Abstract
Nonsteroidal anti-inflammatory drugs are often prescribed after muscle injury. However, the effect of nonsteroidal anti-inflammatory drugs on muscle healing remains primarily controversial. To further examine the validity of using these drugs after muscle injury, we investigated the working mechanism of NS-398, a cyclooxygenase-2-specific inhibitor. In vitro experiments showed that NS-398 inhibited the proliferation and maturation of differentiated myogenic precursor cells, suggesting a detrimental effect on skeletal muscle healing. Using a mouse laceration model, we analyzed the in vivo effect of NS-398 on skeletal muscle healing at time points up to 4 weeks after injury. The in vivo results revealed delayed muscle regeneration at early time points after injury in the NS-398-treated mice. Compared to controls, lacerated muscles treated with NS-398 expressed higher levels of transforming growth factor-beta1, which corresponded with increased fibrosis. In addition, transforming growth factor-beta1 co-localized with myostatin, a negative regulator of skeletal muscle growth. We also found reduced neutrophil and macrophage infiltration in treated muscles, indicating that the delayed skeletal muscle healing observed after NS-398 treatment could be influenced by the anti-inflammatory effect of NS-398. Our findings suggest that the use of cyclooxygenase-2-specific inhibitors to treat skeletal muscle injuries warrants caution because they may interfere with muscle healing.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / metabolism
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Blotting, Western
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Cell Culture Techniques
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Cell Differentiation / drug effects
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Cell Extracts / pharmacology
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Cell Proliferation / drug effects
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Cells, Cultured
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Collagen / analysis
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Collagen / metabolism
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Cyclooxygenase 2 Inhibitors / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Female
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Fibrosis / chemically induced*
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Flow Cytometry
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Fluorescein
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Fluorescein-5-isothiocyanate
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Fluorescent Antibody Technique, Direct
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Fluorescent Dyes
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Immunohistochemistry
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Indoles
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Kinetics
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Mice
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Mice, Inbred C57BL
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Microscopy, Fluorescence
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Models, Anatomic
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Muscle, Skeletal / cytology
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Muscle, Skeletal / injuries*
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / physiopathology*
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Myostatin
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Nitrobenzenes / pharmacology*
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Regeneration / drug effects*
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Staining and Labeling
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Stem Cells / cytology
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Sulfonamides / pharmacology*
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta1
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Wound Healing / drug effects
Substances
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Antibodies, Monoclonal
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Cell Extracts
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Cyclooxygenase 2 Inhibitors
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Fluorescent Dyes
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Indoles
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Mstn protein, mouse
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Myostatin
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Nitrobenzenes
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Sulfonamides
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Tgfb1 protein, mouse
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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DAPI
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Collagen
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Fluorescein-5-isothiocyanate
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Fluorescein