title: Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness.
abstract: OBJECTIVE
  Targeted metabolomic and transcriptomic approaches were used to evaluate the relationship between skeletal muscle metabolite signatures, gene expression profiles and clinical outcomes in response to various exercise training interventions. We hypothesised that changes in mitochondrial metabolic intermediates would predict improvements in clinical risk factors, thereby offering novel insights into potential mechanisms.
  
  
  METHODS
  Subjects at risk of metabolic disease were randomised to 6 months of inactivity or one of five aerobic and/or resistance training programmes (n = 112). Pre/post-intervention assessments included cardiorespiratory fitness ([Formula: see text]), serum triacylglycerols (TGs) and insulin sensitivity (SI). In this secondary analysis, muscle biopsy specimens were used for targeted mass spectrometry-based analysis of metabolic intermediates and measurement of mRNA expression of genes involved in metabolism.
  
  
  RESULTS
  Exercise regimens with the largest energy expenditure produced robust increases in muscle concentrations of even-chain acylcarnitines (median 37-488%), which correlated positively with increased expression of genes involved in muscle uptake and oxidation of fatty acids. Along with free carnitine, the aforementioned acylcarnitine metabolites were related to improvements in [Formula: see text], TGs and SI (R = 0.20-0.31, p < 0.05). Muscle concentrations of the tricarboxylic acid cycle intermediates succinate and succinylcarnitine (R = 0.39 and 0.24, p < 0.05) emerged as the strongest correlates of SI.
  
  
  CONCLUSIONS
  The metabolic signatures of exercise-trained skeletal muscle reflected reprogramming of mitochondrial function and intermediary metabolism and correlated with changes in cardiometabolic fitness. Succinate metabolism and the succinate dehydrogenase complex emerged as a potential regulatory node that intersects with whole-body insulin sensitivity. This study identifies new avenues for mechanistic research aimed at understanding the health benefits of physical activity. Trial registration ClinicalTrials.gov NCT00200993 and NCT00275145 Funding This work was supported by the National Heart, Lung, and Blood Institute (National Institutes of Health), National Institute on Aging (National Institutes of Health) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health).
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Medical Center, Durham, NC, USA, Huffm007@mc.duke.edu.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Huffman
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Hubal
authors.forename: Hiba
authors.initials: H
authors.lastname: Abouassi
authors.forename: Nina
authors.initials: N
authors.lastname: Beri
authors.forename: Lori A
authors.initials: LA
authors.lastname: Bateman
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D015444:Exercise / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D019802:Succinic Acid / Q000378:metabolism; D055815:Young Adult
chemical_list: D000597:Amino Acids, Branched-Chain; C116917:acylcarnitine; D019802:Succinic Acid; D002331:Carnitine
references.citation: Diabetes. 2007 Jun;56(6):1489-501
references.pmid: 17526912
references.citation: J Appl Physiol (1985). 2012 Dec 15;113(12):1831-7
references.pmid: 23019316
references.citation: Contemp Clin Trials. 2005 Dec;26(6):616-25
references.pmid: 16239128
references.citation: J Appl Physiol (1985). 2004 Jan;96(1):101-6
references.pmid: 12972442
references.citation: Diabetes. 2009 Nov;58(11):2429-43
references.pmid: 19875619
references.citation: Nat Rev Genet. 2004 Mar;5(3):229-37
references.pmid: 14970825
references.citation: Nat Med. 2011 Apr;17(4):448-53
references.pmid: 21423183
references.citation: Circulation. 2012 Aug 28;126(9):1110-20
references.pmid: 22927473
references.citation: Cell Metab. 2012 May 2;15(5):764-77
references.pmid: 22560225
references.citation: N Engl J Med. 2002 Nov 7;347(19):1483-92
references.pmid: 12421890
references.citation: J Biol Chem. 2009 Aug 21;284(34):22840-52
references.pmid: 19553674
references.citation: J Appl Physiol (1985). 2013 Feb;114(3):344-50
references.pmid: 23221957
references.citation: Diabetes Care. 2009 Sep;32(9):1678-83
references.pmid: 19502541
references.citation: Diabetes Care. 2011 Jan;34(1):174-6
references.pmid: 20921216
references.citation: J Appl Physiol (1985). 2005 Oct;99(4):1613-8
references.pmid: 16002776
references.citation: Diabetes. 2009 Dec;58(12):2788-96
references.pmid: 19741162
references.citation: Metabolism. 2008 Jul;57(7):888-95
references.pmid: 18555828
references.citation: Cell Metab. 2008 Jan;7(1):45-56
references.pmid: 18177724
references.citation: Cell Metab. 2009 Apr;9(4):311-26
references.pmid: 19356713
references.citation: Chest. 2005 Oct;128(4):2788-93
references.pmid: 16236956
references.citation: Bioinformatics. 2004 Nov 1;20(16):2534-44
references.pmid: 15117752
references.citation: J Clin Endocrinol Metab. 2011 Mar;96(3):775-81
references.pmid: 21190973
references.citation: J Am Coll Cardiol. 1999 Jun;33(7):1956-63
references.pmid: 10362199
references.citation: J Clin Invest. 2009 Mar;119(3):573-81
references.pmid: 19188683
references.citation: J Biol Chem. 2005 Sep 30;280(39):33588-98
references.pmid: 16079133