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MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice
Rachel J. Roth, … , Gerald I. Shulman, Anton M. Bennett
Rachel J. Roth, … , Gerald I. Shulman, Anton M. Bennett
Published November 16, 2009
Citation Information: J Clin Invest. 2009;119(12):3817-3829. https://doi.org/10.1172/JCI39054.
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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.