MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice
Rachel J. Roth, Annie M. Le, Lei Zhang, Mario Kahn, Varman T. Samuel, Gerald I. Shulman, Anton M. Bennett
Rachel J. Roth, Annie M. Le, Lei Zhang, Mario Kahn, Varman T. Samuel, Gerald I. Shulman, Anton M. Bennett
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Research Article Metabolism

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

Abstract

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

Authors

Rachel J. Roth, Annie M. Le, Lei Zhang, Mario Kahn, Varman T. Samuel, Gerald I. Shulman, Anton M. Bennett

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Figure 7

Enhanced PGC-1α expression and phosphorylation in mkp-1–/– mice.

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Enhanced PGC-1α expression and phosphorylation in mkp-1–/– mice. (A)...
(A) Nuclear extracts of TA muscle from age-matched mkp-1+/+ and mkp-1–/– mice fed chow or HFD for 16 weeks were immunoblotted for phospho–p38 MAPK or p38 MAPK. Also shown are densitometric measurements for phospho–p38 MAPK levels normalized to total p38 MAPK. Data are mean ± SEM (n = 8–9). (B) Nuclear extracts as in A were immunoblotted for phospho-Ser265 PGC-1α. Lanes were run on the same gel but were noncontiguous (white line). Also shown are densitometric measurements for phospho-Ser265 PGC-1α expression normalized to Lamin-β1. Data are mean ± SEM (n = 4–9). (C) TA muscle was isolated from mkp-1+/+ and mkp-1–/– mice fed chow or HFD for 16 weeks. Muscle lysates were immunoblotted with PGC-1α antibodies, and densitometric measurements for PGC-1α expression were normalized to p38 MAPK. Data are mean ± SEM (n = 6). (D) Under HFD conditions, exposure to FAs increases MKP-1 expression, causing inactivation of nuclear p38 MAPK. Reduced p38 MAPK–mediated phosphorylation of PGC-1α decreases PGC-1α expression. Impaired skeletal muscle PGC-1α function facilitates loss of oxidative myofiber composition. ‡P = 0.05; *P < 0.05; **P < 0.005.