Abstract
Skeletal muscle regeneration after myonecrosis involves the activation, proliferation and fusion of myogenic cells, and a coordinated inflammatory response encompassing phagocytosis of necrotic cell debris, and the concerted synthesis of cytokines and growth factors. Myonecrosis often occurs in snakebite envenomings. In the case of venoms that cause myotoxicity without affecting the vasculature, such as those of many elapid snakes, regeneration proceeds successfully. In contrast, in envenomings by most viperid snakes, which affect the vasculature and extracellular matrix in addition to muscle fibers, regeneration is largely impaired and, therefore, the muscle mass is reduced and replaced by fibro-adipose tissue. This review discusses possible causes for such poor regenerative outcome including: (a) damage to muscle microvasculature, which causes tissue hypoxia and affects the inflammatory response and the timely removal of necrotic tissue; (b) damage to intramuscular nerves, which results in atrophy of regenerating fibers; (c) degradation of muscle cell basement membrane, compromising the spatial niche for proliferating myoblasts; (d) widespread degradation of the extracellular matrix; and (e) persistence of venom components in the damaged tissue, which may affect myogenic cells at critical points in the regenerative process. Understanding the causes of poor muscle regeneration may pave the way for the development of novel therapeutic interventions aimed at fostering the regenerative process in envenomed patients.
Highlights
Snakebite envenoming is a neglected tropical disease that kills and maims hundreds of thousands of people every year, especially in sub-Saharan Africa, Asia, Latin America and parts of Oceania [1,2].The pathophysiology and clinical manifestations of these envenomings vary depending on the typeToxins 2018, 10, 182; doi:10.3390/toxins10050182 www.mdpi.com/journal/toxinsToxins 2018, 10, 182 of venom
The present review summarizes the basic aspects of the process of skeletal muscle regeneration and discusses possible causes for the deficient regenerative outcome in snakebite patients, together with possible therapeutic interventions aimed at improving regeneration
In the case of viperid venoms that contain myotoxic, hemorrhagic and edema-forming toxins, myonecrosis occurs by a combination of the direct action of myotoxins on muscle fibers, as well as indirectly, through the ischemia resulting from venom-induced vascular alterations
Summary
Snakebite envenoming is a neglected tropical disease that kills and maims hundreds of thousands of people every year, especially in sub-Saharan Africa, Asia, Latin America and parts of Oceania [1,2]. Most viperid snake venoms (family Viperidae) cause local tissue damage (hemorrhage, necrosis, blistering, and edema) and systemic alterations associated with bleeding, coagulopathy, hemodynamic alterations and nephrotoxicity [1,2,3]. This basic pattern is an oversimplification of a highly complex and variable profile of clinical manifestations of envenomings, and specific pathophysiological profiles have been described for several snake venoms [4,5]. The present review summarizes the basic aspects of the process of skeletal muscle regeneration and discusses possible causes for the deficient regenerative outcome in snakebite patients, together with possible therapeutic interventions aimed at improving regeneration
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