The early inhibition of the COX-2 pathway in viperid phospholipase A2-induced skeletal muscle myotoxicity accelerates the tissue regeneration

Author(s)

Zuntini, Ana Carolina Siqueira ; Damico, Marcio Vinicius ; Gil, Cristiane Damas ; Godinho, Rosely Oliveira ; Pacini, Enio Setsuo Arakaki ; Fortes-Dias, Consuelo Latorre ; Moreira, Vanessa

• Document type: Journal article
• Source: Toxicology and Applied Pharmacology; v. 461, p. 12-pg., 2023-02-04.

Abstract

The administration of non-steroidal anti-inflammatory drugs in the treatment of injury and muscle regeneration is still contradictory in effectiveness, especially regarding the timing of their administration. This can interfere with the production of prostaglandins originating from inflammatory isoform cyclooxygenase-2 (COX-2), which is essential to modulate tissue regeneration. The phospholipases A2 (PLA2) from viperid venoms cause myo-toxicity, therefore constituting a tool for the study of supportive therapies to improve skeletal muscle regener-ation. This study investigated the effect of early administration of lumiracoxib (selective inhibitor of COX-2) on the degeneration and regeneration stages of skeletal muscle after injury induced by a myotoxic PLA2. After 30 min and 48 h of intramuscular injection of PLA2, mice received lumiracoxib orally and histological, functional, and transcriptional parameters of muscle were evaluated from 6 h to 21 days. Inhibition of COX-2 in the early periods of PLA2-induced muscle degeneration reduced leukocyte influx, edema, and tissue damage. After the second administration of lumiracoxib, in regenerative stage, muscle showed increase in number of basophilic fibers, reduction in fibrosis content and advanced recovery of functionality characterized by the presence of fast type II fibers. The expression of Pax7 and myogenin were increased, indicating a great capacity for storing satellite cells and advanced mature state of tissue. Our data reveals a distinct role of COX-2-derived products during muscle degeneration and regeneration, in which early administration of lumiracoxib was a therapeutic strategy to modulate the effects of prostaglandins, providing a breakthrough in muscle tissue regeneration induced by a myotoxic PLA2. (AU)

• FAPESP's process: 15/25437-8 - Characterization of the release profile and the regulatory activity of eicosanoids in the degeneration and regeneration of skeletal muscle following injury
• Grantee: Vanessa Moreira
• Support Opportunities: Regular Research Grants