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Characterization of the release profile and the regulatory activity of eicosanoids in the degeneration and regeneration of skeletal muscle following injury

Grant number: 15/25437-8
Support type:Regular Research Grants
Duration: June 01, 2016 - May 31, 2018
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Vanessa Moreira
Grantee:Vanessa Moreira
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Skeletal muscle injuries are frequent occurrences both in sports or clinical area such as myopathic diseases, like miodegenerativas diseases and myotoxic activity resulting of using of drugs or snakebites. It is well established that the regenerative capacity of skeletal muscle tissue after an injury, is started by the activation of quiescent cells and regulated by several intrinsic factors, such as transcription factors and microRNAs expressed sequentially during distincts phases of muscle degeneration and regeneration. Besides, these events are usually accompanied by inflammatory response characterized by leukocytes migration and local release of inflammatory mediators, such as chemokines, cytokines and growth factors. Evidence suggests that the nature, duration and prevalence of different profiles of inflammatory mediators and leukocytes, after muscle injury, determine the muscle repair, or alternatively, the fibrosis formation and loss of tissue function. In accord to complexity of inflammatory response, it is noteworthy that the role of another set of important mediators, derived metabolites of arachidonic acid metabolism pathways, named eicosanoids, has not been well understood, in in vivo experimental models. Currently, it is known that some eicosanoids when added to quiescent muscle cells in culture can activate their proliferation and differentiation. In this context, the present study raises the possibility that these mediators might affect the quality of skeletal muscle regeneration, by regulating both transcriptional and tissue factors, as well as components of inflammatory response, in different phases of tissue regeneration, using more complex experimental models. However, the profile set of eicosanoid production, such as prostaglandins, leukotrienes, hydroxy-eicosatetraenoic acid, epoxides, lipoxins and its regulatory role in distinct phases of degeneration and regeneration of skeletal muscle tissue was not yet investigated systematically. The present study aims to investigate the profile of production and the regulatory role of eicosanoids, synthesized from the cyclooxygenase pathways, lipoxygenase and cytochrome P450 in model myotoxicity induced by a snake venom myotoxin under such aspects: i) histological / morphological-myogenesis, fibrosis, degree of innervation, apoptosis; ii) inflammatory - characterization of leukocyte influx profile and release of inflammatory mediators; iii) transcriptional - expression of transcription factors and microRNAs; iv) functional - capacity of skeletal muscle contraction. The characterization of the role of eicosanoids in degenerative and regenerative skeletal muscle tissue after injury will expand the functional knowledge about inflammatory response in those events. Moreover, the elucidation of the lipid mediators influence in such processes, will contribute to the identification of new therapeutic targets that aim the efficient repair of damaged skeletal muscle. (AU)