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The physiological effects of IGF-1 (class 1:Ea transgene) over-expression on exercise-induced damage and adaptation in dystrophic muscles of mdx mice

  • Muscle Physiology
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disorder in which muscle weakness and fragility contribute to ongoing muscle degeneration. Although exercise-induced muscle damage is associated with adaptation that protects normal muscle from further damage, exploiting this process to protect dystrophic muscle has been avoided for fear of inducing excessive muscle degeneration. However, muscle-specific over-expression of the class 1:Ea isoform of insulin-like growth factor-1 (IGF-1) reduces myofibre necrosis in dystrophic mdx mice (a model for DMD) and, therefore, may enhance the adaptation process in response to eccentric exercise. To test this hypothesis, we evaluated the effect of transgenic class 1:Ea IGF-1 over-expression on the susceptibility to muscle damage and subsequent adaptation in 12-week-old dystrophic mdx and non-dystrophic control mice. Experiments were conducted in vivo using a custom-built isokinetic mouse dynamometer to measure the deficit in joint torque (indicating muscle damage) after 20 maximal lengthening (eccentric) contractions. Adaptation to this damaging exercise was evaluated by repeating the protocol 7 days after the initial exercise. The over-expression of IGF-1 significantly increased the normalised joint torque in non-dystrophic mice and appeared to ameliorate the muscle weakness in dystrophic mice. All mice displayed a marked reduction in the susceptibility to muscle damage on day 7; however, this adaptation was unaffected by IGF-1, showing that IGF-1 does not protect the dystrophic muscles of adult mdx mice against damage resulting from maximal lengthening contractions.

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References

  1. Angelini C (2007) The role of corticosteroids in muscular dystrophy: a critical appraisal. Muscle Nerve 36:424–435

    Article  PubMed  CAS  Google Scholar 

  2. Ansved T (2003) Muscular dystrophies: influence of physical conditioning on the disease evolution. Curr Opin Clin Nutr Metab Care 6:435–439

    Article  PubMed  Google Scholar 

  3. Ashton-Miller JA, He Y, Kadhiresan VA et al (1992) An apparatus to measure in vivo biomechanical behavior of dorsi- and plantarflexors of mouse ankle. J Appl Physiol 72:1205–1211

    PubMed  CAS  Google Scholar 

  4. Barton ER, Morris L, Musaro A et al (2002) Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J Cell Biol 157:137–148

    Article  PubMed  CAS  Google Scholar 

  5. Brooks SV (1998) Rapid recovery following contraction-induced injury to in situ skeletal muscles in mdx mice. J Muscle Res Cell Motil 19:179–187

    Article  PubMed  CAS  Google Scholar 

  6. Broussard SR, McCusker RH, Novakofski JE et al (2003) Cytokine-hormone interactions: Tumor necrosis factor (alpha) impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts. Endocrinology 144:2988–2996

    Article  PubMed  CAS  Google Scholar 

  7. Call JA, Voelker KA, Wolff AV et al (2008) Endurance capacity in maturing mdx mice is markedly enhanced by combined voluntary wheel running and green tea extract. J Appl Physiol. doi:10.1152/japplphysiol.00028.2008

  8. Carter GT, Wineinger MA, Walsh SA et al (1995) Effect of voluntary wheel-running exercise on muscles of the mdx mouse. Neuromuscul Disord 5:323–332

    Article  PubMed  CAS  Google Scholar 

  9. Childers MK, Okamura CS, Bogan DJ et al (2002) Eccentric contraction injury in dystrophic canine muscle. Arch Phys Med Rehabil 83:1572–1578

    Article  PubMed  Google Scholar 

  10. De Luca A, Pierno S, Liantonio A et al (2003) Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. J Pharmacol Exp Ther 304:453–463

    Article  PubMed  CAS  Google Scholar 

  11. Dupont-Versteegden EE, McCarter RJ, Katz MS (1994) Voluntary exercise decreases progression of muscular dystrophy in diaphragm of mdx mice. J Appl Physiol 77:1736–1741

    PubMed  CAS  Google Scholar 

  12. Fraysse B, Liantonio A, Cetrone M et al (2004) The alteration of calcium homeostasis in adult dystrophic mdx muscle fibers is worsened by a chronic exercise in vivo. Neurobiol Dis 17:144–154

    Article  PubMed  CAS  Google Scholar 

  13. Friden J, Lieber RL (2001) Serum creatine kinase level is a poor predictor of muscle function after injury. Scand J Med Sci Sports 11:126–127

    Article  PubMed  CAS  Google Scholar 

  14. Frost RA, Nystrom GJ, Lang CH (2003) Tumor necrosis factor-alpha decreases insulin-like growth factor-I messenger ribonucleic acid expression in C2C12 myoblasts via a jun N-terminal kinase pathway. Endocrinology 144:1770–1779

    Article  PubMed  CAS  Google Scholar 

  15. Gehrig SM, Ryall JG, Schertzer JD et al (2008) IGF-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage. Exp Physiol. doi:10.1113/expphysiol.2008.042838

  16. Gleeson N, Eston R, Marginson V et al (2003) Effects of prior concentric training on eccentric exercise induced muscle damage. Br J Sports Med 37:119–125

    Article  PubMed  CAS  Google Scholar 

  17. Gosselin LE, Burton H (2002) Impact of initial muscle length on force deficit following lengthening contractions in mammalian skeletal muscle. Muscle Nerve 25:822–827

    Article  PubMed  Google Scholar 

  18. Grange RW, Call JA (2007) Recommendations to define exercise prescription for Duchenne muscular dystrophy. Exerc Sport Sci Rev 35:12–17

    Article  PubMed  Google Scholar 

  19. Gregorevic P, Plant DR, Lynch GS (2004) Administration of insulin-like growth factor-I improves fatigue resistance of skeletal muscles from dystrophic mdx mice. Muscle Nerve 30:295–304

    Article  PubMed  CAS  Google Scholar 

  20. Gregory J, Morgan D, Allen T et al (2007) The shift in muscle’s length–tension relation after exercise attributed to increased series compliance. Eur J Appl Physiol 99:431–441

    Article  PubMed  CAS  Google Scholar 

  21. Grounds MD, Radley HG, Gebski BL et al (2008) Implications of cross-talk between TNF and IGF-1 signalling in skeletal muscle. Clin Exp Pharmacol Physiol 35:846–851

    Article  PubMed  CAS  Google Scholar 

  22. Grounds MD, Radley HG, Lynch GS et al (2008) Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol Dis 31:1–19

    Article  PubMed  CAS  Google Scholar 

  23. Grounds MD, Sorokin L, White J (2005) Strength at the extracellular matrix–muscle interface. Scand J Med Sci Sports 15:381–391

    Article  PubMed  CAS  Google Scholar 

  24. Hamer PW, McGeachie JM, Davies MJ et al (2002) Evans blue dye as an in vivo marker of myofibre damage: optimising parameters for detecting initial myofibre membrane permeability. J Anat 200:69–79

    Article  PubMed  CAS  Google Scholar 

  25. Hayes A, Lynch GS, Williams DA (1993) The effects of endurance exercise on dystrophic mdx mice. I. Contractile and histochemical properties of intact muscles. Proc R Soc Lond B Biol Sci 253:19–25

    Article  CAS  Google Scholar 

  26. Hodgetts S, Radley H, Davies M et al (2006) Reduced necrosis of dystrophic muscle by depletion of host neutrophils, or blocking TNF[alpha] function with Etanercept in mdx mice. Neuromuscul Disord 16:591–602

    Article  PubMed  Google Scholar 

  27. Kilmer DD, Aitkens SG, Wright NC et al (2001) Response to high-intensity eccentric muscle contractions in persons with myopathic disease. Muscle Nerve 24:1181–1187

    Article  PubMed  CAS  Google Scholar 

  28. Kornegay JN, Bogan DJ, Bogan JR et al (1999) Contraction force generated by tarsal joint flexion and extension in dogs with golden retriever muscular dystrophy. J Neurol Sci 166:115–121

    Article  PubMed  CAS  Google Scholar 

  29. Lynn R, Morgan DL (1994) Decline running produces more sarcomeres in rat vastus intermedius muscle fibers than does incline running. J Appl Physiol 77:1439–1444

    PubMed  CAS  Google Scholar 

  30. McGeachie JK, Grounds MD, Partridge TA et al (1993) Age-related changes in replication of myogenic cells in mdx mice: quantitative autoradiographic studies. J Neurol Sci 119:169–179

    Article  PubMed  CAS  Google Scholar 

  31. McHugh MP (2003) Recent advances in the understanding of the repeated bout effect: the protective effect against muscle damage from a single bout of eccentric exercise. Scand J Med Sci Sports 13:88–97

    Article  PubMed  Google Scholar 

  32. Morgan DL (1990) New insights into the behavior of muscle during active lengthening. Biophys J 57:209–221

    Article  PubMed  CAS  Google Scholar 

  33. Musaro A, McCullagh K, Paul A et al (2001) Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27:195–200

    Article  PubMed  CAS  Google Scholar 

  34. Okano T, Yoshida K, Nakamura A et al (2005) Chronic exercise accelerates the degeneration-regeneration cycle and downregulates insulin-like growth factor-1 in muscle of mdx mice. Muscle Nerve 32:191–199

    Article  PubMed  CAS  Google Scholar 

  35. Proske U, Morgan DL (2001) Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications. J Physiol (Lond) 537:333–345

    Article  CAS  Google Scholar 

  36. Radley HG, Davies MJ, Grounds MD (2008) Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment. Neuromuscul Disord 18:227–238

    Article  PubMed  Google Scholar 

  37. Schertzer JD, van der Poel C, Shavlakadze T et al (2008) Muscle-specific overexpression of IGF-I improves E–C coupling in skeletal muscle fibers from dystrophic mdx mice. Am J Physiol Cell Physiol 294:C161–168

    Article  PubMed  CAS  Google Scholar 

  38. Shavlakadze T, Boswell JM, Burt DW et al (2006) Rsk[alpha]-actin/hIGF-1 transgenic mice with increased IGF-I in skeletal muscle and blood: impact on regeneration, denervation and muscular dystrophy. Growth Horm IGF Res 16:157–173

    Article  PubMed  CAS  Google Scholar 

  39. Shavlakadze T, White J, Hoh JFY et al (2004) Targeted expression of insulin-like growth factor-1 reduces early myofiber necrosis in dystrophic mdx mice. Mol Ther 10:829–843

    Article  PubMed  CAS  Google Scholar 

  40. Shavlakadze T, White JD, Davies M et al (2005) Insulin-like growth factor I slows the rate of denervation induced skeletal muscle atrophy. Neuromuscular Disord 15:139–146

    Article  Google Scholar 

  41. Shavlakadze T, Winn N, Rosenthal N et al (2005) Reconciling data from transgenic mice that overexpress IGF-I specifically in skeletal muscle. Growth Horm IGF Res 15:4–18

    Article  PubMed  CAS  Google Scholar 

  42. Sveen M-L, Jeppesen TD, Hauerslev A et al (2007) Endurance training: an effective and safe treatment for patients with LGMD2I. Neurology 68:59–61

    Article  PubMed  Google Scholar 

  43. Tidball JG (2005) Mechanical signal transduction in skeletal muscle growth and adaptation. J Appl Physiol 98:1900–1908

    Article  PubMed  CAS  Google Scholar 

  44. Warren GL, Hulderman T, Jensen N et al (2002) Physiological role of tumor necrosis factor a in traumatic muscle injury. FASEB J 16:1630–1632

    PubMed  CAS  Google Scholar 

  45. Whitehead NP, Yeung EW, Allen DG (2006) Muscle damage in mdx (dystrophic) mice: role of calcium and reactive oxygen species. Clin Exp Pharmacol Physiol 33:657–662

    Article  PubMed  CAS  Google Scholar 

  46. Wineinger MA, Abresch RT, Walsh SA et al (1998) Effects of aging and voluntary exercise on the function of dystrophic muscle from mdx mice. Am J Phys Med Rehab 77:20–27

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the assistance of Thea Shavlakadze and Marilyn Davies with the supply of the transgenic class 1:Ea mdx/IGF-1 mice. We sincerely thank Hannah Radley and Thea Shavlakadze for the critical reading of the manuscript and Adam Piers for the assistance with the EBD experiments. Construction of the mouse dynamometer was partially supported from a grant to PH from the Physiotherapy Research Foundation (Australia).

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Authors and Affiliations

  1. School of Anatomy and Human Biology (M309), The University of Western Australia, Crawley, WA, 6009, Australia

    James A. Ridgley, Gavin J. Pinniger & Miranda D. Grounds

  2. School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, WA, 6009, Australia

    Gavin J. Pinniger

  3. Discipline of Physiotherapy, The University of Notre Dame Australia, Fremantle, WA, 6160, Australia

    Peter W. Hamer

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  1. James A. Ridgley
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  2. Gavin J. Pinniger
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  4. Miranda D. Grounds
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Correspondence to Miranda D. Grounds.

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Ridgley, J.A., Pinniger, G.J., Hamer, P.W. et al. The physiological effects of IGF-1 (class 1:Ea transgene) over-expression on exercise-induced damage and adaptation in dystrophic muscles of mdx mice. Pflugers Arch - Eur J Physiol 457, 1121–1132 (2009). https://doi.org/10.1007/s00424-008-0568-4

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  • DOI: https://doi.org/10.1007/s00424-008-0568-4

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