Abstract/Summary

The interactions between specific snake venom toxins and muscle constituents are the major cause of severe muscle damage that often results in amputations and subsequent socioeconomic ramifi-cations for victims and/or their families. Therefore, improving our understanding of ven-om-induced muscle damage and determining the underlying mechanisms of muscle degenera-tion/regeneration following snakebites is critical to developing better strategies to tackle this is-sue. Here, we analysed the intramuscular bleeding and thrombosis in two different snake venom toxins [CAMP - Crotalus atrox metalloprotease (a PIII metalloprotease from the venom of this snake) and a three-finger toxin (CTX, cardiotoxin from the venom of Naja pallida)]-mediated muscle injuries in mice. Classically, these toxins represent diverse scenarios characterised by per-sistent muscle damage (CAMP) and successful regeneration (CTX) following acute damage, as normally observed in envenomation by most vipers and some elapid snakes of Asian, Australa-sian, and African origin, respectively. Our immunohistochemical analysis confirmed that both CAMP and CTX induced extensive muscle destruction on day 5, although, the effects of CTX were reversed over time. We identified the presence of fibrinogen and P-selectin exposure inside the damaged muscle sections, suggesting the signs of bleeding and the formation of platelet aggre-gates/microthrombi in tissues, respectively. Intriguingly, CAMP causes integrin shedding but does not affect any blood clotting parameters, whereas, CTX significantly extends the clotting time and has no impact on integrin shedding. The rates of fibrinogen clearance and reduction in microthrombi were greater in CTX-treated muscle compared to CAMP-treated. Together, these findings reveal novel aspects of venom-induced muscle damage and highlight the relevance of haemostatic events such as bleeding and thrombosis for muscle regeneration and provide useful mechanistic insights for developing better therapeutic interventions.