Uncoupling protein 3 (UCP3) is highly selectively expressed in skeletal muscle and is known to lower mitochondrial reactive oxygenspecies andpromote fatty acidoxidation;however, the global impactofUCP3 activity on skeletal muscle and whole-body metabolism have not been extensively studied. We utilized untargeted metabolomics to identify novel metabolites that distinguish mice overexpressing UCP3 inmuscle, both at rest and after exercise regimens that challenged muscle metabolism, to potentially unmask subtle phenotypes.Male wildtype (WT) and muscle-specific UCP3-overexpressing transgenic (UCP3 Tg) C57BL/6J mice were compared with or without a 5 wk endurance training protocol at rest or after an acute exercise bout (EB). Skeletal muscle, liver, and plasma sampleswere analyzed by gas chromatography time-of-flightmass spectrometry.Discriminantmetabolites were considered if within the top 99th percentile of variable importance measurements obtained from partial leastsquares discriminant analysis models. A total of 80 metabolites accurately discriminated UCP3 Tg mice from WT when modeled within a specific exercise condition (i.e., untrained/rested, endurance trained/rested, untrained/EB, and endurance trained/EB). Results revealed that several amino acids and amino acid derivatives in skeletal muscle and plasma of UCP3 Tg mice (e.g., Asp, Glu, Lys, Tyr, Ser, Met) were significantly reduced after an EB; that metabolites associatedwith skeletalmuscle glutathione/Met/Cysmetabolism(2-hydroxybutanoic acid, oxoproline, Gly, andGlu)were altered in UCP3 Tgmice across all training and exercise conditions; and thatmuscle metabolite indices of dehydrogenase activity were increased in UCP3 Tg mice, suggestive of a shift in tissue NADH/NAD+ ratio. The results indicate that mitochondrial UCP3 activity affects metabolism well beyond fatty acid oxidation, regulating biochemical pathways associated with amino acidmetabolism and redox status. That select metabolites were altered in liver of UCP3 Tg mice highlights that changes in muscle UCP3 activity can also affect other organ systems, presumably through changes in systemic metabolite trafficking. - Aguer, C., Piccolo, B. D., Fiehn, O., Adams, S. H., Harper, M.-E. A novel amino acid and metabolomics signature in mice overexpressing muscle uncoupling protein 3. FASEB J. 31, 814-827 (2017). www.fasebj.org.
ASJC Scopus subject areas
- Molecular Biology