Cell Stem Cell
Volume 16, Issue 2, 5 February 2015, Pages 171-183
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Article
The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells

https://doi.org/10.1016/j.stem.2014.12.004Get rights and content
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Highlights

  • Satellite cells undergo a metabolic shift to glycolysis during activation

  • Decreased NAD+ reduces SIRT1 activity and promotes H4K16 acetylation

  • Ablation of SIRT1 in satellite cells leads to premature differentiation

  • SIRT1 activity loss in muscles disrupts gene expression, development, and regeneration

Summary

Stem cells undergo a shift in metabolic substrate utilization during specification and/or differentiation, a process that has been termed metabolic reprogramming. Here, we report that during the transition from quiescence to proliferation, skeletal muscle stem cells experience a metabolic switch from fatty acid oxidation to glycolysis. This reprogramming of cellular metabolism decreases intracellular NAD+ levels and the activity of the histone deacetylase SIRT1, leading to elevated H4K16 acetylation and activation of muscle gene transcription. Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in SCs. Moreover, mice with muscle-specific inactivation of the SIRT1 deacetylase domain display reduced myofiber size, impaired muscle regeneration, and derepression of muscle developmental genes. Overall, these findings reveal how metabolic cues can be mechanistically translated into epigenetic modifications that regulate skeletal muscle stem cell biology.

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Present address: Stem Cell Metabolism and Regenerative Medicine Group, Basic & Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Melbourne, VIC, 3010 Australia