The authors have tested the hypothesis that plasma membrane disruptions are an early form of structural damage to the fibers of eccentrically exercised muscle. Rat serum albumin (RSA) was used as a marker for muscle-fiber wounding in the rat tricep (medial head) exercised eccentrically by downhill running. In all muscles examined, strong staining with a horseradish peroxidase (HRP)-conjugated anti-RSA antibody was observed between fibers (intercellular staining) and also within certain fibers (intracellular staining). This intracellular staining was interpreted as identifying muscle fibers wounded at their plasma membranes and hence rendered transiently or permanently permeable to extracellular RSA. The most striking finding of this study was a 6.9-fold increase relative to unexercised controls in the number of wounded cells in the medial head immediately after eccentric exercise. The authors also reproducibly observed, albeit less frequently, myocytes that stained with anti-RSA in the medial head and several other muscles of the "unexercised," caged laboratory rat. The extreme vulnerability of muscle plasma membranes to mechanically induced stress was revealed in this study by HRP injections into the triceps long head. A single injection of 200 microliters HRP through a 26-gauge needle resulted in extensive labeling of the muscle fibers present in the long head cross-sectioned at the injection site. The authors propose that initially resealable and/or highly localized, unsealable membrane wounds are an early form of exercise-induced damage that could progress along the length of the fiber until, 1 to 4 days after eccentric exercise, it becomes sufficiently severe that it can be readily recognized as the frank fiber necrosis and cellular infiltration described in numerous previous studies. In possessing cells wounded at their plasma membranes, normal, undisturbed rat muscle and eccentrically exercised muscle appears to resemble gut and skin, two additional tissues routinely exposed to mechanical forces in vivo. The authors propose that membrane disruptions provide a route into and out of myofiber cytoplasm distinct from the conventional, membrane-bounded routes of endo- and exocytosis, and therefore may be of importance both technically, as a route for introducing foreign genes into muscle cells, and biologically, as a route for release of the growth factor, basic fibroblast growth factor.