Skip to main content
Log in

Beneficial Effects of Exercise on Muscle Mitochondrial Function in Diabetes Mellitus

  • review article
  • Exercise and Diabetic Mitochondria
  • Published:
Sports Medicine Aims and scope Submit manuscript

Abstract

The physiopathology of diabetes mellitus has been closely associated with a variety of alterations in mitochondrial histology, biochemistry and function. Generally, the alterations comprise increased mitochondrial reactive oxygen and nitrogen species (RONS) generation, resulting in oxidative stress and damage; decreased capacity to metabolize lipids, leading to intramyocyte lipid accumulation; and diminished mitochondrial density and reduced levels of uncoupling proteins (UCPs), with consequent impairment in mitochondrial function. Chronic physical exercise is a physiological stimulus able to induce mitochondrial adaptations that can counteract the adverse effects of diabetes on muscle mitochondria. However, the mechanisms responsible for mitochondrial adaptations in the muscles of diabetic patients are still unclear. The main mechanisms by which exercise may be considered an important non-pharmacological strategy for preventing and/or attenuating diabetes-induced mitochondrial impairments may involve (i) increased mitochondrial biogenesis, which is dependent on the increased expression of some important proteins, such as the ‘master switch’ peroxisome proliferator-activated receptor (PPAR)-γ-coactivator-1α (PGC-1α) and heat shock proteins (HSPs), both of which are severely downregulated in the muscles of diabetic patients; and (ii) the restoration or attenuation of the low UCP3 expression in skeletal muscle mitochondria of diabetic patients, which is suggested to play a pivotal role in mitochondrial dysfunction.

There is evidence that chronic exercise and lifestyle interventions reverse impairments in mitochondrial density and size, in the activity of respiratory chain complexes and in cardiolipin content; however, the mechanisms by which chronic exercise alters mitochondrial respiratory parameters, mitochondrial antioxidant systems and other specific proteins involved in mitochondrial metabolism in the muscles of diabetic patients remain to be elucidated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I
Table II
Fig. 3

Similar content being viewed by others

References

  1. Rahimi R, Nikfar S, Larijani B, et al. A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother 2005; 59 (7): 365–73

    Article  PubMed  CAS  Google Scholar 

  2. Roglic G, Unwin N, Bennett PH, et al. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 2005; 28 (9): 2130–5

    Article  PubMed  Google Scholar 

  3. International Diabetes Federation. Diabetes atlas. 2nd ed. Brussels: International Diabetes Federation, 2003

    Google Scholar 

  4. Luft R. The development of mitochondrial medicine. Proc Natl Acad Sci USA 1994; 91 (19): 8731–8

    Article  PubMed  CAS  Google Scholar 

  5. Fosslien E. Mitochondrial medicine: molecular pathology of defective oxidative phosphorylation. Ann Clin Lab Sci 2001;31 (1): 25–67

    PubMed  CAS  Google Scholar 

  6. Duchen MR. Roles of mitochondria in health and disease. Diabetes 2004; 53 Suppl.1: 96–102

    Article  Google Scholar 

  7. Cadenas E. Mitochondrial free radical production and cell signaling. Mol Aspects Med 2004; 25 (1-2): 17–26

    Article  PubMed  CAS  Google Scholar 

  8. Brookes PS, Yoon Y, Robotham JL, et al. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 2004; 287 (4): 817–33

    Article  Google Scholar 

  9. Brookes PS. Mitochondrial H(+) leak and ROS generation: an odd couple. Free Radic Biol Med 2005; 38 (1): 12–23

    Google Scholar 

  10. Skulachev VP. Mitochondrial physiology and pathology; concepts of programmed death of organelles, cells and organisms. Mol Aspects Med 1999; 20 (3): 139–84

    Article  PubMed  CAS  Google Scholar 

  11. Brown GC, Borutaite V. Nitric oxide inhibition of mitochondrialrespiration and its role in cell death. Free Radic Biol Med 2002; 33 (11): 1440–50

    Article  PubMed  CAS  Google Scholar 

  12. Brown GC, Borutaite V. Nitric oxide, mitochondria, and cell death. IUBMB Life 2001; 52 (3-5): 189–95

    Article  PubMed  CAS  Google Scholar 

  13. Kelley DE, He J, Menshikova EV, et al. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51 (10): 2944–50

    Article  PubMed  CAS  Google Scholar 

  14. Toledo FG, Watkins S, Kelley DE. Changes induced by physical activity and weight loss in the morphology of intermy ofibrillar mitochondria in obese men and women. J Clin En docrinol Metab 2006; 91 (8): 3224–7

    Article  CAS  Google Scholar 

  15. Mootha VK, Lindgren CM, Eriksson KF, et al. PGC-1alph responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34 (3): 267–73

    Article  PubMed  CAS  Google Scholar 

  16. Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 2003; 100 (14): 8466–71

    Article  PubMed  CAS  Google Scholar 

  17. Petersen KF, Dufour S, Befroy D, et al. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350 (7): 664–71

    Article  PubMed  CAS  Google Scholar 

  18. Morino K, Petersen KF, Dufour S, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005; 115 (12): 3587–93

    Article  PubMed  CAS  Google Scholar 

  19. Irrcher I, Adhihetty PJ, Joseph AM, et al. Regulation of mitochondrial biogenesis in muscle by endurance exercise. Sports Med 2003; 33 (11): 783–93

    Article  PubMed  Google Scholar 

  20. Adhihetty PJ, Irrcher I, Joseph AM, et al. Plasticity of skeletal muscle mitochondria in response to contractile activity. Exp Physiol 2003; 88 (1): 99–107

    Article  PubMed  CAS  Google Scholar 

  21. Henriksen EJ. Invited review: effects of acute exercise and exercise training on insulin resistance. J Appl Physiol 2002; 93 (2): 788–96

    PubMed  CAS  Google Scholar 

  22. Roberts CK, Won D, Pruthi S, et al. Effect of a diet and exercise intervention on oxidative stress, inflammation and monocyte adhesion in diabetic men. Diabetes Res Clin Pract 2006; 73 (3): 249–59

    Article  PubMed  CAS  Google Scholar 

  23. Short KR, Vittone JL, Bigelow ML, et al. Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 2003; 52 (8): 1888–96

    Article  PubMed  CAS  Google Scholar 

  24. Ascensao A, Ferreira R, Magalhaes J. Exercise-induced cardioprotection: biochemical, morphological and functional evidence in whole tissue and isolated mitochondria. Int J Cardiol 2007; 117: 16–30

    Article  PubMed  Google Scholar 

  25. el Midaoui A, Tancrede G, Nadeau A. Effect of physical training on mitochondrial function in skeletal muscle of normal and diabetic rats. Metabolism 1996; 45 (7): 810–6

    Article  PubMed  Google Scholar 

  26. Baar K. Involvement of PPAR gamma co-activator-1, nuclear respiratory factors 1 and 2, and PPAR alpha in the adaptive response to endurance exercise. Proc Nutr Soc 2004; 63 (2): 269–73

    Article  PubMed  CAS  Google Scholar 

  27. Fritz T, Kramer DK, Karlsson HK, et al. Low-intensity exercise increases skeletal muscle protein expression of PPARdelta and UCP3 in type 2 diabetic patients. Diabetes Metab Res Rev 2006; 22 (6): 492–8

    Article  PubMed  CAS  Google Scholar 

  28. van Loon LJ, Goodpaster BH. Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state. Pflugers Arch 2006; 451 (5): 606–16

    Article  PubMed  CAS  Google Scholar 

  29. Toledo FG, Menshikova EV, Ritov VB, et al. Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes 2007; 56 (8): 2142–7

    Article  PubMed  CAS  Google Scholar 

  30. McCarty MF. Up-regulation of PPARgamma coac tivator-1alpha as a strategy for preventing and reversing insulin resistance and obesity. Med Hypotheses 2005; 64 (2): 399–407

    Article  PubMed  CAS  Google Scholar 

  31. Sriwijitkamol A, Ivy JL, Christ-Roberts C, et al. LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training. Am J Physiol Endocrinol Metab 2006; 290 (5): 925–32

    Article  CAS  Google Scholar 

  32. Oliveira PJ, Rolo AP, Seica R, et al. Decreased susceptibility of heart mitochondria from diabetic GK rats to mitochondrial permeability transition induced by calcium phosphate. Biosci Rep 2001; 21 (1): 45–53

    Article  PubMed  CAS  Google Scholar 

  33. Oliveira PJ, Seica R, Santos DL, et al. Vitamin E or coenzyme Q10 administration is not fully advantageous for heart mitochondrial function in diabetic goto kakizaki rats. Mitochondrion 2004; 3 (6): 337–45

    Google Scholar 

  34. Kayali R, Cakatay U, Telci A, et al. Decrease in mitochondrial oxidative protein damage parameters in the streptozotocindiabetic rat. Diabetes Metab Res Rev 2004; 20 (4): 315–21

    Article  PubMed  CAS  Google Scholar 

  35. Shen X, Zheng S, Thongboonkerd V, et al. Cardiac mitochonial damage and biogenesis in a chronic model of type 1 diabetes. Am J Physiol Endocrinol Metab 2004; 287 (5):896–905

    Article  CAS  Google Scholar 

  36. Antonetti DA, Reynet C, Kahn CR. Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes mellitus. J Clin Invest 1995; 95 (3): 1383–8

    Article  PubMed  CAS  Google Scholar 

  37. Sreekumar R, Halvatsiotis P, Schimke JC, et al. Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 2002; 51 (6): 1913–20

    Article  PubMed  CAS  Google Scholar 

  38. Hojlund K, Wrzesinski K, Larsen PM, et al. Proteome analysis reveals phosphorylation of ATP synthase beta-subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes. J Biol Chem 2003; 278 (12): 10436–42

    Article  PubMed  CAS  Google Scholar 

  39. Ritov VB, Menshikova EV, He J, et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005; 54 (1): 8–14

    Article  PubMed  CAS  Google Scholar 

  40. Befroy DE, Petersen KF, Dufour S, et al. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 2007; 56 (5): 1376–81

    Article  PubMed  CAS  Google Scholar 

  41. Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003; 300 (5622): 1140–2

    Google Scholar 

  42. He J, Goodpaster BH, Kelley DE. Effects of weight loss and physical activity on muscle lipid content and droplet size. ObesRes 2004; 12 (5): 761–9

    Article  PubMed  Google Scholar 

  43. Mogensen M, Sahlin K, Fernstrom M, et al. Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 2007; 56 (6): 1592–9

    Article  PubMed  CAS  Google Scholar 

  44. Franks PW, Loos RJ. PGC-1alpha gene and physical activity in type 2 diabetes mellitus. Exerc Sport Sci Rev 2006; 34 (4): 171–5

    Article  PubMed  Google Scholar 

  45. Tanaka T, Yamamoto J, Iwasaki S, et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci USA 2003; 100 (26): 15924–9

    Article  PubMed  CAS  Google Scholar 

  46. Frenzel H, Schwartzkopff B, Holtermann W, et al. Regression of cardiac hypertrophy: morphometric and biochemical studies in rat heart after swimming training. J Mol Cell Cardiol 1988:20 (8): 737–51

    Article  Google Scholar 

  47. Hoppeler H, Fluck M. Plasticity of skeletal muscle mitochondria: structure and function. Med Sci Sports Exerc 2003; 35 (1): 95–10

    Article  PubMed  CAS  Google Scholar 

  48. Hood DA. Invited Review: contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 2001;90 (3): 1137–57

    PubMed  CAS  Google Scholar 

  49. Hood DA, Adhihetty PJ, Colavecchia M, et al. Mitochondrial biogenesis and the role of the protein import pathway. Med Sci Sports Exerc 2003; 35 (1): 86–94

    Article  PubMed  CAS  Google Scholar 

  50. Ascensão A, Magalhães J. Exercise and mitochondrial function in striated muscle. In: Moreno AJ, Oliveira PJ, Palmeira MC, editors. Mitochondrial pharmacology and toxicology. Kerala: Transworld Research Network, 2006: 237–70

    Google Scholar 

  51. Scarpulla RC. Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene 2002; 286 (1): 81–9

    Article  PubMed  CAS  Google Scholar 

  52. Scarpulla RC. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta 2002; 1576 (1-2): 1–14

    Article  PubMed  CAS  Google Scholar 

  53. Bergeron R, Ren JM, Cadman KS, et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 2001; 281 (6): 1340–6

    Google Scholar 

  54. Lehman JJ, Barger PM, Kovacs A, et al. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 2000; 106 (7): 847–56

    Article  PubMed  CAS  Google Scholar 

  55. Murakami T, Shimomura Y, Yoshimura A, et al. Induction of nuclear respiratory factor-1 expression by an acute bout of exercise in rat muscle. Biochim Biophys Acta 1998; 1381 (1): 113–22

    Article  PubMed  CAS  Google Scholar 

  56. Xia Y, Buja LM, McMillin JB. Activation of the cytochrome cgene by electrical stimulation in neonatal rat cardiac myocytes:role of NRF-1 and c-Jun. J Biol Chem 1998; 273 (20): 12593–8

    Article  PubMed  CAS  Google Scholar 

  57. Xia Y, Buja LM, Scarpulla RC, et al. Electrical stimulation of neonatal cardiomyocytes results in the sequential activation of nuclear genes governing mitochondrial proliferation and differentiation. Proc Natl Acad Sci USA 1997; 94 (21): 11399–404

    Article  PubMed  CAS  Google Scholar 

  58. Garnier A, Fortin D, Zoll J, et al. Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle. Faseb J 2005; 19 (1): 43–52

    Article  PubMed  CAS  Google Scholar 

  59. Baar K, Wende AR, Jones TE, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. Faseb J 2002; 16 (14): 1879–86

    Article  PubMed  CAS  Google Scholar 

  60. Koves TR, Li P, An J, et al. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 2005; 280 (39): 33588–98

    Article  PubMed  CAS  Google Scholar 

  61. Bengtsson J, Gustafsson T, Widegren U, et al. Mitochondrial transcription factor A and respiratory complex IV increase in response to exercise training in humans. Pflugers Arch 2001; 443 (1): 61–6

    Article  PubMed  CAS  Google Scholar 

  62. Gordon JW, Rungi AA, Inagaki H, et al. Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle. J Appl Physiol 2001; 90 (1): 389–96

    Article  PubMed  CAS  Google Scholar 

  63. Chilibeck PD, Syrotuik DG, Bell GJ. The effect of strength training on estimates of mitochondrial density and distribution throughout muscle fibres. Eur J Appl Physiol Occup Physiol 1999; 80 (6): 604–9

    Article  PubMed  CAS  Google Scholar 

  64. Holten MK, Zacho M, Gaster M, et al. Strength training in creases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes 2004; 53 (2): 294–305

    Article  PubMed  CAS  Google Scholar 

  65. Goto M, Terada S, Kato M, et al. cDNA Cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming exercise rats. Biochem Biophys Res Commun 2000; 274 (2): 350–4

    Google Scholar 

  66. Pilegaard H, Saltin B, Neufer PD. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 2003; 546 (Pt 3): 851–83

    Article  PubMed  CAS  Google Scholar 

  67. Akimoto T, Pohnert SC, Li P, et al. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem 2005; 280 (20): 19587–93

    Article  PubMed  CAS  Google Scholar 

  68. Cartoni R, Leger B, Hock MB, et al. Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise. J Physiol 2005; 567 (Pt 1): 349–58

    Article  PubMed  CAS  Google Scholar 

  69. Mahoney DJ, Parise G, Melov S, et al. Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise. Faseb J 2005; 19 (11): 1498–500

    PubMed  CAS  Google Scholar 

  70. Russell AP, Hesselink MK, Lo SK, et al. Regulation of metabolic transcriptional co-activators and transcription factors with acute exercise. Faseb J 2005; 19 (8): 986–8

    PubMed  CAS  Google Scholar 

  71. Terada S, Kawanaka K, Goto M, et al. Effects of high-intensity intermittent swimming on PGC-1alpha protein expression in rat skeletal muscle. Acta Physiol Scand 2005; 184 (1): 59–65

    Article  PubMed  CAS  Google Scholar 

  72. Adhihetty PJ, Taivassalo T, Haller RG, et al. The effect of training on the expression of mitochondrial biogenesis andapoptosis-related proteins in skeletal muscle of patients with mtDNA defects. Am J Physiol Endocrinol Metab 2007; 293 (3): 672–80

    Article  CAS  Google Scholar 

  73. Wright DC, Han DH, Garcia-Roves PM, et al. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J Biol Chem 2007; 282 (1): 194–9

    Article  PubMed  CAS  Google Scholar 

  74. Hood DA, Joseph AM. Mitochondrial assembly: protein import. Proc Nutr Soc 2004; 63 (2): 293–300

    Article  PubMed  CAS  Google Scholar 

  75. Hood D, Rungi A, Colavecchia M, et al. Stress proteins and mitochondria. In: Locke M, Noble E, editors. Exercise and stress response: the role of stress proteins. Boca Raton (FL): CRC Press, 2002: 151–62

    Google Scholar 

  76. Takahashi M, Chesley A, Freyssenet D, et al. Contractile activity induced adaptations in the mitochondrial protein import system. Am J Physiol 1998; 274 (5 Pt 1): 1380–7

    Google Scholar 

  77. Ornatsky OI, Connor MK, Hood DA. Expression of stress proteins and mitochondrial chaperonins in chronically stimulated skeletal muscle. Biochem J 1995; 311 (Pt 1): 119–23

    PubMed  CAS  Google Scholar 

  78. Craig EE, Chesley A, Hood DA. Thyroid hormone modifies mitochondrial phenotype by increasing protein import without altering degradation. Am J Physiol 1998; 275 (6 Pt 1): 1508–15

    Google Scholar 

  79. Lennon SL, Quindry JC, French JP, et al. Exercise and myocardial tolerance to ischaemia-reperfusion. Acta Physiol Scand 2004; 182 (2): 161–9

    Article  PubMed  CAS  Google Scholar 

  80. Powers SK, Demirel HA, Vincent HK, et al. Exercise training improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. Am J Physiol 1998; 275 (5 Pt 2): 1468–77

    Google Scholar 

  81. Hamilton KL, Staib JL, Phillips T, et al. Exercise, antioxidants, and HSP72: protection against myocardial ischemia/reperfusion. Free Radic Biol Med 2003; 34 (7): 800–9

    Article  PubMed  CAS  Google Scholar 

  82. Ascensao A, Magalhaes J, Soares J, et al. Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. Int J Cardiol 2005; 100 (3): 451–60

    Article  PubMed  Google Scholar 

  83. Ascensao A, Magalhaes J, Soares JM, et al. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. Am J Physiol Heart Circ Physiol 2005; 289 (2): 722–31

    Article  CAS  Google Scholar 

  84. Ascensao A, Magalhaes J, Soares JM, et al. Endurance training limits the functional alterations of heart rat mitochondria submitted to in vitro anoxia-reoxygenation. Int J Cardiol 2006; 109 (2): 169–78

    Article  PubMed  Google Scholar 

  85. Ascensao A, Ferreira R, Oliveira PJ, et al. Effects of endurance chondrial alterations induced by in vitro anoxia-reoxygenation. Cardiovasc Toxicol 2006; 6 (3-4): 159–72

    Article  PubMed  CAS  Google Scholar 

  86. Takahashi M, Hood DA. Chronic stimulation-induced changes in mitochondria and performance in rat skeletal muscle. J Appl Physiol 1993; 74 (2): 934–41

    PubMed  CAS  Google Scholar 

  87. Atalay M, Oksala NK, Laaksonen DE, et al. Exercise training modulates heat shock protein response in diabetic rats. J Appl Physiol 2004; 97 (2): 605–11

    Article  PubMed  CAS  Google Scholar 

  88. Bota DA, Davies KJ. Protein degradation in mitochondria:implications for oxidative stress, aging and disease: a novel etiological classification of mitochondrial proteolytic disorders. Mitochondrion 2001; 1 (1): 33–49

    Article  PubMed  CAS  Google Scholar 

  89. Luciakova K, Sokolikova B, Chloupkova M, et al. Enhanced mitochondrial biogenesis is associated with increased expression of the mitochondrial ATP-dependent Lon protease. FEBS Lett 1999; 444 (2-3): 186–8

    Article  PubMed  CAS  Google Scholar 

  90. Smirnova E, Griparic L, Shurland DL, et al. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 2001; 12 (8): 2245–56

    PubMed  CAS  Google Scholar 

  91. Santel A, Frank S, Gaume B, et al. Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. J Cell Sci 2003; 116 (Pt 13): 2763–74

    Article  PubMed  CAS  Google Scholar 

  92. Rojo M, Legros F, Chateau D, et al. Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 2002; 115 (Pt 8): 1663–74

    Google Scholar 

  93. Legros F, Lombes A, Frachon P, et al. Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell 2002; 13 (12): 4343–54

    Article  PubMed  CAS  Google Scholar 

  94. Soriano FX, Liesa M, Bach D, et al. Evidence for a mitochondral regulatory pathway defined by peroxisome proliferator activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes 2006; 55 (6): 1783–91

    Article  PubMed  CAS  Google Scholar 

  95. Bach D, Naon D, Pich S, et al. Expression of Mfn2, the Charcot Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes 2005; 54 (9): 2685–93

    Article  PubMed  CAS  Google Scholar 

  96. Brand MD, Brindle KM, Buckingham JA, et al. The significance and mechanism of mitochondrial proton conductance. Int J Obes Relat Metab Disord 1999; 23 Suppl. 6: 4–11

    Article  Google Scholar 

  97. Ricquier D, Bouillaud F. Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance. J Physiol 2000; 529 Pt 1: 3–10

    Article  Google Scholar 

  98. Schrauwen P, Saris WH, Hesselink MK. An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix. Faseb J 2001; 15 (13): 2497–502

    Article  PubMed  CAS  Google Scholar 

  99. Himms-Hagen J, Harper ME. Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Exp Biol Med (Maywood) 2001; 226 (2): 78–84

    CAS  Google Scholar 

  100. Hesselink MK, Greenhaff PL, Constantin-Teodosiu D, et al. Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo. J Clin Invest 2003; 111 (4): 479–86

    PubMed  CAS  Google Scholar 

  101. Hesselink MK, Keizer HA, Borghouts LB, et al. Protein expression of UCP3 differs between human type 1, type 2a, and type 2b fibers. Faseb J 2001; 15 (6): 1071–3

    PubMed  CAS  Google Scholar 

  102. Goglia F, Skulachev VP. A function for novel uncoupling proteins: antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet. Faseb J 2003; 17 (12): 1585–91

    Article  PubMed  CAS  Google Scholar 

  103. Vidal-Puig AJ, Grujic D, Zhang CY, et al. Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem 2000; 275 (21): 16258–66

    Article  PubMed  CAS  Google Scholar 

  104. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 1997; 416 (1): 15–8

    Google Scholar 

  105. Brand MD, Pamplona R, Portero-Otin M, et al. Oxidative damage and phospholipid fatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3. Biochem J 2002; 368 (Pt 2): 597–603

    Article  PubMed  CAS  Google Scholar 

  106. Hildebrandt AL, Pilegaard H, Neufer PD. Differential transcriptional activation of select metabolic genes in response to variations in exercise intensity and duration. Am J Physiol variations in exercise intensity and dura Endocrinol Metab 2003; 285 (5): 1021–7

    Google Scholar 

  107. Schrauwen P, Troost FJ, Xia J, et al. Skeletal muscle UCP2 and UCP3 expression in trained and untrained male subjects. Int J Obes Relat Metab Disord 1999; 23 (9): 966–72

    Article  PubMed  CAS  Google Scholar 

  108. Russell A, Wadley G, Snow R, et al. Slow component of [V]O(2) kinetics: the effect of training status, fibre type, UCP3 mRNA and citrate synthase activity. Int J Obes Relat Metab Disord 2002; 26 (2): 157–64

    Article  PubMed  CAS  Google Scholar 

  109. Russell AP, Wadley G, Hesselink MK, et al. UCP3 protein expression is lower in type I, IIa and IIx muscle fiber types of endurance-trained compared to untrained subjects. Pflugers Arch 2003; 445 (5): 563–9

    PubMed  CAS  Google Scholar 

  110. Zhou M, Lin BZ, Coughlin S, et al. UCP-3 expression in skeletal muscle: effects of exercise, hypoxia, and AMP-activated protein kinase. Am J Physiol Endocrinol Metab 2000; 279 (3): 622–9

    Google Scholar 

  111. Pilegaard H, Keller C, Steensberg A, et al. Influence of pre-exercise muscle glycogen content on exercise-induced transcriptional regulation of metabolic genes. J Physiol 2002; 541 (Pt 1): 261–71

    Article  PubMed  CAS  Google Scholar 

  112. Schrauwen P, Hesselink MK, Vaartjes I, et al. Effect of acute exercise on uncoupling protein 3 is a fat metabolism-mediated effect. Am J Physiol Endocrinol Metab 2002; 282 (1): 11–17

    Google Scholar 

  113. Boss O, Samec S, Desplanches D, et al. Effect of endurance training on mRNA expression of uncoupling proteins 1, 2, and 3 in the rat. Faseb J 1998; 12 (3): 335–9

    PubMed  CAS  Google Scholar 

  114. Hjeltnes N, Fernstrom M, Zierath JR, et al. Regulation of UCP2 and UCP3 by muscle disuse and physical activity in tetraplegic subjects. Diabetologia 1999; 42 (7): 826–30

    Article  PubMed  CAS  Google Scholar 

  115. Tonkonogi M, Krook A, Walsh B, et al. Endurance training increases stimulation of uncoupling of skeletal muscle mitochondriain humans by non-esterified fatty acids: an uncoupling- protein-mediated effect? Biochem J 2000; 351 Pt 3: 805–10

    Article  Google Scholar 

  116. Jones TE, Baar K, Ojuka E, et al. Exercise induces an increase in muscle UCP3 as a component of the increase in mitochondrial biogenesis. Am J Physiol Endocrinol Metab 2003; 284 (1): 96–101

    Google Scholar 

  117. Russell AP, Somm E, Praz M, et al. UCP3 protein regulation in human skeletal muscle fibre types I, IIa and IIx is dependent on exercise intensity. J Physiol 2003; 550 (Pt 3): 855–61

    Article  PubMed  CAS  Google Scholar 

  118. Fernstrom M, Tonkonogi M, Sahlin K. Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle. J Physiol 2004; 554 (Pt 3): 755–63

    PubMed  Google Scholar 

  119. Schrauwen P, Russell AP, Moonen-Kornips E, et al. Effect of 2 weeks of endurance training on uncoupling protein 3 content in untrained human subjects. Acta Physiol Scand 2005; 183 (3): 273–80

    Article  PubMed  CAS  Google Scholar 

  120. Tsuboyama-Kasaoka N, Tsunoda N, Maruyama K, et al. Upregulation of uncoupling protein 3 (UCP3) mRNA by exercise training and down-regulation of UCP3 by denervation in skeletal muscles. Biochem Biophys Res Commun 1998; 247 (2): 498–503

    Article  PubMed  CAS  Google Scholar 

  121. Cortright RN, Zheng D, Jones JP, et al. Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation. Am J Physiol 1999; 276 (1 Pt 1): 217–21

    Google Scholar 

  122. Tunstall RJ, Mehan KA, Hargreaves M, et al. Fasting activates the gene expression of UCP3 independent of genes necessary for lipid transport and oxidation in skeletal muscle. Biochem Biophys Res Commun 2002; 294 (2): 301–8

    Article  PubMed  CAS  Google Scholar 

  123. Pilegaard H, Ordway GA, Saltin B, et al. Transcriptional regulationof gene expression in human skeletal muscle during recovery from exercise. Am J Physiol Endocrinol Metab 2000; 279 (4): 806–14

    Google Scholar 

  124. Busquets S, Almendro V, Barreiro E, et al. Activation of UCPs gene expression in skeletal muscle can be independent on both circulating fatty acids and food intake: involvement of ROS in a model of mouse cancer cachexia. FEBS Lett 2005; 579 (3): 717–22

    Article  PubMed  CAS  Google Scholar 

  125. Schrauwen P, Hesselink MK. Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 2004;53 (6): 1412–7

    Article  PubMed  CAS  Google Scholar 

  126. Hesselink MK, Schrauwen P, Holloszy JO, et al. Divergent effects of acute exercise and endurance training on UCP3 expression. Am J Physiol Endocrinol Metab 2003; 284 (2): 449–50; author reply 50-1

    Google Scholar 

  127. Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 1999; 277 (1 Pt 1): 1–10

    Google Scholar 

  128. Sriwijitkamol A, Coletta DK, Wajcberg E, et al. Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. Diabetes 2007; 56 (3): 836–48

    Article  PubMed  CAS  Google Scholar 

  129. Searls YM, Smirnova IV, Fegley BR, et al. Exercise attenuates diabetes-induced ultrastructural changes in rat cardiac tissue. Med Sci Sports Exerc 2004; 36 (11): 1863–70

    Google Scholar 

  130. Mokhtar N, Lavoie JP, Rousseau-Migneron S, et al. Physical training reverses defect in mitochondrial energy production inheart of chronically diabetic rats. Diabetes 1993; 42 (5): 682–7

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

José A. Lumini and António Ascensão are supported by grants from the Portuguese Foundation for Science and Technology (SFRH/BD/30906/2006 and SFRH/BPD/4225/2007, respectively). The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to António Ascensão.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lumini, J.A., Magalhães, J., Oliveira, P.J. et al. Beneficial Effects of Exercise on Muscle Mitochondrial Function in Diabetes Mellitus. sports med 38, 735–750 (2008). https://doi.org/10.2165/00007256-200838090-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00007256-200838090-00003

Keywords

Navigation