Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation.
Maximal exercise-associated oxidative capacity is strongly correlated with health and longevity in humans. Rats selectively bred for high running capacity (HCR) have improved metabolic health and are longer-lived than their low-capacity counterparts (LCR). Using metabolomic and proteomic profiling, we show that HCR efficiently oxidize fatty acids (FAs) and branched-chain amino acids (BCAAs), sparing glycogen and reducing accumulation of short- and medium-chain acylcarnitines. HCR mitochondria have reduced acetylation of mitochondrial proteins within oxidative pathways at rest, and there is rapid protein deacetylation with exercise, which is greater in HCR than LCR. Fluxomic analysis of valine degradation with exercise demonstrates a functional role of differential protein acetylation in HCR and LCR. Our data suggest that efficient FA and BCAA utilization contribute to high intrinsic exercise capacity and the health and longevity benefits associated with enhanced fitness.
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Katherine A
KA
Overmyer
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Charles R
CR
Evans
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Nathan R
NR
Qi
Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA.
Catherine E
CE
Minogue
Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA.
Joshua J
JJ
Carson
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Christopher J
CJ
Chermside-Scabbo
Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
Lauren G
LG
Koch
Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
Steven L
SL
Britton
Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA.
David J
DJ
Pagliarini
Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA; Genome Center of Wisconsin, University of Wisconsin, Madison, WI 53706, USA.
Joshua J
JJ
Coon
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: burantc@med.umich.edu.
Charles F
CF
Burant
D000107:Acetylation; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D008297:Male; D055432:Metabolomics / Q000379:methods; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal / Q000502:physiology*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D051381:Rats; D012420:Running / Q000502:physiology
D000597:Amino Acids, Branched-Chain; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D020543:Proteome