Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5

J Clin Invest. 2013 May;123(5):2064-77. doi: 10.1172/JCI64375. Epub 2013 Apr 1.

Abstract

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in dystrophin. The degree of functional deterioration in muscle stem cells determines the severity of DMD. The mitogen-activated protein kinases (MAPKs), which are inactivated by MAPK phosphatases (MKPs), represent a central signaling node in the regulation of muscle stem cell function. Here we show that the dual-specificity protein phosphatase DUSP10/MKP-5 negatively regulates muscle stem cell function in mice. MKP-5 controlled JNK to coordinate muscle stem cell proliferation and p38 MAPK to control differentiation. Genetic loss of Mkp5 in mice improved regenerative myogenesis and dystrophin-deficient mdx mice lacking Mkp5 exhibited an attenuated dystrophic muscle phenotype. Hence, enhanced promyogenic MAPK activity preserved muscle stem cell function even in the absence of dystrophin and ultimately curtailed the pathogenesis associated with DMD. These results identify MKP-5 as an essential negative regulator of the promyogenic actions of the MAPKs and suggest that MKP-5 may serve as a target to promote muscle stem cell function in the treatment of degenerative skeletal muscle diseases.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation
  • Crosses, Genetic
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • Dystrophin / genetics
  • Female
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / pathology
  • Muscles / cytology
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / metabolism*
  • Mutation
  • Regeneration*
  • Stem Cells / cytology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Dystrophin
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Dusp10 protein, mouse
  • Dual-Specificity Phosphatases