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Pflügers Archiv - European Journal of Physiology

, Volume 463, Issue 2, pp 327–338 | Cite as

Muscle endurance and mitochondrial function after chronic normobaric hypoxia: contrast of respiratory and limb muscles

  • Jorge L. Gamboa
  • Francisco H. AndradeEmail author
Muscle Physiology

Abstract

Skeletal muscle adaptation to chronic hypoxia includes loss of oxidative capacity and decrease in fiber size. However, the diaphragm may adapt differently since its activity increases in response to hypoxia. Thus, we hypothesized that chronic hypoxia would not affect endurance, mitochondrial function, or fiber size in the mouse diaphragm. Adult male mice were kept in normoxia (control) or hypoxia (hypoxia, FIO2 = 10%) for 4 weeks. After that time, muscles were collected for histological, biochemical, and functional analyses. Hypoxia soleus muscles fatigued faster (fatigue index higher in control, 21.5 ± 2.6% vs. 13.4 ± 2.4%, p < 0.05), but there was no difference between control and hypoxia diaphragm bundles. Mean fiber cross-sectional area was unchanged in hypoxia limb muscles, but it was 25% smaller in diaphragm (p < 0.001). Ratio of capillary length contact to fiber perimeter was significantly higher in hypoxia diaphragm (28.6 ± 1.2 vs. 49.3 ± 1.4, control and hypoxia, p < 0.001). Mitochondrial respiration rates in hypoxia limb muscles were lower: state 2 decreased 19%, state 3 31%, and state 4 18% vs. control, p < 0.05 for all comparisons. There were similar changes in hypoxia diaphragm: state 3 decreased 29% and state 4 17%, p < 0.05. After 4 weeks of hypoxia, limb muscle mitochondria had lower content of complex IV (cytochrome c oxidase), while diaphragm mitochondria had higher content of complexes IV and V (F 1/F 0 ATP synthase) and less uncoupling protein 3 (UCP-3). These data demonstrate that diaphragm retains its endurance during chronic hypoxia, apparently due to a combination of morphometric changes and optimization of mitochondrial energy production.

Keywords

Chronic hypoxia Diaphragm Mitochondria Electron microscopy Fatigue 

Notes

Acknowledgments

This study was supported by a National Institute of Health/National Institute of General Medical Sciences grant to JLG (F31GM846552).

References

  1. 1.
    Bickler PE, Buck LT (2007) Hypoxia tolerance in reptiles, amphibians, and fishes: life with variable oxygen availability. Annu Rev Physiol 69:145PubMedCrossRefGoogle Scholar
  2. 2.
    Bigard AX, Brunet A, Serrurier B, Guezennec CY, Monod H (1992) Effects of endurance training at high altitude on diaphragm muscle properties. Pflugers Arch 422:239–244PubMedCrossRefGoogle Scholar
  3. 3.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  4. 4.
    Caceda R, Gamboa JL, Boero JA, Monge C, Arregui A (2001) Energetic metabolism in mouse cerebral cortex during chronic hypoxia. Neurosci Lett 301:171–174PubMedCrossRefGoogle Scholar
  5. 5.
    Cadenas S, Echtay KS, Harper JA, Jekabsons MB, Buckingham JA, Grau E, Abuin A, Chapman H, Clapham JC, Brand MD (2002) The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3. J Biol Chem 277:2773–2778PubMedCrossRefGoogle Scholar
  6. 6.
    Caquelard F, Burnet H, Tagliarini F, Cauchy E, Richalet JP, Jammes Y (2000) Effects of prolonged hypobaric hypoxia on human skeletal muscle function and electromyographic events. Clin Sci 98:329–337PubMedCrossRefGoogle Scholar
  7. 7.
    Chavez JC, Pichiule P, Boero J, Arregui A (1995) Reduced mitochondrial respiration in mouse cerebral cortex during chronic hypoxia. Neurosci Lett 193:169–172PubMedCrossRefGoogle Scholar
  8. 8.
    Close RI (1972) Dynamic properties of mammalian skeletal muscles. Physiol Rev 52:129–197PubMedGoogle Scholar
  9. 9.
    Costa LE, Boveris A, Koch OR, Taquini AC (1988) Liver and heart mitochondria in rats submitted to chronic hypobaric hypoxia. Am J Physiol 255:C123–C129PubMedGoogle Scholar
  10. 10.
    Degens H, Bosutti A, Gilliver S, Slevin M, van Heijst A, Wüst R (2010) Changes in contractile properties of skinned single rat soleus and diaphragm fibres after chronic hypoxia. Pflügers Archiv Eur J Physiol 460:863–873CrossRefGoogle Scholar
  11. 11.
    Eiken O, Tesch PA (1984) Effects of hyperoxia and hypoxia on dynamic and sustained static performance of the human quadriceps muscle. Acta Physiol Scand 122:629–633PubMedCrossRefGoogle Scholar
  12. 12.
    El-Khoury R, O’Halloran KD, Bradford A (2003) Effects of chronic hypobaric hypoxia on contractile properties of rat sternohyoid and diaphragm muscles. Clin Exp Pharmacol Physiol 30:551–554PubMedCrossRefGoogle Scholar
  13. 13.
    Essop MF, Razeghi P, McLeod C, Young ME, Taegtmeyer H, Sack MN (2004) Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling. Biochem Biophys Res Commun 314:561–564PubMedCrossRefGoogle Scholar
  14. 14.
    Fiskum G, Murphy AN, Beal MF (1999) Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J Cereb Blood Flow Metab 19:351–369PubMedCrossRefGoogle Scholar
  15. 15.
    Fitts RH (1994) Cellular mechanisms of muscle fatigue. Physiol Rev 74:49–94PubMedCrossRefGoogle Scholar
  16. 16.
    Frezza C, Cipolat S, Scorrano L (2007) Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts. Nat Protocols 2:287–295CrossRefGoogle Scholar
  17. 17.
    Fulco CS, Cymerman A, Muza SR, Rock PB, Pandolf KB, Lewis SF (1994) Adductor pollicis muscle fatigue during acute and chronic altitude exposure and return to sea level. J Appl Physiol 77:179–183PubMedGoogle Scholar
  18. 18.
    Galbes O, Goret L, Caillaud C, Mercier J, Obert P, Candau R, Py G (2008) Combined effects of hypoxia and endurance training on lipid metabolism in rat skeletal muscle. Acta Physiol (Oxf) 193:163–173CrossRefGoogle Scholar
  19. 19.
    Gamboa JL, Andrade FH (2010) Mitochondrial content and distribution changes specific to mouse diaphragm after chronic normobaric hypoxia. Am J Physiol Regul Integr Comp Physiol 298:R575–R583PubMedCrossRefGoogle Scholar
  20. 20.
    Gong DW, Monemdjou S, Gavrilova O, Leon LR, Marcus-Samuels B, Chou CJ, Everett C, Kozak LP, Li C, Deng C, Harper ME, Reitman ML (2000) Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J Biol Chem 275:16251–16257PubMedCrossRefGoogle Scholar
  21. 21.
    Green HJ, Sutton JR (2001) The effects of altitude on skeletal muscle. In: Hornbein TF, Schoene RB (eds) High altitude: an exploration of human adaptation. Marcel Dekker, Inc, New York, pp 443–492Google Scholar
  22. 22.
    Green HJ, Sutton JR, Cymerman A, Young PM, Houston CS (1989) Operation Everest II: adaptations in human skeletal muscle. J Appl Physiol 66:2454–2461PubMedGoogle Scholar
  23. 23.
    Green HJ, Sutton JR, Wolfel EE, Reeves JT, Butterfield GE, Brooks GA (1992) Altitude acclimatization and energy metabolic adaptations in skeletal muscle during exercise. J Appl Physiol 73:2701–2708PubMedGoogle Scholar
  24. 24.
    Hepple RT, Agey PJ, Hazelwood L, Szewczak JM, MacMillen RE, Mathieu-Costello O (1998) Increased capillarity in leg muscle of finches living at altitude. J Appl Physiol 85:1871–1876PubMedGoogle Scholar
  25. 25.
    Hochachka PW, Buck LT, Doll CJ, Land SC (1996) Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci U S A 93:9493–9498PubMedCrossRefGoogle Scholar
  26. 26.
    Holloszy JO, Coyle EF (1984) Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol 56:831–838PubMedGoogle Scholar
  27. 27.
    Hood DA (2001) Plasticity in skeletal, cardiac, and smooth muscle: invited review: contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 90:1137–1157PubMedGoogle Scholar
  28. 28.
    Hoppeler H, Vogt M (2001) Muscle tissue adaptations to hypoxia. J Exp Biol 204:3133–3139PubMedGoogle Scholar
  29. 29.
    Hoppeler H, Kleinert E, Schlegel C, Claassen H, Howald H, Kayar SR, Cerretelli P (1990) Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med 11(Suppl 1):S3–S9PubMedCrossRefGoogle Scholar
  30. 30.
    Hoppeler H, Vogt M, Weibel ER, Fluck M (2003) Response of skeletal muscle mitochondria to hypoxia. Exp Physiol 88:109–119PubMedCrossRefGoogle Scholar
  31. 31.
    Jammes Y, Zattara-Hartmann MC, Badier M (1997) Functional consequences of acute and chronic hypoxia on respiratory and skeletal muscles in mammals. Comp Biochem Physiol A Physiol 118:15–22PubMedCrossRefGoogle Scholar
  32. 32.
    Kayser B, Narici M, Binzoni T, Grassi B, Cerretelli P (1994) Fatigue and exhaustion in chronic hypobaric hypoxia: influence of exercising muscle mass. J Appl Physiol 76:634–640PubMedGoogle Scholar
  33. 33.
    LaManna JC, Kutina-Nelson KL, Hritz MA, Huang Z, Wong-Riley MT (1996) Decreased rat brain cytochrome oxidase activity after prolonged hypoxia. Brain Res 720:1–6PubMedCrossRefGoogle Scholar
  34. 34.
    MacDougall JD, Green HJ, Sutton JR, Coates G, Cymerman A, Young P, Houston CS (1991) Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand 142:421–427PubMedCrossRefGoogle Scholar
  35. 35.
    Magalhaes J, Ascensao A, Soares JMC, Ferreira R, Neuparth MJ, Marques F, Duarte JA (2005) Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle. J Appl Physiol 99:1247–1253PubMedCrossRefGoogle Scholar
  36. 36.
    Mainwood GW, Rakusan K (1982) A model for intracellular energy transport. Can J Physiol Pharmacol 60:98–102PubMedCrossRefGoogle Scholar
  37. 37.
    Mathieu-Costello O, Hepple RT (2002) Muscle structural capacity for oxygen flux from capillary to fiber mitochondria. Exercise Sport Sci Rev 30(2):80–84CrossRefGoogle Scholar
  38. 38.
    McMorrow C, Fredsted A, Carberry J, OGÇÖConnell RA, Bradford A, Jones JFX, O’Halloran KD (2011) Chronic hypoxia increases rat diaphragm muscle endurance and sodium-potassium ATPase pump content. Eur Respir J 37:1474–1481PubMedCrossRefGoogle Scholar
  39. 39.
    Mogensen M, Bagger M, Pedersen PK, Fernstrom M, Sahlin K (2006) Cycling efficiency in humans is related to low UCP3 content and to type I fibres but not to mitochondrial efficiency. J Physiol 571:669–681PubMedCrossRefGoogle Scholar
  40. 40.
    Mortola JP, Naso L (1997) Brown adipose tissue and its uncoupling protein in chronically hypoxic rats. Clin Sci 93:349–354PubMedGoogle Scholar
  41. 41.
    Mortola JP, Naso L (1998) Thermogenesis in newborn rats after prenatal or postnatal hypoxia. J Appl Physiol 85:84–90PubMedGoogle Scholar
  42. 42.
    Nouette-Gaulain K, Malgat M, Rocher C, Savineau JP, Marthan R, Mazat JP, Sztark F (2005) Time course of differential mitochondrial energy metabolism adaptation to chronic hypoxia in right and left ventricles. Cardiovasc Res 66:132–140PubMedCrossRefGoogle Scholar
  43. 43.
    Patel SP, Gamboa JL, McMullen CA, Rabchevsky A, Andrade FH (2009) Lower respiratory capacity in extraocular muscle mitochondria: evidence for intrinsic differences in mitochondrial composition and function. Invest Ophthalmol Vis Sci 50:180–186PubMedCrossRefGoogle Scholar
  44. 44.
    Ramirez JM, Folkow LP, Blix AS (2007) Hypoxia tolerance in mammals and birds: from the wilderness to the clinic. Annu Rev Physiol 69:113–143PubMedCrossRefGoogle Scholar
  45. 45.
    Russell AP, Wadley G, Hesselink MK, Schaart G, Lo S, Leger B, Garnham A, Kornips E, Cameron-Smith D, Giacobino JP, Muzzin P, Snow R, Schrauwen P (2003) UCP3 protein expression is lower in type I. IIa and IIx muscle fiber types of endurance-trained compared to untrained subjects. Pflugers Arch 445:563–569PubMedGoogle Scholar
  46. 46.
    Sharp JT, Hyatt RE (1986) Mechanical and electrical properties of respiratory muscles. In: Handbook of physiology. Section 3: the respiratory system. American Physiological Society (ed) Bethesda pp 389–414Google Scholar
  47. 47.
    Snyder GK, Wilcox EE, Burnham EW (1985) Effects of hypoxia on muscle capillarity in rats. Respir Physiol 62:135–140PubMedCrossRefGoogle Scholar
  48. 48.
    St-Pierre J, Tattersall GJ, Boutilier RG (2000) Metabolic depression and enhanced O2 affinity of mitochondria in hypoxic hypometabolism. Am J Physiol Regul Integr Comp Physiol 279:R1205–R1214PubMedGoogle Scholar
  49. 49.
    Sullivan SM, Pittman RN (1987) Relationship between mitochondrial volume density and capillarity in hamster muscles. Am J Physiol Heart Circ Physiol 252:H149–H155Google Scholar
  50. 50.
    Svedenhag J, Henriksson J, Sylven C (1983) Dissociation of training effects on skeletal muscle mitochondrial enzymes and myoglobin in man. Acta Physiol Scand 117:213–218PubMedCrossRefGoogle Scholar
  51. 51.
    Totsuka Y, Nagao Y, Horii T, Yonekawa H, Imai H, Hatta H, Izaike Y, Tokunaga T, Atomi Y (2003) Physical performance and soleus muscle fiber composition in wild-derived and laboratory inbred mouse strains. J Appl Physiol 95:720–727PubMedGoogle Scholar
  52. 52.
    Vidal-Puig A, Solanes G, Grujic D, Flier JS, Lowell BB (1997) UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun 235:79–82PubMedCrossRefGoogle Scholar
  53. 53.
    Vidal-Puig AJ, Grujic D, Zhang CY, Hagen T, Boss O, Ido Y, Szczepanik A, Wade J, Mootha V, Cortright R, Muoio DM, Lowell BB (2000) Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem 275:16258–16266PubMedCrossRefGoogle Scholar
  54. 54.
    Wen JJ, Bhatia V, Popov VL, Garg NJ (2006) Phenyl-{alpha}-tert-butyl nitrone reverses mitochondrial decay in acute Chagas’ disease. Am J Pathol 169:1953–1964PubMedCrossRefGoogle Scholar
  55. 55.
    Zattara-Hartmann MC, Badier M, Guillot C, Tomei C, Jammes Y (1995) Maximal force and endurance to fatigue of respiratory and skeletal muscles in chronic hypoxemic patients: the effects of oxygen breathing. Muscle Nerve 18:495–502PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of PhysiologyUniversity of KentuckyLexingtonUSA
  2. 2.Division of Clinical PharmacologyVanderbilt University Medical CenterNashvilleUSA

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