A comparison of factors associated with collagen metabolism in different skeletal muscles from dystrophic (mdx) mice: impact of pirfenidone.
Skeletal muscles in mdx mice exhibit differential degrees of pathological changes and fibrosis. The purpose of this study was to examine differences in various indices of collagen metabolism in skeletal muscles with widely different functions and activity profiles in mdx mice, and to determine whether pirfenidone would attenuate the development of fibrosis. Mice in the pirfenidone group were orally fed pirfenidone (500 mg/kg) daily for 4 weeks. Marked differences were noted in hydroxyproline concentration between muscles, which could not be explained solely by the level of type I collagen and transforming growth factor-beta1 (TGF-beta1) mRNA. In normal mice, matrix metalloproteinase (MMP)-2 mRNA was significantly higher in the gastrocnemius than in the diaphragm or genioglossus muscles, suggesting that collagen degradation plays an important role in regulating collagen accretion in skeletal muscle. In mdx mice, the levels of both MMP-2 and MMP-9 mRNA were significantly elevated relative to control, although the response was muscle specific. Pirfenidone treatment resulted in a significant reduction in the level of hydroxyproline concentration across all muscles, although the effect was small. Results from this study reveal intrinsic dissimilarities in collagen metabolism between functionally different skeletal muscles. Moreover, the pharmacological use of pirfenidone may be beneficial in preventing fibrosis in muscular dystrophy.
Gosselin
Luc E
LE
Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, New York 14214, USA. gosselin@buffalo.edu
Williams
Jacqueline E
JE
Personius
Kirkwood
K
Farkas
Gaspar A
GA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D011728:Pyridones / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; D053773:Transforming Growth Factor beta1; D003094:Collagen; C093844:pirfenidone; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9