In a previous study, we showed that the Polybia paulista wasp venom causes strong myonecrosis. This study was undertaken to characterize the myotoxic potency of mastoparan (Polybia-MPII) isolated from venom (0.25 microg/microl) and injected in the tibial anterior (TA) muscle (i.m.) of Balb/c mice. The time course of the changes was followed at muscle degenerative (3 and 24h) and regenerative (3, 7, and 21 days) periods (n=6) after injection and compared to matched controls by calculation of the percentage of cross-sectional area affected and determination of creatine kinase (CK) activity (n=10). The results showed that although MP was strongly myotoxic, its capacity for regeneration was maintained high. Since the extent of tissue damage was not correlated with the CK serum levels, which remained very low, we raised the hypothesis that the enzyme underwent denaturation by the peptide. Evidence suggested that MP induced the death of TA fibers by necrosis and apoptosis and had the sarcolemma as its primordial target. Given its amphiphilic polycationic nature and based on the vast spectrum of functions attributed to the peptide, we suggest that MP interaction with cell membrane impaired the phosphorylation of dystrophin essential for sarcolemma mechanical stability, and disturbed Ca2+ mobilization with obvious implications on sarcoplasmic reticulum and mitochondrial functioning.