Streptomycin and ethylene diamine tetraacetic acid (EDTA) were used to examine the role of extracellular calcium in stretch-induced muscle injury. Streptomycin was injected in one group of rats, three times daily for 8 days (S, 300 mg.kg(-1).day(-1) intraperitoneally). In another group, EDTA was administered (150 mg.kg(-1) IP) 20 min before and 24 h after the injury protocol. Untreated rats (C) served as controls. Muscle injury was produced by 40 stretches of active dorsiflexor muscles by ankle rotation from 80 degrees to 130 degrees (velocity 1.75 rad.s(-1)). Ten minutes after the injury protocols, all animals lost the same amount of isometric force at both low and high stimulation frequencies (20 HZ; S, 56 +/- 6%; EDTA, 47 +/- 7%; C, 55 +/- 4%) and 120 HZ; S, 11 +/- 3%, EDTA, 13 +/- 3%; C, 11 +/- 3%). Tibialis anterior (TA) muscles were removed after 48 h for morphometric analysis. In both streptomycin-and EDTA-treated rats, the percent of injured (i.e., desmin-negative) myofibers in TA was reduced compared to untreated, injured muscles (S, 0.35 +/- 0.08%; EDTA, 0.64 +/- 0.19%; C, 1.81 +/- 0.43%). Thus, streptomycin and EDTA treatment did not alter the development of muscle weakness (i.e., isometric force deficit), but almost abolished the histopathologic changes. This study shows that the mechanisms for muscle weakness and histopathologic changes (inflammation) following repeated muscle strains can largely be dissociated from each other and helps explain why there is no correlation between isometric force deficits and the number of pathologic cells.