Exercise improves the success of myoblast transplantation in mdx mice

Transplantation of normal muscle precursor cells is a potential approach to restore dystrophin expression within dystrophin [deficient] mdx mice, a model of Duchenne Muscular Dystrophy. This study aims to evaluate whether exercise could improve graft success and hybrid fiber distribution within mdx muscle. eGFP(+) Muscle precursor cells were transplanted into tibialis anterior muscles of mdx mice using a single injection trajectory. During the following weeks, muscle fiber breaks were induced by making mdx mice swim. To evaluate fiber damage, Evans blue solution was injected intraperitoneally to mice 16h before their sacrifice. Tibialis anterior muscles were then harvested and eGFP, dystrophin and Evans blue labeling were analyzed by fluorescent microscopy. Twenty minutes of exercise (i.e., swimming) were used to induce damage in about 30% of TA muscle fibers. Graft success, evaluated as the percentage of hybrid fibers which are eGFP(+), was improved by 1.9-fold after swimming 3 times per week during 4 weeks and by 1.8-fold after daily swimming. Hybrid muscle fiber transversal and longitudinal distribution were also increased after repeated physical efforts. Exercise induced fiber breaks, which improved MPC recruitment and fusion and increased long-term graft success and also transverse and longitudinal distribution of hybrid fibers.

[1]  Hamish Simpson,et al.  Cloning and characterization of an IGF-1 isoform expressed in skeletal muscle subjected to stretch , 1996, Journal of Muscle Research & Cell Motility.

[2]  J. Bouchard,et al.  Dystrophin Expression in Muscles of Duchenne Muscular Dystrophy Patients After High-Density Injections of Normal Myogenic Cells , 2006, Journal of neuropathology and experimental neurology.

[3]  F. Booth,et al.  Insulin-like growth factor immunoreactivity increases in muscle after acute eccentric contractions. , 1993, Journal of applied physiology.

[4]  D. Skuk,et al.  Efficacy of Myoblast Transplantation in Nonhuman Primates Following Simple Intramuscular Cell Injections: Toward Defining Strategies Applicable to Humans , 2002, Experimental Neurology.

[5]  J. Rousseau,et al.  Novel Duchenne Muscular Dystrophy Treatment Through Myoblast Transplantation Tolerance with Anti‐CD45RB, Anti‐CD154 and Mixed Chimerism , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[6]  J. Tremblay,et al.  The urokinase plasminogen activator: an interesting way to improve myoblast migration following their transplantation. , 2002, Experimental cell research.

[7]  G. Goldspink,et al.  Expression and Splicing of the Insulin‐Like Growth Factor Gene in Rodent Muscle is Associated with Muscle Satellite (stem) Cell Activation following Local Tissue Damage , 2003, The Journal of physiology.

[8]  Johnny Huard,et al.  Identification of a novel population of muscle stem cells in mice , 2002, The Journal of cell biology.

[9]  S. Wilton,et al.  Massive Idiosyncratic Exon Skipping Corrects the Nonsense Mutation in Dystrophic Mouse Muscle and Produces Functional Revertant Fibers by Clonal Expansion , 2000, The Journal of cell biology.

[10]  N. Caron,et al.  In vivo migration of transplanted myoblasts requires matrix metalloproteinase activity. , 2000, Experimental cell research.

[11]  P. Mills,et al.  GROWTH FACTORS IMPROVE THE IN VIVO MIGRATION OF HUMAN SKELETAL MYOBLASTS BY MODULATING THEIR ENDOGENOUS PROTEOLYTIC ACTIVITY , 2004, Transplantation.

[12]  J. Faulkner,et al.  Regeneration of new fibers in muscles of old rats reduces contraction-induced injury. , 1999, Journal of applied physiology.

[13]  L. Kunkel,et al.  Dystrophin: the protein product of the Duchene muscular dystrophy locus. 1987. , 1992, Biotechnology.

[14]  J. Vilquin,et al.  Mechanism of increasing dystrophin-positive myofibers by myoblast transplantation: study using mdx/β-galactosidase transgenic mice , 1996, Acta Neuropathologica.

[15]  G. Goldspink,et al.  Different roles of the IGF‐I Ec peptide (MGF) and mature IGF‐I in myoblast proliferation and differentiation , 2002, FEBS letters.

[16]  Helen M. Blau,et al.  Biological Progression from Adult Bone Marrow to Mononucleate Muscle Stem Cell to Multinucleate Muscle Fiber in Response to Injury , 2002, Cell.

[17]  D. Skuk,et al.  Myoblast Transplantation in Whole Muscle of Nonhuman Primates , 2000, Journal of neuropathology and experimental neurology.

[18]  S. Ishiura,et al.  Biochemical aspects of bupivacaine-induced acute muscle degradation. , 1986, Journal of cell science.

[19]  M. Sharma,et al.  Insulin-like growth factor-I protects myoblasts from apoptosis but requires other factors to stimulate proliferation. , 1999, The Journal of endocrinology.

[20]  Charlotte Collins,et al.  Direct Isolation of Satellite Cells for Skeletal Muscle Regeneration , 2005, Science.

[21]  J. Harris,et al.  Myotoxic Activity of the Toxic Phospholipase, Notexin, from the Venom of the Australian Tiger Snake , 1996, Journal of neuropathology and experimental neurology.

[22]  J R Florini,et al.  Growth hormone and the insulin-like growth factor system in myogenesis. , 1996, Endocrine reviews.

[23]  J. Vilquin,et al.  Pretreatment of myoblast cultures with basic fibroblast growth factor increases the efficacy of their transplantation in mdx mice , 1995, Muscle & nerve.

[24]  D. Skuk,et al.  Progress in myoblast transplantation: a potential treatment of dystrophies , 2000, Microscopy research and technique.

[25]  Reconstruction of ablated rat rectus abdominis by muscle regeneration. , 2004, Plastic and reconstructive surgery.

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

[27]  J. Faulkner,et al.  The regeneration of skeletal muscle fibers following injury: a review. , 1983, Medicine and science in sports and exercise.

[28]  K. Kurachi,et al.  Implanted myoblasts not only fuse with myofibers but also survive as muscle precursor cells. , 1993, Journal of cell science.

[29]  J. Bouchard,et al.  Dystrophin expression in myofibers of Duchenne muscular dystrophy patients following intramuscular injections of normal myogenic cells. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[30]  P. Mcneil,et al.  Disruptions of muscle fiber plasma membranes. Role in exercise-induced damage. , 1992, The American journal of pathology.

[31]  D. Skuk,et al.  Successful Myoblast Transplantation in Primates Depends on Appropriate Cell Delivery and Induction of Regeneration in the Host Muscle , 1999, Experimental Neurology.

[32]  A. Hattori,et al.  Release of hepatocyte growth factor from mechanically stretched skeletal muscle satellite cells and role of pH and nitric oxide. , 2002, Molecular biology of the cell.

[33]  T. Hawke.  Muscle Stem Cells and Exercise Training , 2005, Exercise and sport sciences reviews.

[34]  T. Partridge,et al.  Patterns of repair of dystrophic mouse muscle: Studies on isolated fibers , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[35]  F. Chrétien,et al.  In vivo fusion of circulating fluorescent cells with dystrophin-deficient myofibers results in extensive sarcoplasmic fluorescence expression but limited dystrophin sarcolemmal expression. , 2005, The American journal of pathology.

[36]  J. Micallef,et al.  Changes in Mass and Performance in Rabbit Muscles after Muscle Damage with or without Transplantation of Primary Satellite Cells , 2002, Cell transplantation.