Muthu, Priya; Kazmierczak, Katarzyna; Szczesna-Cordary, Danuta; Moore, Jeffrey R.

In: Journal of applied physiology (Bethesda, Md. : 1985), Vol. 117, No. 12, 15.12.2014, p. 1471-1477.

Research output: Contribution to journalArticle

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