Effect of the mimetic peptide Ac9-22, derived from Annexin A1, on skeletal muscle degeneration and regeneration, induced by Bothrops asper snake venom

Abstract

Ophidian accidents are a public health problem of the world order and are currently considered to be tropical diseases neglected by the World Health Organization. In Latin America, most accidents are caused by Bothrops genus snakes, highlighting, in Brazil, Bothrops jararaca and Bothrops atrox species, and in Central America Bothrops asper snake. Accidents with botrhopic snake venoms lead to local clinical manifestations as myonecrosis and a prominent inflammatory response, accompanied by systemic effects, such as coagulopathy, hemorrhage and nephrotoxicity. Myonecrosis is caused by the major components of the venom, such as phospholipasase myotoxins and metalloproteinases that cause necrosis of muscle fibers and damage to the extracellular matrix of adjacent tissues, affecting the vascular network surrounding the muscle injury. This injury impairs the muscle tissue regeneration process, which depends on the interaction between various circulating elements and those of the inflammatory and tissue process which can result in fibrosis and possible loss of muscle function. The most common treatment for snakebite accidents is seroterarpia which is effective for treating systemic effects, but is not effective for local effects such as inflammation and tissue injury, raising the need for investigating new agents as new treatment therapies. Among the various new possibilities, Annexin 1 (AnxA1), an endogenous protein located on the surface of several cells, has varied effects such as anti-inflammatory activity, maintenance of cytoskeleton and extracellular matrix integrity, apoptosis, in addition to stimulation of cell proliferation and differentiation. Some studies have shown that endogenous AnxA1 positively modulates the cellular differentiation of myoblasts, promoting the migration of myogenic cells and, consequently, differentiation in mature tissue, by promoting the fusion of myotubes and repair of the myofiber sarcolemma, after injury. In this context, its mimetic peptides, which can be considered new sources of therapeutic molecules, although they also provide most of the effects already observed by the AnxA1 protein, have never been tested in models of muscle regeneration, especially in in vivo models of degeneration and regeneration induced by bothropic snake venom. Thus, the present work aims to study the activity of the peptide Ac9-22 derived from AnxA1 on the regeneration of skeletal muscle tissue, after injury induced by Bothrops asper snake venom, regarding: a) local morphological/histological aspects of muscle tissue; b) changes in neurofilaments; c) the production of TGFb, IL-1b, IL-6 and VEGF; d) the contractile function of the tissue. The present research project will provide new perspectives for accessory treatments of local effects, resulting from botropic accidents, mainly to reduce myionecrosis, regulate the inflammatory process and improve the quality of skeletal muscle tissue regeneration after injury. (AU)