, Volume 57, Issue 11, pp 2282–2295 | Cite as

Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness

  • Kim M. HuffmanEmail author
  • Timothy R. Koves
  • Monica J. Hubal
  • Hiba Abouassi
  • Nina Beri
  • Lori A. Bateman
  • Robert D. Stevens
  • Olga R. Ilkayeva
  • Eric P. Hoffman
  • Deborah M. Muoio
  • William E. Kraus



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.


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 (\( \overset{\cdot }{V}{\mathrm{O}}_{2\mathrm{peak}} \)), 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.


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 \( \overset{\cdot }{V}{\mathrm{O}}_{2\mathrm{peak}} \), 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.


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 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).


Acylcarnitines Branched-chain amino acids Metabolomics Physical activity Skeletal muscle Succinate 



Branched-chain amino acid


Carnitine acetyltransferase


Insulin sensitivity index


Succinate dehydrogenase


Studies of Targeted Risk Reduction Interventions through Defined Exercise


Tricarboxylic acid



\( \overset{\cdot }{V}{\mathrm{O}}_{2\mathrm{peak}} \)

Cardiopulmonary fitness as determined by a maximal treadmill test



We thank the rest of the STRRIDE research team at East Carolina University and Duke University.


This work was supported by the National Heart, Lung, and Blood Institute (National Institutes of Health) R01HL-57354 (WEK), National Institute on Aging (National Institutes of Health) P30 AGO28716-01 (WEK, KMH), R01AG-028930 and R01DK-089312 (DMM) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) K23AR054904 (KMH).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

KMH, DMM, and WEK participated in conceptual design, data analysis and data interpretation and drafting and editing of the manuscript. EPH participated in conceptual design, data interpretation and editing of the manuscript. TRK, MJH, HA, NB, LAB, RDS and ORI participated in data collection, data interpretation and editing of the manuscript. All authors approved the final version. KMH is the guarantor of this work.

Supplementary material

125_2014_3343_MOESM1_ESM.pdf (15 kb)
ESM Fig. 1 (PDF 15 kb)
125_2014_3343_MOESM2_ESM.pdf (160 kb)
ESM Table 1 (PDF 160 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kim M. Huffman
    • 1
    • 2
    • 3
    Email author
  • Timothy R. Koves
    • 3
    • 4
  • Monica J. Hubal
    • 5
  • Hiba Abouassi
    • 6
  • Nina Beri
    • 7
  • Lori A. Bateman
    • 8
  • Robert D. Stevens
    • 3
  • Olga R. Ilkayeva
    • 3
  • Eric P. Hoffman
    • 5
  • Deborah M. Muoio
    • 3
    • 6
    • 9
    • 10
  • William E. Kraus
    • 3
    • 8
  1. 1.Physical Medicine and Rehabilitation ServiceVeterans Affairs Medical CenterDurhamUSA
  2. 2.Division of Rheumatology, Department of MedicineDuke University Medical CenterDurhamUSA
  3. 3.Duke Molecular Physiology InstituteDuke University Medical CenterDurhamUSA
  4. 4.Division of Geriatrics, Department of MedicineDuke University Medical CenterDurhamUSA
  5. 5.Department of Integrative Systems BiologyChildren’s National Medical CenterWashingtonUSA
  6. 6.Division of EndocrinologyDuke University Medical CenterDurhamUSA
  7. 7.School of MedicineDuke UniversityDurhamUSA
  8. 8.Division of Cardiology, Department of MedicineDuke University Medical CenterDurhamUSA
  9. 9.Department of MedicineDuke University Medical CenterDurhamUSA
  10. 10.Department of Pharmacology and Cancer BiologyDuke University Medical CenterDurhamUSA

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