MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice.
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.
Roth
Rachel J
RJ
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
Le
Annie M
AM
Zhang
Lei
L
Kahn
Mario
M
Samuel
Varman T
VT
Shulman
Gerald I
GI
Bennett
Anton M
AM
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017931:DNA Primers; D004041:Dietary Fats; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse