MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice

J Clin Invest. 2009 Dec;119(12):3817-29. doi: 10.1172/JCI39054. Epub 2009 Nov 16.


Oxidative myofibers, also known as slow-twitch myofibers, help maintain the metabolic health of mammals, and it has been proposed that decreased numbers correlate with increased risk of obesity. The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) plays a central role in maintaining levels of oxidative myofibers in skeletal muscle. Indeed, loss of PGC-1alpha expression has been linked to a reduction in the proportion of oxidative myofibers in the skeletal muscle of obese mice. MAPK phosphatase-1 (MKP-1) is encoded by mkp-1, a stress-responsive immediate-early gene that dephosphorylates MAPKs in the nucleus. Previously we showed that mice deficient in MKP-1 have enhanced energy expenditure and are resistant to diet-induced obesity. Here we show in mice that excess dietary fat induced MKP-1 overexpression in skeletal muscle, and that this resulted in reduced p38 MAPK-mediated phosphorylation of PGC-1alpha on sites that promoted its stability. Consistent with this, MKP-1-deficient mice expressed higher levels of PGC-1alpha in skeletal muscle than did wild-type mice and were refractory to the loss of oxidative myofibers when fed a high-fat diet. Collectively, these data demonstrate an essential role for MKP-1 as a regulator of the myofiber composition of skeletal muscle and suggest a potential role for MKP-1 in metabolic syndrome.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • DNA Primers / genetics
  • Dietary Fats / administration & dosage
  • Dual Specificity Phosphatase 1 / deficiency
  • Dual Specificity Phosphatase 1 / genetics
  • Dual Specificity Phosphatase 1 / metabolism*
  • Energy Metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Muscle Fibers, Slow-Twitch / metabolism*
  • Muscle Fibers, Slow-Twitch / pathology
  • Obesity / etiology
  • Obesity / metabolism*
  • Obesity / pathology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Trans-Activators / metabolism
  • Transcription Factors
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • DNA Primers
  • Dietary Fats
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factors
  • p38 Mitogen-Activated Protein Kinases
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse