Cardiac contractility, motor function, and cross-bridge kinetics in N47K-RLC mutant mice

Li Wang, Katarzyna Kazmierczak, Chen Ching Yuan, Sunil Yadav, Masataka Kawai, Danuta Szczesna-Cordary

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

We have investigated the physiology and mechanical profiles of skinned papillary muscle fibers from transgenic mice expressing the N47K mutation in the myosin regulatory light chain (RLC), shown to cause hypertrophic cardiomyopathy in humans. The results were compared with wild-type (WT) mice, both expressing the human ventricular RLC. Rate constants of a cross-bridge (XB) cycle were deduced from tension transients induced by sinusoidal length changes during maximal Ca2+ activation, and were studied as a function of MgATP, MgADP, and Pi concentrations. N47K mutant showed slower XB cycles but higher actin-activated ATPase activity compared with WT. Consequently, N47K exhibited larger tension than WT. K0 (ADP association constant) and K4 (equilibrium constant of force generation) were larger in N47K, and K1 (ATP association constant) was slightly larger in N47K vs. WT, demonstrating stronger nucleotide binding and force generation abilities of the mutant, but no changes in rigor acto-myosin binding were observed. Tension per XB was similar among groups, but N47K exhibited more XB distribution in the attached state. Larger values of tension and higher ATPase in N47K suggested that more cross-bridges participated in tension production in the mutant myocardium compared with WT. In vivo analysis of heart function, performed in ~ 12.5-month-old mice by echocardiography and invasive hemodynamics, demonstrated a significant decrease in dP/dtmax–end-diastolic volume relationship, indicating a depression of ventricular contractility in N47K mice. Our findings suggest that the N47K mutation exerts its action through direct alterations of myosin motor function that ultimately result in pathological hypertrophic remodeling in N47K hearts.

Original languageEnglish (US)
Pages (from-to)1897-1913
Number of pages17
JournalFEBS Journal
Volume284
Issue number12
DOIs
StatePublished - Jun 1 2017

Keywords

  • cardiac contractility
  • cardiomyopathy
  • cross-bridge cycle
  • elementary steps
  • myosin regulatory light chain
  • N47K-mouse model
  • sinusoidal analysis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Cardiac contractility, motor function, and cross-bridge kinetics in N47K-RLC mutant mice'. Together they form a unique fingerprint.

  • Cite this