Das, Suman, Morvan, Frederic, Jourde, Benjamin, Minetti, Giulia, Brebbia, Pascale, Toussaint, Gauthier, Glass, David and Fornaro, Mara (2017) ATP Citrate Lyase regulates myofiber differentiation by altering histone acetylation. Cell reports, 21 (11). pp. 3003-3011. ISSN 22111247

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 differentiation, and is accompanied by a decrease in fast myosin heavy chain isoforms (Myh1 and Myh4) and MyoD. Conversely, overexpression of ACL enhances MyoD levels and promotes myogenesis. Myogenesis is dependent on transcriptional but also epigenetic mechanisms. We show that ACL regulates the net amount of acetyl groups available, leading to alterations in acetylation of H3K9/14 at the Myod1 locus, thus increasing MyoD expression. Increased MyoD expression is accompanied by upregulation of genes that promote satellite cell (SC) activation and differentiation and in turn regeneration. ACL overexpression in murine skeletal muscle leads to improved regeneration after cardiotoxin-mediated damage, resulting in significantly increased muscle mass. Understanding factors controlling skeletal muscle regeneration is crucial to devising therapeutic approaches for degenerative muscle disease.

Item Type:	Article
Date Deposited:	06 Mar 2018 00:45
Last Modified:	06 Mar 2018 00:45
URI:	https://oak.novartis.com/id/eprint/32825