, Volume 60, Issue 8, pp 1491–1501 | Cite as

Bed rest and resistive vibration exercise unveil novel links between skeletal muscle mitochondrial function and insulin resistance

  • Helena C. Kenny
  • Floriane Rudwill
  • Laura Breen
  • Michele Salanova
  • Dieter Blottner
  • Tim Heise
  • Martina Heer
  • Stephane Blanc
  • Donal J. O’Gorman



Physical inactivity has broad implications for human disease including insulin resistance, sarcopenia and obesity. The present study tested the hypothesis that (1) impaired mitochondrial respiration is linked with blunted insulin sensitivity and loss of muscle mass in healthy young men, and (2) resistive vibration exercise (RVE) would mitigate the negative metabolic effects of bed rest.


Participants (n = 9) were maintained in energy balance during 21 days of bed rest with RVE and without (CON) in a crossover study. Mitochondrial respiration was determined by high-resolution respirometry in permeabilised fibre bundles from biopsies of the vastus lateralis. A hyperinsulinaemic–euglycaemic clamp was used to determine insulin sensitivity, and body composition was assessed by dual-energy x-ray absorptiometry (DEXA).


Body mass (−3.2 ± 0.5 kg vs −2.8 ± 0.4 kg for CON and RVE, respectively, p < 0.05), fat-free mass (−2.9 ± 0.5 kg vs −2.7 ± 0.5 kg, p < 0.05) and peak oxygen consumption (\( \overset{\cdot }{V}{\mathrm{O}}_{2\mathrm{peak}} \)) (10–15%, p < 0.05) were all reduced following bed rest. Bed rest decreased insulin sensitivity in the CON group (0.04 ± 0.002 mg kgFFM−1 [pmol l−1] min−1 vs 0.03 ± 0.002 mg kgFFM−1 [pmol l−1] min−1 for baseline vs post-CON), while RVE mitigated this response (0.04 ± 0.003 mg kgFFM−1 [pmol l−1] min−1). Mitochondrial respiration (oxidative phosphorylation and electron transport system capacity) decreased in the CON group but not in the RVE group when expressed relative to tissue weight but not when normalised for citrate synthase activity. LEAK respiration, indicating a decrease in mitochondrial uncoupling, was the only component to remain significantly lower in the CON group after normalisation for citrate synthase. This was accompanied by a significant decrease in adenine nucleotide translocase protein content.


Reductions in muscle mitochondrial respiration occur concomitantly with insulin resistance and loss of muscle mass during bed rest and may play a role in the adaptations to physical inactivity. Significantly, we show that RVE is an effective strategy to partially prevent some of the deleterious metabolic effects of bed rest.


Bed rest Energy expenditure Exercise Insulin resistance Metabolism Mitochondrial function Skeletal muscle 



Adenine nucleotide translocase






Electron transport system


Fatty acid


Oxidative phosphorylation


Resting metabolic rate


Resistive vibration exercise


Substrate-uncoupler-inhibitor titration


N,N,N′,N′-Tetramethyl-p-phenylenediamine dihydrochloride


Uncoupling protein 3

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

Peak oxygen consumption



The authors acknowledge the dedication and time of the participants in this study. We would also like to thank all the staff at MEDES Institute for Space Medicine and Physiology (Toulouse, France). Particularly M.P. Bareille, project scientist, A. Beck, the medical supervisor throughout the study, J. Mercier and M. Hayot for taking the muscle biopsies. We would like to acknowledge the technical support provided by I. Chery and A. Zahariev from the CNRS in Strasbourg, France; G. Gambara, G. Schiffl and M. Gutsmann from the Charité Universitätsmedizin Berlin, Germany; and J. Noone from Dublin City University, Ireland. We would like to thank P.M. Coen, Translational Research Institute for Metabolism and Diabetes, Florida Hospital and the Sanford-Burnham-Prebys Medical Discovery, USA, for providing insightful feedback and comments on the manuscript.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.


This study was funded by the European Space Agency PRODEX programme and Enterprise Ireland, the French Space Agency (CNES) and by the Federal Ministry of Economics and Energy (BMWi) through the German Aerospace Center (DLRe.V.) (Grants 50WB1231 and 50WB1421 to DB).

Duality of interest

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

Author contribution

HK and DO’G had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. The study was designed by HK, FR, DO’G, SB and MH. HK, FR, DO’G and SB performed all physiological measurements. HK, FR, DO’G, SB, LB and DB performed the muscle analyses. MS, DB and TH contributed to the analysis and interpretation of fibre typing. The data was acquired by HK, SB, DO’G, FR, MH, TH, MS and DB. The data was interpreted and discussed by all authors. HK and DO’G drafted the manuscript and all authors were involved in revising the article for important intellectual content. Approval of final manuscript was given by all authors.

Supplementary material

125_2017_4298_MOESM1_ESM.pdf (561 kb)
ESM (PDF 560 kb)


  1. 1.
    English KL, Paddon-Jones D (2010) Protecting muscle mass and function in older adults during bed rest. Curr Opin Clin Nutr Metab Care 13:34–39CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Dogra S, Stathokostas L (2012) Sedentary behavior and physical activity are independent predictors of successful aging in middle-aged and older adults. J Aging Res. doi: 10.1155/2012/190654
  3. 3.
    Owen N, Bauman A, Brown W (2009) Too much sitting: a novel and important predictor of chronic disease risk? Br J Sports Med 43:81–83CrossRefPubMedGoogle Scholar
  4. 4.
    Rudwill F, Blanc S, Gauquelin-Koch G et al (2013) Effects of different levels of physical inactivity on plasma visfatin in healthy normal-weight men. Appl Physiol Nutr Metab 38:689–693CrossRefPubMedGoogle Scholar
  5. 5.
    Bergouignan A, Rudwill F, Simon C, Blanc S (2011) Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies. J Appl Physiol 111:1201–1210CrossRefPubMedGoogle Scholar
  6. 6.
    Blanc S, Normand S, Pachiaudi C, Fortrat J-O, Laville M, Gharib C (2000) Fuel homeostasis during physical inactivity induced by bed rest 1. J Clin Endocrinol Metab 85:2223–2233PubMedGoogle Scholar
  7. 7.
    Trappe S, Creer A, Slivka D, Minchev K, Trappe T (2007) Single muscle fiber function with concurrent exercise or nutrition countermeasures during 60 days of bed rest in women. J Appl Physiol 103:1242–1250CrossRefPubMedGoogle Scholar
  8. 8.
    Brooks N, Cloutier GJ, Cadena SM et al (2008) Resistance training and timed essential amino acids protect against the loss of muscle mass and strength during 28 days of bed rest and energy deficit. J Appl Physiol 105:241–248CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bosutti A, Blottner D, Salanova M, Rittweger J, Degens H (2015) Whey protein supplementation attenuates the reduction in muscle oxidative capacity during 21 days bed rest. J Muscle Res Cell Motil 36:112–113Google Scholar
  10. 10.
    Graf S, Egert S, Heer M (2011) Effects of whey protein supplements on metabolism: evidence from human intervention studies. Curr Opin Clin Nutr Metab Care 14:569–580CrossRefPubMedGoogle Scholar
  11. 11.
    Kumar V, Selby A, Rankin D et al (2009) Age-related differences in the dose–response relationship of muscle protein synthesis to resistance exercise in young and old men. J Physiol 587:211–217CrossRefPubMedGoogle Scholar
  12. 12.
    Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F (2004) Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes 53:294–305CrossRefPubMedGoogle Scholar
  13. 13.
    Tang JE, Hartman JW, Phillips SM (2006) Increased muscle oxidative potential following resistance training induced fibre hypertrophy in young men. Appl Physiol Nutr Metab 31:495–501CrossRefPubMedGoogle Scholar
  14. 14.
    Akima H, Ushiyama J, Kubo J et al (2003) Resistance training during unweighting maintains muscle size and function in human calf. Med Sci Sports Exerc 35:655–662CrossRefPubMedGoogle Scholar
  15. 15.
    Liu Y, Liu C, Lu M-L et al (2015) Vibration exercise decreases insulin resistance and modulates the insulin signaling pathway in a type 2 diabetic rat model. Int J Clin Exp Med 8:13136PubMedPubMedCentralGoogle Scholar
  16. 16.
    Zange J, Mester J, Heer M, Kluge G, Liphardt A-M (2009) 20-Hz whole body vibration training fails to counteract the decrease in leg muscle volume caused by 14 days of 6 head down tilt bed rest. Eur J Appl Physiol 105:271–277CrossRefPubMedGoogle Scholar
  17. 17.
    Blottner D, Salanova M, Püttmann B et al (2006) Human skeletal muscle structure and function preserved by vibration muscle exercise following 55 days of bed rest. Eur J Appl Physiol 97:261–271CrossRefPubMedGoogle Scholar
  18. 18.
    Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Investig 106:171–176CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Biolo G, Agostini F, Simunic B et al (2008) Positive energy balance is associated with accelerated muscle atrophy and increased erythrocyte glutathione turnover during 5 wk of bed rest. Am J Clin Nutr 88:950–958PubMedGoogle Scholar
  20. 20.
    Zahariev A, Bergouignan A, Caloin M, Normand S, Gauquelin-Koch G, Gharib C et al (2005) Skinfold thickness versus isotope dilution for body fat assessment during simulated microgravity: results from three bed-rest campaigns in men and women with and without countermeasures. Eur J Appl Physiol 95:344–350CrossRefPubMedGoogle Scholar
  21. 21.
    Bergouignan A, Trudel G, Simon C, Chopard A, Schoeller DA, Momken I et al (2008) Physical inactivity differentially alters dietary oleate and palmitate trafficking. Diabetes 58:367–376CrossRefPubMedGoogle Scholar
  22. 22.
    Dirks ML, Wall BT, van de Valk B, Holloway TM, Holloway GP, Chabowski A, et al. (2016) One week of bed rest leads to substantial muscle atrophy and induces whole-body insulin resistance in the absence of skeletal muscle lipid accumulation. Diabetes 65:2862–2875Google Scholar
  23. 23.
    Toledo FG (2014) Mitochondrial involvement in skeletal muscle insulin resistance. Diabetes 63:59–61CrossRefPubMedGoogle Scholar
  24. 24.
    Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Romanello V, Sandri M (2010) Mitochondrial biogenesis and fragmentation as regulators of muscle protein degradation. Curr Hypertens Rep 12:433–439CrossRefPubMedGoogle Scholar
  26. 26.
    Larsen S, Ara I, Rabøl R, Andersen J, Boushel R, Dela F et al (2009) Are substrate use during exercise and mitochondrial respiratory capacity decreased in arm and leg muscle in type 2 diabetes? Diabetologia 52:1400–1408CrossRefPubMedGoogle Scholar
  27. 27.
    Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsøe R, Dela F (2007) Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50:790–796CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Phielix E, Schrauwen-Hinderling VB, Mensink M, Lenaers E, Meex R, Hoeks J et al (2008) Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes 57:2943–2949CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Phielix E, Meex R, Moonen-Kornips E, Hesselink M, Schrauwen P (2010) Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia 53:1714–1721CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Brocca L, Cannavino J, Coletto L, Biolo G, Sandri M, Bottinelli R et al (2012) The time course of the adaptations of human muscle proteome to bed rest and the underlying mechanisms. J Physiol 590:5211–5230CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Belavý DL, Armbrecht G, Gast U, Richardson CA, Hides JA, Felsenberg D (2010) Countermeasures against lumbar spine deconditioning in prolonged bed rest: resistive exercise with and without whole body vibration. J Appl Physiol 109:1801–1811CrossRefPubMedGoogle Scholar
  32. 32.
    Kirwan JP, del Aguila LF, Hernandez JM et al (2000) Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle. J Appl Physiol 88:797–803PubMedGoogle Scholar
  33. 33.
    Bergouignan A, Schoeller DA, Normand S et al (2006) Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary fatty acids: results of a randomized trial. PLOS Clin Trial 1:e27CrossRefGoogle Scholar
  34. 34.
    Capelli C, Antonutto G, Kenfack MA et al (2006) Factors determining the time course of VO2(max) decay during bedrest: implications for VO2(max) limitation. Eur J Appl Physiol 98:152–160CrossRefPubMedGoogle Scholar
  35. 35.
    Holloszy JO, Coyle EF (1984) Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol 56:831–838PubMedGoogle Scholar
  36. 36.
    Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH (2006) Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol Ser A Biol Med Sci 61:534–540CrossRefGoogle Scholar
  37. 37.
    Little JP, Gillen JB, Percival ME et al (2011) Low-volume high-intensity interval training reduces hyperglycemia and increases muscle mitochondrial capacity in patients with type 2 diabetes. J Appl Physiol 111:1554–1560CrossRefPubMedGoogle Scholar
  38. 38.
    Salvadego D, Keramidas ME, Brocca L et al. (2016) Separate and combined effects of a 10-d exposure to hypoxia and inactivity on oxidative function in vivo and mitochondrial respiration ex vivo in humans. J Appl Phys 121:154–163Google Scholar
  39. 39.
    Bassett DR, Howley ET (2000) Limiting factors for maximum oxygen uptake and determinants of endurance performance. Med Sci Sports Exerc 32:70–84CrossRefPubMedGoogle Scholar
  40. 40.
    Gram M, Vigelsø A, Yokota T et al (2014) Two weeks of one-leg immobilization decreases skeletal muscle respiratory capacity equally in young and elderly men. Exp Gerontol 58:269–278CrossRefPubMedGoogle Scholar
  41. 41.
    Joseph AM, Adhihetty PJ, Buford TW et al (2012) The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high-and low-functioning elderly individuals. Aging Cell 11:801–809CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Pesta D, Gnaiger E (2012) High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol 810:25–58CrossRefPubMedGoogle Scholar
  43. 43.
    Brand M, Brindle K, Buckingham J, Harper J, Rolfe D, Smart J (1999) The significance and mechanism of mitochondrial proton conductance. Int J Obes 23:S4–S11CrossRefGoogle Scholar
  44. 44.
    Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435:297–312CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hey-Mogensen M, Gram M, Jensen MB et al (2015) A novel method for determining human ex vivo submaximal skeletal muscle mitochondrial function. J Physiol 593:3991–4010CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cadenas S, Echtay KS, Harper JA et al (2002) The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3. J Biol Chem 277:2773–2778CrossRefPubMedGoogle Scholar
  47. 47.
    Brand M (2005) The efficiency and plasticity of mitochondrial energy transduction. Biochem Soc Trans 33:897–904CrossRefPubMedGoogle Scholar
  48. 48.
    Bevilacqua L, Seifert EL, Estey C, Gerrits MF, Harper M-E (2010) Absence of uncoupling protein-3 leads to greater activation of an adenine nucleotide translocase-mediated proton conductance in skeletal muscle mitochondria from calorie restricted mice. Biochim Biophys Acta (BBA)-Bioenerg 1797:1389–1397CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Helena C. Kenny
    • 1
    • 2
  • Floriane Rudwill
    • 3
  • Laura Breen
    • 2
  • Michele Salanova
    • 4
  • Dieter Blottner
    • 4
  • Tim Heise
    • 5
  • Martina Heer
    • 5
    • 6
  • Stephane Blanc
    • 3
  • Donal J. O’Gorman
    • 1
    • 2
  1. 1.3U Diabetes Consortium, School of Health and Human PerformanceDublin City UniversityDublin 9Ireland
  2. 2.National Institute for Cellular and BiotechnologyDublin City UniversityDublinIreland
  3. 3.Université de Strasbourg, Institut Pluridisiplinaire Hubert Curien, Départment d’Ecologie, Physiologie et Ethologie, CNRS, UMR7178StrasbourgFrance
  4. 4.Charité Universitätsmedizin BerlinBerlinGermany
  5. 5.ProfilNeussGermany
  6. 6.Institute of Nutrition and Food SciencesUniversity of BonnBonnGermany

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