Why is Skeletal Muscle Regeneration Impaired after Myonecrosis Induced by Viperid Snake Venoms?

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.

Mesenchymal Stromal Cell-Based Therapies as Promising Treatments for Muscle Regeneration After Snakebite Envenoming

“…Local damage caused by SBE results in myonecrosis as one of their main complications. Although not yet completely understood, the current knowledge on the pathogenesis of snakebite-induced myonecrosis and its unsuccessful healing have been well described in a recent review ( 7 ).…”

“…Among the various tissue damage effects induced by SBE, myotoxicity-induced local myonecrosis ( 5 ) and hemorrhage ( 6 ) could be the most severe ones. Impaired skeletal muscle regeneration (SMR) ( 7 , 8 ) may be associated or not to low response to antivenom ( 9 ).…”

Deficient Skeletal Muscle Regeneration after Injury Induced by a Clostridium perfringens Strain Associated with Gas Gangrene

“…After muscle injury, the regeneration process is mediated by a specific type of stem cells, SC, but it also involves the interaction of these myogenic cells with other resident cells, inflammatory cells, blood vessels, nerves, and the extracellular matrix (14,37). There are at least three basic requirements for the process of muscle regeneration to occur: (i) adequate blood flow in the regenerative muscle, (ii) innervation of regenerative cells, and (iii) permanence of the basal lamina around the necrotic myofibers, which serves as a scaffold and substrate for regeneration (7). Impairment of any of these contributory factors results in defective muscle regeneration.…”

“…The vascular network has an important role in this process, as it has an impact on the distribution of inflammatory cells, growth factors, cytokines, chemokines, and nutrients. Therefore, alterations in vascular integrity can affect the regenerative process (7). The regeneration phase begins with the activation of satellite cells (SC) that reside on the surface of the myofibers (8).…”

Role of crotoxin in coagulation: novel insights into anticoagulant mechanisms and impairment of inflammation-induced coagulation

“…Snake venom phospholipases A 2 (svPLA 2 ) are enzymes that when secreted catalyze the hydrolysis of phospholipids. These enzymes are responsible for local and systemic effects such as myotoxicity, neuromuscular blockade, inf lammation, and hemostasis alterations [1][2][3][4]. Aside from the toxicological behavior presented by this group of toxins, their wide range of pharmacological properties have brought novel perspectives for svPLA 2 s as antitumoral, analgesic, bactericidal, immunosuppressive and anticoagulant agents [4][5][6][7][8].…”