Brief Communication | Published:

Carbon metabolism–mediated myogenic differentiation

Nature Chemical Biology volume 6, pages 202204 (2010) | Download Citation

Abstract

The role of nutrients and metabolism in cellular differentiation is poorly understood. Using RNAi screening, metabolic profiling and small-molecule probes, we discovered that the knockdown of three metabolic enzymes—phosphoglycerate kinase (Pgk1), hexose-6-phosphate dehydrogenase (H6pd) and ATP citrate lyase (Acl)—induces differentiation of mouse C2C12 myoblasts even in the presence of mitogens. These enzymes and the pathways they regulate provide new targets for the control of myogenic differentiation in myoblasts and rhabdomyosarcoma cells.

  • Compound C3H7O7P

    3-Phosphoglycerate

  • Compound C3H5O6P

    Phosphoenolpyruvate

  • Compound C26H45NO6S

    Tauroursodeoxycholic acid

  • Compound C26H42NO5-

    Glycochenodeoxycholic acid

  • Compound C62H111N11O12

    Cyclosporin A

  • Compound C17H22N2O3

    Trichostatin A

  • Compound C23H36O7

    Pravastatin

  • Compound C33H35FN2O5

    Atorvastatin

  • Compound C24H26FNO4

    Fluvastatin

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Cell Cycle 7, 885–891 (2008).

  2. 2.

    & Dev. Biol. 246, 2–13 (2002).

  3. 3.

    & Differentiation 7, 159–166 (1977).

  4. 4.

    , & Biochim. Biophys. Acta 1397, 102–117 (1998).

  5. 5.

    et al. Science 313, 1137–1140 (2006).

  6. 6.

    et al. J. Biol. Chem. 283, 8453–8461 (2008).

  7. 7.

    , & FASEB J. 21, 2994–3003 (2007).

  8. 8.

    et al. EMBO J. 22, 3825–3832 (2003).

  9. 9.

    & Dev. Biol. 266, 1–16 (2004).

  10. 10.

    & Science 324, 1021–1022 (2009).

  11. 11.

    et al. J. Biol. Chem. 10, 9557–9564 (2004).

  12. 12.

    & Oncologist 4, 34–44 (1999).

  13. 13.

    et al. FASEB J. 18, 403–405 (2004).

  14. 14.

    , & Biochem. Int. 20, 267–274 (1990).

  15. 15.

    , & Endocrinology 146, 2539–2543 (2005).

  16. 16.

    et al. Cancer Cell 8, 311–321 (2005).

Download references

Acknowledgements

We thank the RNAi Consortium for shRNAs and the following members of the RNAi platform of the Broad Institute for their scientific advising: A. Derr, J. Grenier, S. Silver, G. Cowley and O. Alkan. We also thank S. Carr, R. Wei, E. Yang and members of the Broad Institute metabolic profiling platform for scientific advice and analysis of metabolite extracts, and J. Nisbet of Children's Hospital Boston for thoughtful comments. This work was supported in part by US Department of Defense Breast Cancer Innovator Award #BC074986 (to D.E.I.) and US National Institute of General Medical Sciences grant 38627 (to S.L.S.). S.L.S. is an investigator with the Howard Hughes Medical Institute. A.L.B. was supported in part by the US National Science Foundation.

Author information

Author notes

    • Abigail L Bracha
    •  & Arvind Ramanathan

    These authors contributed equally to this work.

Affiliations

  1. Vascular Biology Program, Department of Pathology and Department of Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Abigail L Bracha
    •  & Donald E Ingber
  2. Howard Hughes Medical Institute at the Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Arvind Ramanathan
    •  & Stuart L Schreiber
  3. Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Alberta, Canada.

    • Sui Huang
  4. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts, USA.

    • Donald E Ingber
  5. Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA.

    • Donald E Ingber
  6. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Stuart L Schreiber

Authors

  1. Search for Abigail L Bracha in:

  2. Search for Arvind Ramanathan in:

  3. Search for Sui Huang in:

  4. Search for Donald E Ingber in:

  5. Search for Stuart L Schreiber in:

Contributions

A.L.B. designed and performed the RNAi screen, all validation experiments, quantitative RT-PCR, generation of stable cell lines and studies on cyclosporin, cholesterol and trichostatin. A.R. designed and performed metabolite experiments and the histone acetylation study. S.L.S. participated in the design of the overall study. S.H., D.E.I. and S.L.S. contributed to the preparation of the manuscript. D.E.I. and A.L.B. conceived of the idea for this study. All authors interpreted data, commented on results and participated in writing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Arvind Ramanathan or Stuart L Schreiber.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1-3, Supplementary Tables 1 and 2, and Supplementary Methods

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchembio.301

Further reading