Elsevier

Molecular Metabolism

Volume 6, Issue 12, December 2017, Pages 1574-1584
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2017.10.004Get rights and content
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Highlights

  • Development of a novel muscle-specific GCN5 knockout (mKO) mouse model.

  • GCN5 mKO does not affect body composition or 24 h whole-body metabolism.

  • GCN5 mKO mice do not exhibit changes in basal mitochondrial abundance or respiratory capacity.

  • Exercise-induced mitochondrial biogenesis in skeletal muscle is not enhanced in GCN5 mKO mice.

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-γ coactivator-1α (PGC-1α). 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-1α protein content.

Conclusion

These results demonstrate that loss of GCN5 in vivo does not promote metabolic remodeling in mouse skeletal muscle.

Keywords

Acetylation
GCN5
Mitochondria
SIRT1
Deacetylase
PGC-1α

Abbreviations

AMP
adenosine monophosphate
Ca2+
calcium
CBP
CREB-binding protein
Cre-MCK
creatine kinase promoter
CHO
carbohydrate
DAC
deacetylase
ETC
electron transport chain
ExT
endurance exercise training
FA
fatty acid
GA
gastrocnemius
GCN5
general control of amino acid synthesis 5
GAPDH
glyceraldehyde 3-phosphate dehydrogenase
HKII
hexokinase 2
KAT
acetyltransferase
mKO
muscle knockout
LCAD
long chain acyl CoA dehydrogenase
MCAD
medium-chain acyl-CoA dehydrogenase
Mef2
myocyte enhance factor 2
Myf6
myogenic factor 6
MyoG
myogenin
NAD+
nicotinamide-adenine dinucleotide
PARPs
poly (ADP-ribose) polymerases
PCAF
p300/CBP-associated factor
PDH
pyruvate dehydrogenase
PGC-1α
peroxisome proliferator activated receptor-γ coactivator-1α
Pln
plantaris
Q
quadriceps
RQ
respiratory quotient
SDH
succinate dehyrogenase
SIRT
sirtuin
TA
tibialis anterior
TCA
tricarboxylic acid
Tfam
mitochondrial-specific transcription factor A
TRI
triceps
WT
wildtype
mHZ
muscle heterozygous

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