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

作者：Roth Rachel J; Le Annie M; Zhang Lei; Kahn Mario; Samuel Varman T; Shulman Gerald I; Bennett Anton M^*

来源：Journal of Clinical Investigation, 2009, 119(12): 3817-3829.

DOI：10.1172/JCI39054

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 PPAR gamma coactivator 1 alpha (PGC-1 alpha) plays a central role in maintaining levels of oxidative myofibers in skeletal muscle. Indeed, loss of PGC-1 alpha 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-1 alpha on sites that promoted its stability. Consistent with this, MKP-1-deficient mice expressed higher levels of PGC-1 alpha 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.

• 出版日期2009-12