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

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 mitochondria! biogenesis via its inhibitory action on peroxisome proliferator activated receptor-gamma coactivator-1 alpha (PGC-1 alpha). However, the specific contribution of GCN5 to skeletal muscle metabolism and mitochondria] adaptations to endurance exercise in vivo remain to be defined. We aimed to determine whether loss of GCN5 in skeletal muscle enhances mitochondria! 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 (mK0) and floxed, wildtype (WT) littermates. We measured whole-body energy expenditure, as well as markers of mitochondria! 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 mK0 mice, whole-body energy expenditure as well as skeletal muscle mitochondrial abundance and maximal respiratory capacity were comparable between mK0 and WT mice. Further, there were no genotype differences in endurance exercise-mediated mitochondria! biogenesis or increases in PGC-1 alpha protein content. Conclusion: These results demonstrate that loss of GCN5 in vivo does not promote metabolic remodeling in mouse skeletal muscle. (C) 2017 The Authors. Published by Elsevier GmbH.