Degenerative processes in skeletal muscle of Cd2+-treated rats and Cd2+ inhibition of mitochondrial Ca2+ transport.

In rat skeletal muscle, chronic exposure to 50 ppm Cd2+ in drinking water produced both ultrastructural and functional damage, which took place successively and increased gradually with duration of treatment. Ultrastructurally, the first effect was a regression of the sarcoplasmic reticulum, mitochondrial cristae, and glycogen granules. Then, the number of mitochondria diminished and a degeneration of myofilaments appeared. During the 9-month course of treatment, however, the terminal cisternae and the lateral saccules of sarcoplasmic reticulum remained, and the Z lines maintained their tight and rigorously parallel appearance. Functionally, the activities of two cytosolic Ca2+-sensitive enzymes (lactate dehydrogenase and malate dehydrogenase) decreased. Their partial restoration by EGTA and EDTA suggested the presence of inhibitory divalent cations in the cytosol of treated rats. Cd2+ also inhibited Ca2+ transport in mitochondria through the uncoupling of oxidative phosphorylation. Hence, an increase of Ca2+ concentration of the cytosol of Cd2+-treated rats, activating degradative enzymes such as phospholipases, proteases and phosphorylase b kinase, can be incriminated. A direct inhibitory action of Cd2+ on the activities of lactate dehydrogenase and malate dehydrogenase also occurred. Direct action of Cd2+ on certain other Ca2+-sensitive enzymes, thereby aggravating the indirect damage induced through increasing the Ca2+ concentration in cytosol, is hypothesized. In mitochondria, a Cd2+ activation of phospholipase A2 and/or a Ca2+-sensitive protease is a unique possibility, since Ca2+ accumulation was prevented by cytosolic Cd2+.