Molecular and Cellular Biochemistry

, Volume 183, Issue 1–2, pp 87–96

Impaired mitochondrial oxidative phosphorylation in skeletal muscle of the dystrophin-deficient mdx mouse

  • Andrey V. Kuznetsov
  • Kirstin Winkler
  • Falk Wiedemann
  • Peter von Bossanyi
  • Knut Dietzmann
  • Wolfram S. Kunz


The mdx mouse, an animal model of the Duchenne muscular dystrophy, was used for the investigation of changes in mitochondrial function associated with dystrophin deficiency. Enzymatic analysis of skeletal muscle showed an approximately 50% decrease in the activity of all respiratory chain-linked enzymes in musculus quadriceps of adult mdx mice as compared with controls, while in cardiac muscle no difference was observed. The activities of cytosolic and mitochondrial matrix enzymes were not significantly different from the control values in both cardiac and skeletal muscles. In saponin-permeabilized skeletal muscle fibers of mdx mice the maximal rates of mitochondrial respiration were about two times lower than those of controls. These changes were also demonstrated on the level of isolated mitochondria. Mdx muscle mitochondria had only 60% of maximal respiration activities of control mice skeletal muscle mitochondria and contained only about 60% of hemoproteins of mitochondrial inner membrane. Similar findings were observed in a skeletal muscle biopsy of a Duchenne muscular dystrophy patient. These data strongly suggest that a specific decrease in the amount of all mitochondrial inner membrane enzymes, most probably as result of Ca2+ overload of muscle fibers, is the reason for the bioenergetic deficits in dystrophin-deficient skeletal muscle.

mdx mice dystrophin deficiency skeletal and cardiac muscles skinned fibers mitochondria oxidative phosphorylation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bulfield G, Siller WG, Wight PAL, Moore KJ: X-chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA 81: 1189–1192, 1984PubMedGoogle Scholar
  2. 2.
    Sicinski P, Geng Y, Ryder-Cook AS, Barnard EA, Darlison MG, Barnard PJ: The molecular basis of muscular dystrophy in the mdx mouse: A point mutation. Science 244: 1578–1580, 1989PubMedGoogle Scholar
  3. 3.
    Pasternak C, Wong S, Elson EL: Mechanical function of dystrophin in muscle cells. J Cell Biol 128: 355–361, 1995CrossRefPubMedGoogle Scholar
  4. 4.
    Duncan CJ: Dystrophin and the integrity of the sarcolemma in Duchenne muscular dystrophy. Experientia 45: 175–177, 1989PubMedGoogle Scholar
  5. 5.
    Karpati G, Carpenter S: Small-caliber skeletal muscle fibers do not suffer deleterious consequences of dystrophic gene expression. Am J Med Genet 25: 653–658, 1986PubMedGoogle Scholar
  6. 6.
    Menke A, Jockusch H: Decreased osmotic stability of dystrophin-less muscle cells from the mdx mouse. Nature 349: 69–71, 1991CrossRefPubMedGoogle Scholar
  7. 7.
    Turner PR, Westwood T, Regen CM, Steinhardt RA: Increased protein degradation results from elevated free calcium levels found in muscle from mdx mice. Nature 335: 735–738, 1988CrossRefPubMedGoogle Scholar
  8. 8.
    Franco A, Lansman JB: Calcium entry through stretch-inactivated ion channels in mdx myotubes. Nature 344: 670–673, 1990CrossRefPubMedGoogle Scholar
  9. 9.
    Sandri M, Carraro U, Podhorska-Okolov M, Rizzi C, Arslan P, Monti D, Franceschi C: Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise. FEBS Lett 373: 291–295, 1995CrossRefPubMedGoogle Scholar
  10. 10.
    Tidball JG, Albrecht DE, Lokensgard BE, Spencer MJ: Apoptosis precedes necrosis of dystrophin-deficient muscle. J Cell Sci 108: 2197–2204, 1995PubMedGoogle Scholar
  11. 11.
    Bernardi P: The permeability transition pore. Control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death. Biochim Biophys Acta 1275: 5–9, 1996PubMedGoogle Scholar
  12. 12.
    Liu X, Kim CN, Yang J, Jemmerson R, Wang X: Induction of apoptotic program in cell free extracts: Requirement for dATP and cytochrome c. Cell 86: 147–157, 1996CrossRefPubMedGoogle Scholar
  13. 13.
    Dunn JF, Tracey I, Radda GK: Exercise metabolism in Duchenne muscular dystrophy: a biochemical and [31P] nuclear magnetic resonance study of mdx mice. Proc R Soc Lond B Biol Sci 251: 201–206, 1993PubMedGoogle Scholar
  14. 14.
    Even PC, Decrouy A, Chinet A: Defective regulation of energy metabolism in mdx-mouse skeletal muscles. Biochem J 304: 649–654, 1994PubMedGoogle Scholar
  15. 15.
    Glesby MJ, Rosenmann E, Nylen EG, Wrogemann K: Serum CK, calcium, magnesium, and oxidative phosphorylation in mdx mouse muscular dystrophy. Muscle and Nerve 11: 852–856, 1988PubMedGoogle Scholar
  16. 16.
    Scholte HR, Luyt-Houwen IE, Busch HF, Jennekens FG: Muscle mitochondria from patients with Duchenne muscular dystrophy have a normal β-oxidation, but an impaired oxidative phosphorylation. Neurology 35: 1396–1397, 1985PubMedGoogle Scholar
  17. 17.
    Dupont-Versteegden EE, Baldwin RA, McCarter RJ, Vonlanthen MG: Does muscular dystrophy affect metabolic rate? A study in mdx mice. J Neurol Sci 121: 203–207, 1994CrossRefPubMedGoogle Scholar
  18. 18.
    Gannoun-Zaki L, Fournier-Bidoz S, Le Cam G, Chambon C, Millasseau Ph, Léger JJ, Dechesne, CA: Down-regulation of mitochondrial mRNAs in the mdx mouse model for Duchenne muscular dystrophy. FEBS Lett 375: 268–272, 1995CrossRefPubMedGoogle Scholar
  19. 19.
    Kunz WS, Kuznetsov AV, Schulze W, Eichhorn K, Schild L, Striggow F, Bohnensack R, Neuhof S, Grasshoff H, Neumann HW, Gellerich FN: Functional characterization of mitochondrial oxidative phosphorylation in saponin-skinned human muscle fibers. Biochim Biophys Acta 1144: 46–53, 1993PubMedGoogle Scholar
  20. 20.
    Kunz WS, Kuznetsov AV, Winkler K, Gellerich FN, Neuhof S, Neumann HW: Measurement of fluorescence changes of NAD(P)H and of fluorescent flavoproteins in saponin-skinned human skeletal muscle fibers. Anal Biochem 216: 322–327, 1994CrossRefPubMedGoogle Scholar
  21. 21.
    Lin A, Krockmalnic G, Penman S: Imaging cytoskeleton-mitochondrial membrane attachments by embedment-free electron microscopy of saponin-extracted cells. Proc Natl Acad Sci USA 87: 8565–8569, 1990PubMedGoogle Scholar
  22. 22.
    Veksler VI, Kuznetsov AV, Sharov VG, Kapelko VI, Saks VA: Mitochondrial respiratory parameters in cardiac tissue: A novel method of assessment by using saponin-skinned fibers. Biochim Biophys Acta 892: 191–196, 1987PubMedGoogle Scholar
  23. 23.
    Wisniewski E, Kunz WS, Gellerich FN: Phosphate affects the distribution of flux control among the enzymes of oxidative phosphorylation in rat skeletal mitochondria. J Biol Chem 268: 9343–9346, 1993PubMedGoogle Scholar
  24. 24.
    Bergmeier HU: Methoden der enzymatischen Analyse. 2. Auflage, Akademie Verlag, Berlin, 1970Google Scholar
  25. 25.
    Winkler K, Kuznetsov AV, Lins H, Kirches E, von Bossanyi P, Dietzmann K, Frank B, Feistner H, Kunz WS: Laser-excited fluorescence studies of mitochondrial function in saponin-skinned skeletal muscle fibers of patients with chronic progressive external ophthalmoplegia. Biochim Biophys Acta 1272: 181–184, 1995PubMedGoogle Scholar
  26. 26.
    Balaban RS, Mootha VK, Arai A: Spectroscopic determination of cytochrome c oxidase content in tissues containing myoglobin or hemoglobin. Anal Biochem 237: 274–278, 1996CrossRefPubMedGoogle Scholar
  27. 27.
    Edwards CA, Bowyer JR, Trumpower BL: Function of the iron-sulfur protein of the cytochrome b-c 1 segment in electron transfer reactions of the mitochondrial respiratory chain. J Biol Chem 257: 3705–3713, 1982PubMedGoogle Scholar
  28. 28.
    DiMario JX, Uzman A, Strohman RC: Fiber regeneration is not persistent in dystrophic (mdx) mouse skeletal muscle. Dev Biol 148: 314–321, 1991PubMedGoogle Scholar
  29. 29.
    Sesodia S, Choksi RM, Nemeth PM: Nerve-dependent recovery of metabolic pathways in regenerating soleus muscles. J Muscle Res Cell Motil 15: 573–581, 1994PubMedGoogle Scholar
  30. 30.
    Sharp NJ, Kornegay JN, Bartlett RJ, Hung WY, Dykstra MJ: Notexininduced muscle injury in the dog. J Neurol Sci 116: 73–81, 1993PubMedGoogle Scholar
  31. 31.
    Whalen RG, Harris JB, Butler-Browne C, Sesodia S: Expression of myosin isoforms during notexin-induced regeneration of rat soleus muscles. Dev Biol 141: 24–40, 1990CrossRefPubMedGoogle Scholar
  32. 32.
    Rezvani M, Cafarelli E, Hood, DA: Performance and excitability of mdx mouse muscle at 2, 5, and 13 weeks of age. J Appl Physiol 78: 961–967, 1995PubMedGoogle Scholar
  33. 33.
    Peri V, Ajdukovic B, Holland P, Tuana, BS: Dystrophin predominantly localizes to the transverse tubule/Z-line regions of single ventricular myocytes and exhibits distinct associations with the membrane. Mol Cell Biochem 130: 57–65, 1994PubMedGoogle Scholar
  34. 34.
    Hoffman EP, Morgan JE, Watkins SC, Partridge TA: Somatic reversion/suppression of the mouse mdx phenotype in vivo. J Neurol Sci 99: 9–25, 1990CrossRefPubMedGoogle Scholar
  35. 35.
    Tanaka H, Ikeya K, Ozawa E: Difference in the expression pattern of dystrophin on the surface membrane between the skeletal and cardiac muscles of mdx carrier mice. Histochemistry 93: 447–452, 1990CrossRefPubMedGoogle Scholar
  36. 36.
    Yang B, Ibraghimov-Beskrovnaya O, Moomaw CR, Slaughter CA, Campbell KP: Heterogeneity of the 59 kD dystrophin-associated protein revealed by cDNA cloning and expression. J Biol Chem 269: 6040–6044, 1994PubMedGoogle Scholar
  37. 37.
    Saks VA, Kuznetsov AV, Khuchua ZA, Vasilyeva EV, Belikova YO, Kesvatera T, Tiivel T: Control of cellular respiration in vivo by mitochondrial outer membrane and by creatine kinase. Possible involvement of mitochondrial-cytoskeleton interactions. J Mol Cell Cardiol 27: 625–645, 1995PubMedGoogle Scholar
  38. 38.
    Sun J, Bird CH, Salem HH, Bird P: Association of annexin V with mitochondria. FEBS Lett 329: 79–83, 1993CrossRefPubMedGoogle Scholar
  39. 39.
    Kuznetsov AV, Clark JF, Winkler K, Kunz WS: Increase of flux control of cytochrome c oxidase in copper-deficient mottled brindled mice. J Biol Chem 271: 283–288, 1996CrossRefPubMedGoogle Scholar
  40. 40.
    Gunter TE, Gunter KK, Sheu SS, Gavin CE: Mitochondrial calcium transport: Physiological and pathological relevance. Am J Physiol 267: C313–C339, 1994PubMedGoogle Scholar
  41. 41.
    Lucas-Heron B: Skeletal muscle of patients with Duchenne's muscular dystrophy: Evidence of a mitochondrial proteolytic factor responsible for calmitine deficiency. Biochem Biophys Res Commun 223: 31–35, 1996CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Andrey V. Kuznetsov
    • 1
  • Kirstin Winkler
    • 1
  • Falk Wiedemann
    • 1
  • Peter von Bossanyi
    • 2
  • Knut Dietzmann
    • 2
  • Wolfram S. Kunz
    • 1
  1. 1.Neurobiochemisches Labor der Klinik für NeurologieUniversitätsklinikum der Otto-von-Guericke-UniversitätMagdeburgGermany
  2. 2.Institut für NeuropathologieUniversitätsklinikum der Otto-von-Guericke-UniversitätMagdeburgGermany

Personalised recommendations