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

Das, Suman and Morvan, Frederic and Morozzi, Giulio and Jourde, Benjamin and Minetti, Giulia and Kahle, Peter and Rivet, Helene and Brebbia, Pascale and Toussaint, Gauthier and Glass, David and Fornaro, Mara (2017) ATP Citrate Lyase Regulates Myofiber Differentiation and Increases Regeneration by Altering Histone Acetylation. Cell reports, 21 (11). pp. 3003-3011. ISSN 2211-1247

Abstract

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.

Item Type: Article
Date Deposited: 27 Dec 2017 00:45
Last Modified: 27 Dec 2017 00:45
URI: https://oak.novartis.com/id/eprint/34933

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