title: Correlated NOS-Imu and myf5 expression by satellite cells in mdx mouse muscle regeneration during NOS manipulation and deflazacort treatment.
abstract: Satellite cells, muscle precursor cells in skeletal muscle, are normally quiescent and become activated by disease or injury. A lack of dystrophin and changes in the expression or activity of neuronal nitric oxide synthase (NOS-I) affect the timing of activation in vivo. Nitric oxide synthase inhibition delays muscle repair in normal mice, and worsens muscular dystrophy in the mdx mouse, a genetic homologue of Duchenne muscular dystrophy. However, the potential role of activation and repair events mediated by nitric oxide in determining the outcome of steroid or other treatments for muscular dystrophy is not clear. We tested the hypothesis that the extent of repair in dystrophic muscles of mdx mice is partly dependent on NOS-Imu expression and activity. Myotube formation in regenerating muscle was promoted by deflazacort treatment of mdx dystrophic mice (P<0.05), and improved by combination with the nitric oxide synthase substrate, L-arginine, especially in the diaphragm. NOS-Imu mRNA expression and activity were present in satellite cells and very new myotubes of regenerating and dystrophic muscle. Deflazacort treatment resulted in increased NOS-Imu expression in regenerating muscles in a strong and specific correlation with myf5 expression (r=0.95, P<0.01), a marker for muscle repair. Nitric oxide synthase inhibition prevented the deflazacort-induced rise in NOS-Imu and myf5 expression in the diaphragm without affecting the diameter of non-regenerating fibres. These in vivo studies suggest that gains in NOS-Imu expression and nitric oxide synthase activity in satellite cells can increase the extent and speed of repair, even in the absence of dystrophin in muscle fibres. NOS-Imu may be a useful therapeutic target to augment the effects of steroidal or other treatments of muscular dystrophy.
authors.affiliation: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, 730 William Avenue, Winnipeg, MB, Canada R3E 0W3. janders@ms.umanitoba.ca
authors.forename: Judy E
authors.initials: JE
authors.lastname: Anderson
authors.forename: Cinthya
authors.initials: C
authors.lastname: Vargas
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000494:pharmacology / Q000627:therapeutic use; D015152:Blotting, Northern; D004268:DNA-Binding Proteins; D003964:Diaphragm / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017403:In Situ Hybridization; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009136:Muscular Dystrophies / Q000378:metabolism*; D051787:Myogenic Regulatory Factor 5; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011282:Pregnenediones / Q000494:pharmacology* / Q000627:therapeutic use; D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D016189:Dystrophin; D007166:Immunosuppressive Agents; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D011282:Pregnenediones; D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D015534:Trans-Activators; D001120:Arginine; D019001:Nitric Oxide Synthase; D019859:Proto-Oncogene Proteins c-met; C021988:deflazacort