Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain

FASEB J. 2019 Mar;33(3):3152-3166. doi: 10.1096/fj.201801402R. Epub 2018 Oct 26.


Myosin light chain 2 ( MYL2) gene encodes the myosin regulatory light chain (RLC) simultaneously in heart ventricles and in slow-twitch skeletal muscle. Using transgenic mice with cardiac-specific expression of the human R58Q-RLC mutant, we sought to determine whether the hypertrophic cardiomyopathy phenotype observed in papillary muscles (PMs) of R58Q mice is also manifested in slow-twitch soleus (SOL) muscles. Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force that was not observed in the fast-twitch extensor digitorum longus muscles of R58Q vs. wild-type-RLC mice, but mutant animals did not display gross muscle weakness in vivo. Consistent with SOL muscle abnormalities in R58Q vs. wild-type mice, myosin ATPase staining revealed a decreased proportion of fiber type I/type II only in SOL muscles but not in the extensor digitorum longus muscles. The similarities between SOL muscles and PMs of R58Q mice were further supported by quantitative proteomics. Differential regulation of proteins involved in energy metabolism, cell-cell interactions, and protein-protein signaling was concurrently observed in the hearts and SOL muscles of R58Q mice. In summary, even though R58Q expression was restricted to the heart of mice, functional similarities were clearly observed between the hearts and slow-twitch skeletal muscle, suggesting that MYL2 mutated models of hypertrophic cardiomyopathy may be useful research tools to study the molecular, structural, and energetic mechanisms of cardioskeletal myopathy associated with myosin RLC.-Kazmierczak, K., Liang, J., Yuan, C.-C., Yadav, S., Sitbon, Y. H., Walz, K., Ma, W., Irving, T. C., Cheah, J. X., Gomes, A. V., Szczesna-Cordary, D. Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain.

Keywords: R58Q-RLC mutation; X-ray diffraction; cardioskeletal myopathy; muscle proteomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cardiac Myosins / genetics*
  • Cardiac Myosins / physiology*
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / pathology
  • Cardiomyopathy, Hypertrophic / physiopathology*
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Muscle Contraction / genetics
  • Muscle Contraction / physiology
  • Muscle Fibers, Slow-Twitch / pathology
  • Muscle Fibers, Slow-Twitch / physiology*
  • Mutation, Missense
  • Myocardial Contraction / genetics
  • Myocardial Contraction / physiology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myosin Light Chains / genetics*
  • Myosin Light Chains / physiology*
  • Papillary Muscles / pathology
  • Papillary Muscles / physiopathology
  • Proteomics


  • Myosin Light Chains
  • myosin light chain 2
  • Cardiac Myosins