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 2

HFD and FAs induce MKP-1 overexpression in skeletal muscle.

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HFD and FAs induce MKP-1 overexpression in skeletal muscle. (A) Quadrice...
(A) Quadriceps were isolated from mice fed chow or HFD for the indicated times. Northern blots were performed for MKP-1 and normalized to GAPDH. Shown are normalized mkp-1 mRNA levels for 0–4 weeks of HFD (n = 3–9) or for 16-week chow- or HFD-fed mice (n = 6–7). A representative Northern blot image is shown for the latter. Data are mean ± SEM. (B) C2C12 myoblasts were transfected with MKP-1 promoter–luciferase (–1.4 kb) and TK-Renilla and stimulated for 16 hours with 500 μM palmitate (C16:0), palmitoleate (C16:1n7), eicosapentaenoic acid (C20:5n3), and anisomycin. Data are mean ± SEM of luciferase normalized to Renilla relative to vehicle control (n = 3–7). (C) C2C12 myoblasts were stimulated with 500 μM palmitate for the indicated times, RNA was harvested, and mkp-1 mRNA levels were measured by quantitative real-time RT-PCR and normalized to 18S. Data are mean ± SEM from 3–7 experiments. (D) C2C12 myoblasts were pretreated with the indicated MAPK inhibitors and stimulated with vehicle or 500 μM palmitate for 30 minutes. MKP-1 levels were determined as in C. Data are mean ± SEM from 3–7 experiments. (E) C2C12 myoblasts were stimulated for the indicated times with 500 μM palmitate and immunoblotted for MKP-1 or Erk1/2. Immunoblot is representative of 3 separate experiments. *P < 0.05, **P < 0.005, #P < 0.0005 versus respective control or as otherwise indicated by brackets.