Advertisement

Hypoxia-Induced Gene Activity in Disused Oxidative Muscle

  • Christoph Däpp
  • Max Gassmann
  • Hans Hoppeler
  • Martin Flück
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 588)

Abstract

Hypoxia is an important modulator of the skeletal muscle’s oxidative phenotype. However, little is known regarding the molecular circuitry underlying the muscular hypoxia response and the interaction of hypoxia with other stimuli of muscle oxidative capacity. We hypothesized that exposure of mice to severe hypoxia would promote the expression of genes involved in capillary morphogenesis and glucose over fatty acid metabolism in active or disused soleus muscle of mice. Specifically, we tested whether the hypoxic response depends on oxygen sensing via the alpha-subunit of hypoxia-inducible factor-1 (HIF-1α). Spontaneously active wildtype and HIF-1α heterozygous deficient adult female C57B1/6 mice were subjected to hypoxia (PiO2 70 mmHg). In addition, animals were subjected to hypoxia after 7 days of muscle disuse provoked by hindlimb suspension. Soleus muscles were rapidly isolated and analyzed for transcript level alterations with custom-designed AtlasTM cDNA expression arrays (BD Biosciences) and cluster analysis of differentially expressed mRNAs. Multiple mRNA elevations of factors involved in dissolution and stabilization of blood vessels, glycolysis, and mitochondrial respiration were evident after 24 hours of hypoxia in soleus muscle. In parallel transcripts of fat metabolism were reduced. A comparable hypoxia-induced expression pattern involving complex alterations of the IGF-I axis was observed in reloaded muscle after disuse. This hypoxia response in spontaneously active animals was blunted in the HIF-1α heterozygous deficient mice demonstrating 35% lower HIF-1α mRNA levels. Our molecular observations support the concept that severe hypoxia provides HIF-1-dependent signals for remodeling of existing blood vessels, a shift towards glycolytic metabolism and altered myogenic regulation in oxidative mouse muscle and which is amplified by enhanced muscle use. These findings further imply differential mitochondrial turnover and a negative role of HIF-1α for control of fatty acid oxidation in skeletal muscle exposed to one day of severe hypoxia.

Key Words

HIF-1α microarray angiogenesis altitude ischemia 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Adair TH, Gay WJ and Montani JP. Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am J Physiol 259: R393–R404, 1990.PubMedGoogle Scholar
  2. 2.
    Allaire J, Maltais F, Doyon JF, Noel M, LeBlanc P, Carrier G, Simard C and Jobin J. Peripheral muscle endurance and the oxidative profile of the quadriceps in patients with COPD. Thorax 59: 673–678, 2004.PubMedCrossRefGoogle Scholar
  3. 3.
    Antonucci R, Berton E, Huertas A, Laveneziana P and Palange P. Exercise physiology in COPD. Monaldi Arch Chest Dis 59: 134–139, 2003.PubMedGoogle Scholar
  4. 4.
    Banchero N. Cardiovascular responses to chronic hypoxia. Annu Rev Physiol 49: 465–476, 1987.PubMedCrossRefGoogle Scholar
  5. 5.
    Bass A, Brdiczka D, Eyer P, Hofer S and Pette D. Metabolic differentiation of distinct muscle types at the level of enzymatic organization. Eur J Biochem 10: 198–206, 1969.PubMedCrossRefGoogle Scholar
  6. 6.
    Dapp C, Schmutz S, Hoppeler H and Fluck M. Transcriptional reprogramming and ultrastructure during atrophy and recovery of mouse soleus muscle. Physiol Cenomics 20:97–107, 2004.CrossRefGoogle Scholar
  7. 7.
    Djonov V, Baum O and Burri PH. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res 314: 107–117, 2003.PubMedCrossRefGoogle Scholar
  8. 8.
    Eisen MB, Spellman PT, Brown PO and Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95: 14863–14868, 1998.PubMedCrossRefGoogle Scholar
  9. 9.
    Gosker HR, Wouters EF, van der Vusse GJ and Schols AM. Skeletal muscle dysfunction in chronic obstructive pulmonary disease and chronic heart failure: underlying mechanisms and therapy perspectives. Am J Clin Nutr 71: 1033–1047, 2000.PubMedGoogle Scholar
  10. 10.
    Haddad F and Adams GR. Selected contribution: acute cellular and molecular responses to resistance exercise. J Appl Physiol 93: 394–403, 2002.PubMedGoogle Scholar
  11. 11.
    Hepple RT. Skeletal muscle: microcirculatory adaptation to metabolic demand. Med Sci Sports Exerc 32: 117–123, 2000.PubMedCrossRefGoogle Scholar
  12. 12.
    Hochberg Y and Benjamini Y. More powerful procedures for multiple signifi cance testing. Stat Med 9: 811–818, 1990.PubMedGoogle Scholar
  13. 13.
    Hofer T, Wenger RH, Kramer MF, Ferreira GC and Gassmann M. Hypoxic up-regulation of erythroid 5-aminolevulinate synthase. Blood 101: 348–350, 2003.PubMedCrossRefGoogle Scholar
  14. 14.
    Hopfl G, Ogunshola O and Gassmann M. HIFs and tumors-causes and consequences. Am J Physiol Regul Integr Comp Physiol 286: R608–R623, 2004.PubMedGoogle Scholar
  15. 15.
    Hopfl G, Ogunshola O and Gassmann M. Hypoxia and high altitude. The molecular response. Adv Exp Med Biol 543: 89–115, 2003.PubMedGoogle Scholar
  16. 16.
    Hoppeler H and Vogt M. Muscle tissue adaptations to hypoxia. J Exp Biol 204: 3133–3139, 2001.PubMedGoogle Scholar
  17. 17.
    Hoppeler H, Luthi P, Claassen H, Weibel ER and Howald H. The ultrastructure of the normal human skeletal muscle. A morphometric analysis on untrained men, women and well-trained orienteers. Pfl ugers Arch 344: 217–232, 1973.CrossRefGoogle Scholar
  18. 18.
    Hoppeler H and Desplanches D. Muscle structural modifi cations in hypoxia. Int J Sports Med 13Suppl 1: S166–S168, 1992.PubMedCrossRefGoogle Scholar
  19. 19.
    Hoppeler H. Vascular growth in hypoxic skeletal muscle. Adv Exp Med Biol 474: 277–286, 1999.PubMedGoogle Scholar
  20. 20.
    Hoppeler H, Vogt M, Weibel ER and Fluck M. Response of skeletal muscle mitochondria to hypoxia. Exp Physiol 88: 109–119, 2003.PubMedCrossRefGoogle Scholar
  21. 21.
    Hudlicka O. Is physiological angiogenesis in skeletal muscle regulated by changes in microcirculation? Microcirculation 5: 5–23, 1998.PubMedGoogle Scholar
  22. 22.
    Jagoe RT, Lecker SH, Gomes M and Goldberg AL. Patterns of gene expression in atrophying skeletal muscles: response to food deprivation. FASEB J 16: 1697–1712, 2002.PubMedCrossRefGoogle Scholar
  23. 23.
    Kilic N, Oliveira-Ferrer L, Wurmbach JH, Loges S, Chalajour F, Vahid SN, Weil J, Fernando M and Ergun S. Pro-angiogenic signaling by the endothelial presence of CEACAM1. J Biol Chem 280: 2361–2369, 2005.PubMedCrossRefGoogle Scholar
  24. 24.
    Mador MJ and Bozkanat E. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Respir Res 2: 216–224, 2001.PubMedCrossRefGoogle Scholar
  25. 25.
    Mason SD, Howlett RA, Kim MJ, Olfert IM, Hogan MC, McNulty W, Hickey RP, Wagner PD, Kahn CR, Giordano FJ and Johnson RS. Loss of skeletal muscle HIF-1alpha results in altered exercise endurance. PLoS Biol 2: e288, 2004.PubMedCrossRefGoogle Scholar
  26. 26.
    Mathieu-Costello O. Muscle adaptation to altitude: tissue capillarity and capacity for aerobic metabolism. High Alt Med Biol 2: 413–425, 2001.PubMedCrossRefGoogle Scholar
  27. 27.
    McGuigan MR, Bronks R, Newton RU, Sharman MJ, Graham JC, Cody DV and Kraemer WJ. Resistance training in patients with peripheral arterial disease: effects on myosin isoforms, fi ber type distribution, and capillary supply to skeletal muscle. J Gerontol A Biol Sci Med Sci 56: B302–B310, 2001.PubMedGoogle Scholar
  28. 28.
    Millis RM, Stephens TA, Harris G, Anonye C and Reynolds M. Relationship between intracellular oxygenation and neuromuscular conduction during hypoxic hypoxia. Life Sci 35: 2443–2451, 1984.PubMedCrossRefGoogle Scholar
  29. 29.
    Narici MV and Kayser B. Hypertrophie response of human skeletal muscle to strength training in hypoxia and normoxia. Eur J Appl Physiol Occup Physiol 70: 213–219, 1995.PubMedCrossRefGoogle Scholar
  30. 30.
    Nilsson I, Shibuya M and Wennstrom S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res 299: 476–485, 2004.PubMedCrossRefGoogle Scholar
  31. 31.
    Ning W, Chu TJ, Li CJ, Choi AM and Peters DG. Genome-wide analysis of the endothelial transcriptome under short-term chronic hypoxia. Physiol Genomics 18: 70–78, 2004.PubMedCrossRefGoogle Scholar
  32. 32.
    Nioka S, McCully K, McClellan G, Park J and Chance B. Oxygen transport and intracellular bioenergetics on stimulated cat skeletal muscle. Adv Exp Med Biol 510: 267–272, 2003.PubMedGoogle Scholar
  33. 33.
    Pastoris O, Foppa P, Catapano M and Dossena M. Effects of hypoxia on enzyme activities in skeletal muscle of rats of different ages. An attempt at pharmacological treatment. Pharmacol Res 32: 375–381, 1995.PubMedCrossRefGoogle Scholar
  34. 34.
    Pette D and Spamer C. Metabolic properties of muscle fi bers. Fed Proc 45: 2910–2914, 1986.PubMedGoogle Scholar
  35. 35.
    Raguso CA, Guinot SL, Janssens JP, Kayser B and Pichard C. Chronic hypoxia: common traits between chronic obstructive pulmonary disease and altitude. Curr Opin Clin Nutr Metab Care 7: 411–417, 2004.PubMedCrossRefGoogle Scholar
  36. 36.
    Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS and Wagner PD. Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J Clin Invest 96: 1916–1926, 1995.PubMedGoogle Scholar
  37. 37.
    Sauleda J, Garcia-Palmer F, Wiesner RJ, Tarraga S, Halting I, Tomas P, Gomez C, Saus C, Palou A and Agusti AG. Cytochrome oxidase activity and mitochondrial gene expression in skeletal muscle of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 157: 1413–1417, 1998.PubMedGoogle Scholar
  38. 38.
    Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88: 1474–1480, 2000.PubMedGoogle Scholar
  39. 39.
    Slate RK, Ryan M and Bongard FS. Dependence of tissue oxygen on oxygen delivery. J Surg Res 61: 201–205, 1996.PubMedCrossRefGoogle Scholar
  40. 40.
    Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M and Candinas D. HIF-1 is expressed in normoxic tissue and displays an organ-specifi c regulation under systemic hypoxia. FASEB J 15: 2445–2453, 2001.PubMedGoogle Scholar
  41. 41.
    Tsai AG, Johnson PC and Intaglietta M. Oxygen gradients in the microcirculation. Physiol Rev 83: 933–963, 2003.PubMedGoogle Scholar
  42. 42.
    Weineck J. Optimales Training. Erlangen: Perimed Fachbuch-Verlagsgesellschaft, 1983.Google Scholar
  43. 43.
    Wittwer M, Billeter R, Hoppeler H and Fluck M. Regulatory gene expression in skeletal muscle of highly endurance-trained humans. Acta Physiol Scand 180: 217–227, 2004.PubMedCrossRefGoogle Scholar
  44. 44.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ and Holash J. Vascularspecifi c growth factors and blood vessel formation. Nature 407: 242–248, 2000.PubMedCrossRefGoogle Scholar
  45. 45.
    Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JS, Wiener CM, Sylvester JT and Semenza GL. Impaired physiological responses to chronic hypoxia in mice partially defi cient for hypoxia-inducible factor lalpha. J Clin Invest 103: 691–696, 1999PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Christoph Däpp
    • 1
  • Max Gassmann
    • 2
  • Hans Hoppeler
    • 1
  • Martin Flück
    • 1
  1. 1.Department of AnatomyUniversity of BerneSwitzerland
  2. 2.Vetsuisse Faculty and Zurich Center for Integrative Human PhysiologyUniversity if ZurichSwitzerland

Personalised recommendations