ATP Citrate Lyase Regulates Myofiber Differentiation and Increases Regeneration by Altering Histone Acetylation

Publication date: 12 December 2017
Source:Cell Reports, Volume 21, Issue 11
Author(s): Suman Das, Frederic Morvan, Giulio Morozzi, Benjamin Jourde, Giulia C. Minetti, Peter Kahle, Helene Rivet, Pascale Brebbia, Gauthier Toussaint, David J. Glass, Mara Fornaro
ATP citrate lyase (ACL) plays a key role in regulating mitochondrial function, as well as glucose and lipid metabolism in skeletal muscle. We report here that ACL silencing impairs myoblast and satellite cell (SC) differentiation, and it is accompanied by a decrease in fast myosin heavy chain isoforms and MYOD. Conversely, overexpression of ACL enhances MYOD levels and promotes myogenesis. Myogenesis is dependent on transcriptional but also other mechanisms. We show that ACL regulates the net amount of acetyl groups available, leading to alterations in acetylation of H3(K9/14) and H3(K27) at the MYOD locus, thus increasing MYOD expression. ACL overexpression in murine skeletal muscle leads to improved regeneration after cardiotoxin-mediated damage. Thus, our findings suggest a mechanism for regulating SC differentiation and enhancing regeneration, which might be exploited for devising therapeutic approaches for treating skeletal muscle disease.

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Teaser

Das et al. report that ATP citrate lyase (ACL) acts downstream of IGF-1 to stimulate myoblast and satellite cell differentiation. ACL stimulates acetyl-CoA, which is utilized by acetyl transferases (e.g., P300) to enhance Acetyl-H3(K9/14/27) at the MYOD promoter, resulting in increased MYOD expression and improved muscle regeneration following injury.


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