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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Accession codes


Gene Expression Omnibus


  1. 1

    Kelley, D.E., He, J., Menshikova, E.V. & Ritov, V.B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).

    CAS  Article  Google Scholar 

  2. 2

    Lillioja, S. et al. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J. Clin. Invest. 80, 415–424 (1987).

    CAS  Article  Google Scholar 

  3. 3

    Mootha, V.K. et al. PGC-1α–responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

    CAS  Article  Google Scholar 

  4. 4

    Patti, M.E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc. Natl. Acad. Sci. USA 100, 8466–8471 (2003).

    CAS  Article  Google Scholar 

  5. 5

    Petersen, K.F., Dufour, S., Befroy, D., Garcia, R. & Shulman, G.I. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664–671 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Muoio, D.M. Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim. Biophys. Acta 1801, 281–288 (2010).

    CAS  Article  Google Scholar 

  7. 7

    Turner, N. & Heilbronn, L.K. Is mitochondrial dysfunction acause of insulin resistance? Trends Endocrinol. Metab. 19, 324–330 (2008).

    CAS  Article  Google Scholar 

  8. 8

    Muoio, D.M. & Neufer, P.D. Lipid-induced mitochondrial stress and insulin action in muscle. Cell Metab. 15, 595–605 (2012).

    CAS  Article  Google Scholar 

  9. 9

    Schiaffino, S. & Reggiani, C. Fiber types in mammalian skeletal muscles. Physiol. Rev. 91, 1447–1531 (2011).

    CAS  Article  Google Scholar 

  10. 10

    Bassel-Duby, R. & Olson, E.N. Signaling pathways in skeletal muscle remodeling. Annu. Rev. Biochem. 75, 19–37 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    CAS  Article  Google Scholar 

  12. 12

    Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).

    CAS  Article  Google Scholar 

  13. 13

    Lavery, G.G. et al. Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy. J. Biol. Chem. 283, 8453–8461 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Wu, J.I., Lessard, J. & Crabtree, G.R. Understanding the words of chromatin regulation. Cell 136, 200–206 (2009).

    CAS  Article  Google Scholar 

  15. 15

    Choi, C.S. et al. Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc. Natl. Acad. Sci. USA 105, 19926–19931 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Miura, S., Kai, Y., Ono, M. & Ezaki, O. Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1α down-regulates GLUT4 mRNA in skeletal muscles. J. Biol. Chem. 278, 31385–31390 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Gordon, B.A., Benson, A.C., Bird, S.R. & Fraser, S.F. Resistance training improves metabolic health in type 2 diabetes: a systematic review. Diabetes Res. Clin. Pract. 83, 157–175 (2009).

    CAS  Article  Google Scholar 

  18. 18

    LeBrasseur, N.K., Walsh, K. & Arany, Z. Metabolic benefits of resistance training and fast glycolytic skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 300, E3–E10 (2011).

    CAS  Article  Google Scholar 

  19. 19

    Izumiya, Y. et al. Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 7, 159–172 (2008).

    CAS  Article  Google Scholar 

  20. 20

    Peterson, T.R. et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873–886 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Niro, C. et al. Six1 and Six4 gene expression is necessary to activate the fast-type muscle gene program in the mouse primary myotome. Dev. Biol. 338, 168–182 (2010).

    CAS  Article  Google Scholar 

  22. 22

    Civitarese, A.E. et al. Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL. Cell Metab. 11, 412–426 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Nalbantoglu, J. et al. Muscle-specific overexpression of the adenovirus primary receptor CAR overcomes low efficiency of gene transfer to mature skeletal muscle. J. Virol. 75, 4276–4282 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Forcales, S.V. et al. Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex. EMBO J. 31, 301–316 (2012).

    CAS  Article  Google Scholar 

  25. 25

    Lickert, H. et al. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development. Nature 432, 107–112 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Li, S. et al. Genome-wide coactivation analysis of PGC-1α identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab. 8, 105–117 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Banks, A.S. et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 8, 333–341 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Narkar, V.A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).

    CAS  Article  Google Scholar 

  29. 29

    Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612–622 (2011).

    CAS  Article  Google Scholar 

  30. 30

    Akpan, I. et al. The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. Int. J. Obes. (Lond.) 33, 1265–1273 (2009).

    CAS  Article  Google Scholar 

  31. 31

    Sternberg, E.A. et al. Identification of upstream and intragenic regulatory elements that confer cell-type–restricted and differentiation-specific expression on the muscle creatine kinase gene. Mol. Cell Biol. 8, 2896–2909 (1988).

    CAS  Article  Google Scholar 

  32. 32

    Waters, R.E., Rotevatn, S., Li, P., Annex, B.H. & Yan, Z. Voluntary running induces fiber type-specific angiogenesis in mouse skeletal muscle. Am. J. Physiol. Cell Physiol. 287, C1342–C1348 (2004).

    CAS  Article  Google Scholar 

  33. 33

    Dunn, S.E. & Michel, R.N. Coordinated expression of myosin heavy chain isoforms and metabolic enzymes within overloaded rat muscle fibers. Am. J. Physiol. 273, C371–C383 (1997).

    CAS  Article  Google Scholar 

  34. 34

    Chen, H. et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141, 280–289 (2010).

    CAS  Article  Google Scholar 

  35. 35

    Kim, J.K. et al. PKC-θ knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004).

    CAS  Article  Google Scholar 

  36. 36

    Gan, Z. et al. The nuclear receptor PPARβ/δ programs muscle glucose metabolism in cooperation with AMPK and MEF2. Genes Dev. 25, 2619–2630 (2011).

    CAS  Article  Google Scholar 

  37. 37

    Aragonés, J. et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat. Genet. 40, 170–180 (2008).

    Article  Google Scholar 

  38. 38

    Hughes, S.D., Quaade, C., Johnson, J.H., Ferber, S. & Newgard, C.B. Transfection of AtT-20ins cells with GLUT-2 but not GLUT-1 confers glucose-stimulated insulin secretion. Relationship to glucose metabolism. J. Biol. Chem. 268, 15205–15212 (1993).

    CAS  PubMed  Google Scholar 

Download references


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).

Author information




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.

Corresponding author

Correspondence to Jiandie D Lin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1 and 2 (PDF 844 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing