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Celecoxib Impairs Differentiation of Primary Human Skeletal Myoblasts

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are medications commonly consumed for their anti‐inflammatory, analgesic, and antipyretic effects. NSAIDs act by inhibiting cyclooxygenase (COX) enzymes, which mediate the synthesis of pro‐inflammatory prostaglandins from substrates such as arachidonic acid. Despite the widespread use of NSAIDs, the risks of taking NSAIDs are only beginning to be defined; in particular, their effects on highly metabolic tissues such as skeletal muscle. We therefore sought to determine whether celecoxib, an NSAID selective for COX2, impaired the differentiation and hypertrophy of cultured primary human skeletal myoblasts. Myoblasts were exposed to celecoxib at concentrations from 50 μM – 0.08 μM and allowed to differentiate for 72 hours. Vehicle‐treated myotubes showed a robust fusion index and myotube area as determined by immunocytochemistry and confocal microscopy; however, the fusion indices and areas of myotubes exposed to 50 μM and 25 μM celecoxib were significantly reduced (90% reduced fusion index and 89% reduced myotube area in cells exposed to 50 μM celecoxib; P<0.001, and 33% reduced fusion index and 25% reduced myotube area in cells exposed to 25 μM celecoxib; P<0.001). The total nuclei present across all treatments did not differ. Myoblasts treated with NS‐398 (a COX2‐selective pharmacological inhibitor) showed no impaired differentiation at any concentration. These observations were associated with dose‐dependent decreases in expression of myosin heavy chain mRNA transcripts of slow (Myh7) and developmental (Myh3 and Myh8) myosins, and exposure to 50 μM celecoxib virtually eliminated expression of all myosin heavy chain transcripts (P<0.001 for all). Phosphorylation of AKT (S473), p70S6K (T389), and S6 (S235/236) were dose‐dependently reduced in celecoxib‐treated myotubes (P<0.05), whereas administration of NS‐398 had no effect on phosphorylation of any of these molecules at any concentration. These data reveal that celecoxib inhibits differentiation of primary human skeletal myoblasts, possibly through a mechanism that regulates the activation of molecules involved in protein synthesis. Celecoxib‐mediated impairment of human myoblast differentiation may be independent of its actions on COX2, because treatment with NS‐398 did not alter differentiation. The exact mechanism through which celecoxib acts to alter muscle cell differentiation and physiology remains to be established.