RESUMO
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.
Assuntos
Músculo Esquelético/efeitos dos fármacos , Necrose/induzido quimicamente , Regeneração/efeitos dos fármacos , Venenos de Víboras/toxicidade , Animais , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Humanos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/patologia , Músculo Esquelético/fisiologia , Necrose/patologia , ViperidaeRESUMO
INTRODUCTION: Viperid snakebite envenomings are characterized by muscle necrosis and a deficient regenerative response. METHODS: Homogenates from gastrocnemius muscles of mice injected with the venom of the snake Bothrops asper or with 2 tissue-damaging toxins were added to cultures of C2C12 myogenic cells. Myoblasts proliferation and fusion were assessed. Venom was detected by immunoassay in mouse muscle during the first week after injection. RESULTS: Homogenates from venom-injected muscle induced a drop in the number of proliferating myoblasts and a complete elimination of myotube formation. The inhibitory effect induced by homogenates from venom-injected mice was abrogated by preincubation of the homogenate with antivenom antibodies but not with control antibodies. This finding provides evidence that the effect is due to the action of venom in the tissue. CONCLUSIONS: Our observations suggest that traces of venom in muscle tissue might inhibit myotube formation and preclude a successful regenerative response.