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Muscle-specific knockout of general control of amino acid synthesis 5 (GCN5) does not enhance basal or endurance exercise-induced mitochondrial adaptation

Abstract

OBJECTIVE: Lysine acetylation is an important post-translational modification that regulates metabolic function in skeletal muscle. The acetyltransferase, general control of amino acid synthesis 5 (GCN5), has been proposed as a regulator of mitochondrial biogenesis via its inhibitory action on peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha). However, the specific contribution of GCN5 to skeletal muscle metabolism and mitochondrial adaptations to endurance exercise in vivo remain to be defined. We aimed to determine whether loss of GCN5 in skeletal muscle enhances mitochondrial density and function, and the adaptive response to endurance exercise training. METHODS: We used Cre-LoxP methodology to generate mice with muscle-specific knockout of GCN5 (mKO) and floxed, wildtype (WT) littermates. We measured whole-body energy expenditure, as well as markers of mitochondrial density, biogenesis, and function in skeletal muscle from sedentary mice, and mice that performed 20 days of voluntary endurance exercise training. RESULTS: Despite successful knockdown of GCN5 activity in skeletal muscle of mKO mice, whole-body energy expenditure as well as skeletal muscle mitochondrial abundance and maximal respiratory capacity were comparable between mKO and WT mice. Further, there were no genotype differences in endurance exercise-mediated mitochondrial biogenesis or increases in PGC-1alpha protein content. CONCLUSION: These results demonstrate that loss of GCN5 in vivo does not promote metabolic remodeling in mouse skeletal muscle.

Type Journal
ISBN 2212-8778 (Electronic) 2212-8778 (Linking)
Authors Dent, J. R.; Martins, V. F.; Svensson, K.; LaBarge, S. A.; Schlenk, N. C.; Esparza, M. C.; Buckner, E. H.; Meyer, G. A.; Hamilton, D. L.; Schenk, S.; Philp, A.
Responsible Garvan Author Dr Andy Philp
Publisher Name Molecular Metabolism
Published Date 2017-10-16
Published Volume 6
Published Issue 12
Published Pages 1574-1584
Status Published in-print
DOI 10.1016/j.molmet.2017.10.004
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/29111103