Acute heart failure with cardiomyocyte atrophy induced in adult mice by ablation of cardiac myosin light chain kinase

Cardiovasc Res. 2016 Jul 1;111(1):34-43. doi: 10.1093/cvr/cvw069. Epub 2016 Mar 29.


Aims: Under pressure overload, initial adaptive hypertrophy of the heart is followed by cardiomyocyte elongation, reduced contractile force, and failure. The mechanisms governing the transition to failure are not fully understood. Pressure overload reduced cardiac myosin light chain kinase (cMLCK) by ∼80% within 1 week and persists. Knockdown of cMLCK in cardiomyocytes resulted in reduced cardiac contractility and sarcomere disorganization. Thus, we hypothesized that acute reduction of cMLCK may be causative for reduced contractility and cardiomyocyte remodelling during the transition from compensated to decompensated cardiac hypertrophy.

Methods and results: To mimic acute cMLCK reduction in adult hearts, the floxed-Mylk3 gene that encodes cMLCK was inducibly ablated in Mylk3(flox/flox)/merCremer mice (Mylk3-KO), and compared with two control mice (Mylk3(flox/flox) and Mylk3(+/+)/merCremer) following tamoxifen injection (50 mg/kg/day, 2 consecutive days). In Mylk3-KO mice, reduction of cMLCK protein was evident by 4 days, with a decline to below the level of detection by 6 days. By 7 days, these mice exhibited heart failure, with reduction of fractional shortening compared with those in two control groups (19.8 vs. 28.0% and 27.7%). Severely convoluted cardiomyocytes with sarcomeric disorganization, wavy fibres, and cell death were demonstrated in Mylk3-KO mice. The cardiomyocytes were also unable to thicken adaptively to pressure overload.

Conclusion: Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization.

Keywords: Heart failure; Inducible knockout; Kinase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Adaptation, Physiological
  • Animals
  • Atrophy
  • Calcium Signaling
  • Cardiac Myosins / metabolism
  • Cardiomegaly / enzymology*
  • Cardiomegaly / genetics
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Genetic Predisposition to Disease
  • Heart Failure / enzymology*
  • Heart Failure / genetics
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Contraction
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Myosin Light Chains / metabolism
  • Myosin-Light-Chain Kinase / deficiency*
  • Myosin-Light-Chain Kinase / genetics
  • Phenotype
  • Phosphorylation
  • Sarcomeres / enzymology
  • Sarcomeres / pathology
  • Time Factors
  • Ventricular Function, Left*
  • Ventricular Remodeling*


  • Myosin Light Chains
  • myosin light chain 2
  • Myosin-Light-Chain Kinase
  • cardiac myosin light chain kinase, mouse
  • Cardiac Myosins