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Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation

Nature Medicine volume 19, pages 640–645 (2013)Cite this article

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Abstract

A shift from oxidative to glycolytic metabolism has been associated with skeletal muscle insulin resistance in type 2 diabetes1,2,3,4,5. However, whether this metabolic switch is deleterious or adaptive remains under debate6,7,8, in part because of a limited understanding of the regulatory network that directs the metabolic and contractile specification of fast-twitch glycolytic muscle. Here we show that Baf60c (also called Smarcd3), a transcriptional cofactor enriched in fast-twitch muscle, promotes a switch from oxidative to glycolytic myofiber type through DEP domain–containing mTOR-interacting protein (Deptor)-mediated Akt activation. Muscle-specific transgenic expression of Baf60c activates a program of molecular, metabolic and contractile changes characteristic of glycolytic muscle. In addition, Baf60c is required for maintaining glycolytic capacity in adult skeletal muscle in vivo. Baf60c expression is significantly lower in skeletal muscle from obese mice compared to that from lean mice. Activation of the glycolytic muscle program by transgenic expression of Baf60c protects mice from diet-induced insulin resistance and glucose intolerance. Further mechanistic studies revealed that Deptor is induced by the Baf60c-Six4 transcriptional complex and mediates activation of Akt and glycolytic metabolism by Baf60c in a cell-autonomous manner. This work defines a fundamental mechanism underlying the specification of fast-twitch glycolytic muscle and illustrates that the oxidative-to-glycolytic metabolic shift in skeletal muscle is potentially adaptive and beneficial in the diabetic state.

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Figure 1: Baf60c promotes fast-twitch glycolytic muscle formation.
Figure 2: Baf60c transgenic mice are protected from diet-induced insulin resistance.
Figure 3: Baf60c activates the Akt pathway through Deptor in a cell-autonomous manner.
Figure 4: Baf60c is required for maintaining glycolytic metabolism in adult skeletal muscle.

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Acknowledgements

We thank S. Gu and C. Rui for assistance in experiments and lab members for discussion. We thank J. Nalbantoglu and P.C. Holland (McGill University) for the gift of the MCK-CAR transgenic mouse strain. We thank the staff at the University of Michigan Transgenic Animal Core for the generation of MCK-Baf60c transgenic mice and D. Sorenson for help with electron microscopy study and acknowledge support from the Michigan Diabetes Research and Training Center (DK020572) and the Nutrition Obesity Research Center (DK089503). This work was supported by the US National Institutes of Health (NIH) (DK095151 and DK077086 to J.D.L.). Z.-X.M. and S.L. are supported by a Postdoctoral Fellowship and a Scientist Development Grant from the American Heart Association, respectively. Clamp studies were performed at the University of Massachusetts Mouse Metabolic Phenotyping Center and were supported by the NIH (U24-DK093000 and R01-DK080756 to J.K.K.). M.O. and Z.Y. are supported by the NIH (AR050429).

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Authors and Affiliations

  1. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    Zhuo-Xian Meng, Siming Li, Lin Wang & Jiandie D Lin

  2. Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USA

    Zhuo-Xian Meng, Siming Li, Lin Wang & Jiandie D Lin

  3. Program in Molecular Medicine and Division of Endocrinology, Department of Medicine, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Hwi Jin Ko, Yongjin Lee, Dae Young Jung & Jason K Kim

  4. Department of Medicine, University of Virginia, Charlottesville, Virginia, USA

    Mitsuharu Okutsu & Zhen Yan

  5. Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA

    Mitsuharu Okutsu & Zhen Yan

  6. Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA

    Mitsuharu Okutsu & Zhen Yan

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  1. Zhuo-Xian Meng
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Contributions

J.D.L. and Z.-X.M. conceived the project and designed research. Z.-X.M., S.L. and L.W. performed the studies. H.J.K., Y.L., D.Y.J. and J.K.K. performed hyperinsulinemic-euglycemic clamp studies. M.O. and Z.Y. performed muscle fiber typing. Z.-X.M. and J.D.L. analyzed the data and wrote the manuscript.

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Correspondence to Jiandie D Lin.

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Meng, ZX., Li, S., Wang, L. et al. Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation. Nat Med 19, 640–645 (2013). https://doi.org/10.1038/nm.3144

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