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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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 1

Resistance to diet-induced obesity and increased energy expenditure in mkp-1–/– mice.

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Resistance to diet-induced obesity and increased energy expenditure in m...
(A) 129/J mkp-1+/– mice were backcrossed to wild-type C57BL6/J mice for 8 generations. At weaning, backcrossed mkp-1+/+ and mkp-1–/– mice were placed on a HFD, and weights were monitored weekly for 16 weeks. Data are mean ± SEM (n = 8–16 per time point). (B) mkp-1+/+ and mkp-1–/– mice were subjected to proton magnetic resonance spectroscopy analysis after 16 weeks of HFD feeding (n = 6–8). Data are mean ± SEM. (C–F) mkp-1+/+ and mkp-1–/– mice were subjected to open circuit calorimetry after 16 weeks of HFD feeding, and (C) oxygen consumption, (D) energy expenditure, (E) food consumption, and (F) locomotor activity were recorded. Data in C–F are mean ± SEM (n = 6–8). *P < 0.05, **P < 0.005, #P < 0.0005 versus mkp-1+/+.