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

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.

[1]  Marinos C. Dalakas,et al.  Muscle biopsy — a practical approach , 1986, The Ulster Medical Journal.

[2]  J. Faulkner,et al.  Force and power output of fast and slow skeletal muscles from mdx mice 6‐28 months old , 2001, The Journal of physiology.

[3]  D. Stephenson,et al.  Abnormalities in structure and function of limb skeletal muscle fibres of dystrophic mdx mice , 1992, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[4]  J. Gillis,et al.  Understanding dystrophinopathies: an inventory of the structural and functional consequences of the absence of dystrophin in muscles of the mdx mouse , 1999, Journal of Muscle Research & Cell Motility.

[5]  J. Chamberlain,et al.  Developments in gene therapy for muscular dystrophy , 2000, Microscopy research and technique.

[6]  G. Vrbóva,et al.  Contractile properties and susceptibility to exercise-induced damage of normal and mdx mouse tibialis anterior muscle. , 1992, Clinical science.

[7]  R. Lieber,et al.  Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb , 1994, Journal of morphology.

[8]  G. Maréchal,et al.  Increased susceptibility of EDL muscles from mdx mice to damage induced by contractions with stretch , 1993, Journal of Muscle Research & Cell Motility.

[9]  J. Faulkner,et al.  Contraction-induced injury to single permeabilized muscle fibers from mdx, transgenic mdx, and control mice. , 2000, American journal of physiology. Cell physiology.

[10]  D. Wells,et al.  Immune responses to dystropin: implications for gene therapy of Duchenne muscular dystrophy. , 2000, Gene therapy.

[11]  A. Ossipov,et al.  Duchenne muscular dystrophy , 2004 .

[12]  S. Brooks.  Rapid recovery following contraction-induced injury to in situ skeletal muscles in mdx mice , 1998, Journal of Muscle Research & Cell Motility.

[13]  J. Shrager,et al.  The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy , 1991, Nature.

[14]  J. Gillis,et al.  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 , 1998, Neuromuscular Disorders.

[15]  A. Coffey.  Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice , 1996 .

[16]  K. Davies,et al.  Prevention of the dystrophic phenotype in dystrophin/utrophin-deficient muscle following adenovirus-mediated transfer of a utrophin minigene , 2000, Gene Therapy.

[17]  H. Sweeney,et al.  Dystrophin protects the sarcolemma from stresses developed during muscle contraction. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A. Keys,et al.  Density and composition of mammalian muscle , 1960 .

[19]  J. Faulkner,et al.  Injury to muscle fibres after single stretches of passive and maximally stimulated muscles in mice. , 1995, The Journal of physiology.

[20]  R. Balice-Gordon,et al.  Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector , 1999, Nature Medicine.

[21]  J. Huh,et al.  Efficient expression of the vascular endothelial growth factor gene in vitro and in vivo, using an adeno-associated virus vector. , 2001, Journal of molecular and cellular cardiology.

[22]  D. Wells,et al.  Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy , 2000, Gene Therapy.

[23]  J. Tremblay,et al.  Muscle fibers of mdx mice are more vulnerable to exercise than those of normal mice , 1997, Neuromuscular Disorders.

[24]  B. Cooper,et al.  Intracellular calcium in canine muscle biopsies. , 1989, Journal of Comparative Pathology.

[25]  E A Barnard,et al.  The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. , 1989, Science.

[26]  J. Tremblay,et al.  Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric running exercise , 1998, Muscle & nerve.

[27]  J. Bodensteiner,et al.  Intracellular calcium accumulation in Duchenne dystrophy and other myopathies , 1978, Neurology.

[28]  R. Abresch,et al.  Profiles of neuromuscular diseases. Becker's muscular dystrophy. , 1995, American journal of physical medicine & rehabilitation.

[29]  J. Nalbantoglu,et al.  Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice. , 2000, Physiological genomics.

[30]  K. Campbell,et al.  Animal Models for Muscular Dystrophy Show Different Patterns of Sarcolemmal Disruption , 1997, The Journal of cell biology.

[31]  G. Goldspink,et al.  Accumulation of collagen and altered fiber‐type ratios as indicators of abnormal muscle gene expression in the mdx dystrophic mouse , 1989, Muscle & nerve.

[32]  K. Davies,et al.  Adenovirus-mediated utrophin gene transfer mitigates the dystrophic phenotype of mdx mouse muscles. , 1999, Human gene therapy.

[33]  A. Nishikawa,et al.  Visualization of dystrophic muscle fibers in mdx mouse by vital staining with Evans blue: evidence of apoptosis in dystrophin-deficient muscle. , 1995, Journal of biochemistry.

[34]  K. Moore,et al.  X chromosome-linked muscular dystrophy (mdx) in the mouse. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[35]  B. Cooper,et al.  Canine X-linked muscular dystrophy: Morphologic lesions , 1990, Journal of the Neurological Sciences.

[36]  N. McKee,et al.  Skeletal Muscle Damage in the Rat Hindlimb Following Single or Repeated Daily Bouts of Downhill Exercise , 1997, International journal of sports medicine.

[37]  K. Campbell,et al.  Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity , 1993, Nature.

[38]  Eric P. Hoffman,et al.  Dystrophin: The protein product of the duchenne muscular dystrophy locus , 1987, Cell.