Skip to main content
SpringerLink
Log in

Tibialis anterior muscles in mdx mice are highly susceptible to contraction-induced injury

  • Published:
Journal of Muscle Research & Cell Motility Aims and scope Submit manuscript

Abstract

Skeletal muscles of patients with Duchenne muscular dystrophy (DMD) and mdx mice lack dystrophin and are more susceptible to contraction-induced injury than control muscles. Our purpose was to develop an assay based on the high susceptibility to injury of limb muscles in mdx mice for use in evaluating therapeutic interventions. The assay involved two stretches of maximally activated tibialis anterior (TA) muscles in situ. Stretches of 40% strain relative to muscle fiber length were initiated from the plateau of isometric contractions. The magnitude of damage was assessed one minute later by the deficit in isometric force. At all ages (2–19 months), force deficits were four- to seven-fold higher for muscles in mdx compared with control mice. For control muscles, force deficits were unrelated to age, whereas force deficits increased dramatically for muscles in mdx mice after 8 months of age. The increase in susceptibility to injury of muscles from older mdx mice did not parallel similar adverse effects on muscle mass or force production. The in situ stretch protocol of TA muscles provides a valuable assay for investigations of the mechanisms of injury in dystrophic muscle and to test therapeutic interventions for reversing DMD.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bodensteiner JB and Engel AG (1978) Intracellular calcium accumulation in Duchenne dystrophy and other myopathies: a study of 567,000 muscle fibers in 114 biopsies. Neurology 28: 439–446.

    PubMed  CAS  Google Scholar 

  • 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 

  • Brooks SV, Zerba E and Faulkner JA (1995) Injury to muscle fibres after single stretches of passive and maximally stimulated muscles in mice. J Physiol (Lond) 488: 459–469.

    CAS  Google Scholar 

  • Brussee V, Tardif F and Tremblay JP (1997) Muscle fibers of mdx mice are more vulnerable to exercise than those of normal mice. Neuromuscul Disord 7: 487–492.

    Article  PubMed  CAS  Google Scholar 

  • Bulfield G, Siller WG, Wight PA and Moore KJ (1984) X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA 81: 1189–1192.

    Article  PubMed  CAS  Google Scholar 

  • Burkholder TJ, Fingado B, Baron S and Lieber RL (1994) Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J Morphol 221: 177–190.

    Article  PubMed  CAS  Google Scholar 

  • Byun J, Heard JM, Huh JE, Park SJ, Jung EA, Jeong JO, Gwon HC and Kim DK (2001) Efficient expression of the vascular endothelial growth factor gene in vitro and in vivo, using an adeno-associated virus vector. J Mol Cell Cardiol 33: 295–305.

    Article  PubMed  CAS  Google Scholar 

  • Cox GA, Cole NM, Matsumura K, Phelps SF, Hauschka SD, Campbell KP, Faulkner JA and Chamberlain JS (1993) Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity. Nature 364: 725–729.

    Article  PubMed  CAS  Google Scholar 

  • Deconinck N, Rafael JA, Beckers-Bleukx G, Kahn D, Deconinck AE, Davies KE and Gillis JM (1998) Consequences of the combined deficiency in dystrophin and utrophin on the mechanical properties and myosin composition of some limb and respiratory muscles of the mouse. Neuromuscul Disord 8: 362–370.

    Article  PubMed  CAS  Google Scholar 

  • Dubowitz V (1985) Muscle Biopsy: A practical approach. Bailliere Tindall Ltd., London.

    Google Scholar 

  • Ebihara S, Guibinga GH, Gilbert R, Nalbantoglu J, Massie B, Karpati G and Petrof BJ (2000) Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice. Physiol Genom 3: 133–144.

    CAS  Google Scholar 

  • Emery AEH (1993) Duchenne Muscular Dystrophy. Oxford Medical Publications, Oxford.

    Google Scholar 

  • Faulkner JA and Brooks SV (1994) An in situ single skeletal muscle model of contraction-induced injury: mechanistic interpretations. Basic Appl Myol 4: 17–23.

    Google Scholar 

  • Faulkner JA, Brooks SV, Dennis RG and Lynch GS (1997) The functional status of dystrophic muscles and functional recovery by skeletal muscles following myoblast transfer. Basic Appl Myol 7: 257–264.

    Google Scholar 

  • Ferrer A, Wells KE and Wells DJ (2000) Immune responses to dystropin: implications for gene therapy of Duchenne muscular dystrophy. Gene Ther 7: 1439–1446.

    Article  PubMed  CAS  Google Scholar 

  • Gilbert R, Nalbantoglu J, Petrof BJ, Ebihara S, Guibinga GH, Tinsley JM, Kamen A, Massie B, Davies KE and Karpati G (1999) Adenovirus-mediated utrophin gene transfer mitigates the dystrophic phenotype of mdx mouse muscles. Hum Gene Ther 10: 1299–1310.

    Article  PubMed  CAS  Google Scholar 

  • Gillis JM (1999) Understanding dystrophinopathies: an inventory of the structural and functional consequences of the absence of dystrophin in muscles of the mdx mouse. J Muscle Res Cell Motil 20: 605–625.

    Article  PubMed  CAS  Google Scholar 

  • Greelish JP, Su LT, Lankford EB, Burkman JM, Chen H, Konig SK, Mercier IM, Desjardins PR, Mitchell MA, Zheng XG, Leferovich J, Gao GP, Balice-Gordon RJ, Wilson JM and Stedman HH (1999) Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector. Nat Med 5: 439–443.

    Article  PubMed  CAS  Google Scholar 

  • Hartigan-O'Connor D and Chamberlain JS (2000) Developments in gene therapy for muscular dystrophy. Microsc Res Tech 48: 223–238.

    Article  PubMed  Google Scholar 

  • Head SI, Williams DA and Stephenson DG (1992) Abnormalities in structure and function of limb skeletal muscle fibres of dystrophic mdx mice. Proc R Soc Lond B Biol Sci 248: 163–169.

    CAS  Google Scholar 

  • Homan EP, Brown RH Jr and Kunkel LM (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51: 919–928.

    Article  Google Scholar 

  • Lynch GS, Hinkle RT, Chamberlain JS, Brooks SV and Faulkner JA (2001) Force output of fast and slow skeletal muscles from young, adult and old mdx mice. J Physiol London 535: 591–600.

    Article  PubMed  CAS  Google Scholar 

  • Lynch GS, Rafael JA, Chamberlain JS and Faulkner JA (2000) Contraction-induced injury to single permeabilized muscle bers from mdx, transgenic mdx, and control mice. Am J Physiol Cell Physiol 279: C1290–C1294.

    PubMed  CAS  Google Scholar 

  • Marshall PA, Williams PE and Goldspink G (1989) Accumulation of collagen and altered fiber-type ratios as indicators of abnormal muscle gene expression in the mdx dystrophic mouse. Muscle Nerve 12: 528–537.

    Article  PubMed  CAS  Google Scholar 

  • Matsuda R, Nishikawa A and Tanaka H (1995) Visualization of dystrophic muscle fibers in mdx mouse by vital staining with Evans blue: evidence of apoptosis in dystrophin-deficient muscle. J Biochem (Tokyo) 118: 959–964.

    CAS  Google Scholar 

  • Mendez J and Keys A (1960) Density and composition of mammalian muscle. Metabolism 9: 184–188.

    CAS  Google Scholar 

  • Moens P, Baatsen PH and Marechal G (1993) Increased susceptibility of EDL muscles from mdx mice to damage induced by contractions with stretch. J Muscle Res Cell Motil 14: 446–451.

    Article  PubMed  CAS  Google Scholar 

  • Petrof BJ, Shrager JB, Stedman HH, Kelly AM and Sweeney HL (1993) Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci USA 90: 3710–3714.

    Article  PubMed  CAS  Google Scholar 

  • Phelps SF, Hauser MA, Cole NM, Rafael JA, Hinkle RT, Faulkner JA and Chamberlain JS (1995) Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice. Hum Mol Genet 4: 1251–1258.

    PubMed  CAS  Google Scholar 

  • Sacco P, Jones DA, Dick JR and Vrbova G (1992) Contractile properties and susceptibility to exercise-induced damage of normal and mdx mouse tibialis anterior muscle. Clin Sci (Colch) 82: 227–236.

    CAS  Google Scholar 

  • Sicinski P, Geng Y, Ryder-Cook AS, Barnard EA, Darlison MG and Barnard PJ (1989) The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science 244: 1578–1580.

    PubMed  CAS  Google Scholar 

  • Smith HK, Plyley MJ, Rodgers CD and McKee NH (1997) Skeletal muscle damage in the rat hindlimb following single or repeated daily bouts of downhill exercise. Int J Sports Med 18: 94–100.

    PubMed  CAS  Google Scholar 

  • Stedman HH, Sweeney HL, Shrager JB, Maguire HC, Panettieri RA, Petrof B, Narusawa M, Leferovich JM, Sladky JT and Kelly AM (1991) The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature 352: 536–539.

    Article  PubMed  CAS  Google Scholar 

  • Straub V, Rafael JA, Chamberlain JS and Campbell KP (1997) Animal models for muscular dystrophy show different patterns of sarcolemmal disruption. J Cell Biol 139: 375–385.

    Article  PubMed  CAS  Google Scholar 

  • Valentine BA, Cooper BJ and Gallagher EA (1989) Intracellular calcium in canine muscle biopsies. J Compar Pathol 100: 223–230.

    Article  CAS  Google Scholar 

  • Valentine BA, Cooper BJ, Cummings JF and de Lahunta A (1990) Canine X-linked muscular dystrophy: morphologic lesions. J Neurol Sci 97: 1–23.

    Article  PubMed  CAS  Google Scholar 

  • Vilquin JT, Brussee V, Asselin I, Kinoshita I, Gingras M and Tremblay JP (1998) Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric running exercise. Muscle Nerve 21: 567–576.

    Article  PubMed  CAS  Google Scholar 

  • Wakefield PM, Tinsley JM, Wood MJ, Gilbert R, Karpati G and Davies KE (2000) Prevention of the dystrophic phenotype in dystrophin/utrophin-deficient muscle following adenovirus-mediated transfer of a utrophin minigene. Gene Ther 7: 201–204.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Human Genetics, University of Michigan, 300 North Ingalls Building, Ann Arbor, Michigan, 48109-2007, USA

    Christiana Dellorusso, Robert W. Crawford & Jeffrey S. Chamberlain

  2. Departments of Physiology, University of Michigan, 300 North Ingalls Building, Ann Arbor, Michigan, 48109-2007, USA

    Christiana Dellorusso & Susan V. Brooks

  3. Department of Neurology, University of Washington, Seattle, WA, 98195-7720

    Christiana Dellorusso, Robert W. Crawford & Jeffrey S. Chamberlain

  4. Institute of Gerontology, University of Michigan, 300 North Ingalls Building, Ann Arbor, Michigan, 48109-2007, USA

    Susan V. Brooks

Authors
  1. Christiana Dellorusso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert W. Crawford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey S. Chamberlain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan V. Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dellorusso, C., Crawford, R.W., Chamberlain, J.S. et al. Tibialis anterior muscles in mdx mice are highly susceptible to contraction-induced injury. J Muscle Res Cell Motil 22, 467–475 (2001). https://doi.org/10.1023/A:1014587918367

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1014587918367

Keywords

Search

Navigation