The COX-2 pathway is essential during early stages of skeletal muscle regeneration

TLDR

Skeletal muscle regeneration involves overlapping processes of inflammation and myogenesis, and prostaglandins—produced by cyclooxygenase (COX) isoforms—are thought to modulate these stages, yet the specific roles of COX‑1 versus COX‑2 remain unclear. The study aimed to determine how COX‑1 and COX‑2 influence muscle regeneration by inducing a localized freeze injury in mice treated chronically with selective COX‑1 (SC‑560) or COX‑2 (SC‑236) inhibitors. Mice received the inhibitors before injury, and regenerating myofibers were assessed over five weeks to evaluate the impact of COX inhibition on muscle repair. COX‑2 inhibition or knockout reduced early myofiber growth, lowered myoblast and inflammatory cell numbers, while COX‑1 inhibition had no effect, indicating that COX‑2‑dependent prostaglandin synthesis is essential during the early phase of muscle regeneration and cautioning against COX‑2‑selective inhibitors in injured muscle.

Abstract

Skeletal muscle regeneration comprises several overlapping cellular processes, including inflammation and myogenesis. Prostaglandins (PGs) may regulate muscle regeneration, because they modulate inflammation and are involved in various stages of myogenesis in vitro. PG synthesis is catalyzed by different isoforms of cyclooxygenase (COX), which are inhibited by nonsteroidal anti-inflammatory drugs. Although experiments employing nonsteroidal anti-inflammatory drugs have implicated PGs in tissue repair, how PGs regulate muscle regeneration remains unclear, and the potentially distinct roles of different COX isoforms have not been investigated. To address these questions, a localized freeze injury was induced in the tibialis anterior muscles of mice chronically treated with either a COX-1- or COX-2-selective inhibitor (SC-560 and SC-236, respectively), starting before injury. The size of regenerating myofibers was analyzed at time points up to 5 wk after injury and found to be decreased by SC-236 and in COX-2(-/-) muscles, but unaffected by SC-560. In contrast, SC-236 had no effect on myofiber growth when administered starting 7 days after injury. The attenuation of myofiber growth by SC-236 treatment and in COX-2(-/-) muscles is associated with decreases in the number of myoblasts and intramuscular inflammatory cells at early times after injury. Together, these data suggest that COX-2-dependent PG synthesis is required during early stages of muscle regeneration and thus raise caution about the use of COX-2-selective inhibitors in patients with muscle injury or disease.