Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo

Peiguo Ding, Jian Huang, Pavan K. Battiprolu, Joseph A Hill, Kristine E Kamm, James T Stull

Research output: Contribution to journalArticle

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Abstract

In contrast to studies on skeletal and smooth muscles, the identity of kinases in the heart that are important physiologically for direct phosphorylation of myosin regulatory light chain (RLC) is not known. A Ca 2+/calmodulin-activated myosin light chain kinase is expressed only in cardiac muscle (cMLCK), similar to the tissue-specific expression of skeletal muscle MLCK and in contrast to the ubiquitous expression of smooth muscle MLCK. We have ablated cMLCK expression in male mice to provide insights into its role in RLC phosphorylation in normally contracting myocardium. The extent of RLC phosphorylation was dependent on the extent of cMLCK expression in both ventricular and atrial muscles. Attenuation of RLC phosphorylation led to ventricular myocyte hypertrophy with histological evidence of necrosis and fibrosis. Echocardiography showed increases in left ventricular mass as well as end-diastolic and end-systolic dimensions. Cardiac performance measured as fractional shortening decreased proportionally with decreased cMLCK expression culminating in heart failure in the setting of no RLC phosphorylation. Hearts from female mice showed similar responses with loss of cMLCK associated with diminished RLC phosphorylation and cardiac hypertrophy. Isoproterenol infusion elicited hypertrophic cardiac responses in wild type mice. In mice lacking cMLCK, the hypertrophic hearts showed no additional increases in size with the isoproterenol treatment, suggesting a lack of RLC phosphorylation blunted the stress response. Thus, cMLCK appears to be the predominant protein kinase that maintains basal RLC phosphorylation that is required for normal physiological cardiac performance in vivo.

Original languageEnglish (US)
Pages (from-to)40819-40829
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number52
DOIs
StatePublished - Dec 24 2010

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Cardiac Myosins
Myosin-Light-Chain Kinase
Myosin Light Chains
Phosphorylation
Light
Muscle
Isoproterenol
Smooth Muscle
Myocardium
Skeletal Muscle
Echocardiography
Cardiomegaly
Calmodulin
Protein Kinases
Muscle Cells
Hypertrophy
Fibrosis
Necrosis
Phosphotransferases
Heart Failure

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo. / Ding, Peiguo; Huang, Jian; Battiprolu, Pavan K.; Hill, Joseph A; Kamm, Kristine E; Stull, James T.

In: Journal of Biological Chemistry, Vol. 285, No. 52, 24.12.2010, p. 40819-40829.

Research output: Contribution to journalArticle

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