CYCLOSPORINE-A DECREASES RAT SKELETAL-MUSCLE MITOCHONDRIAL RESPIRATION IN-VIVO

Cyclosporine A (CsA) is a potent immunosuppressant used to decrease or gan rejection after transplantation surgery. Reported limitations to u se of CsA have been hepatotoxicity and nephrotoxicity. Additionally ex ercise capacity is much less than expected following transplantation e ven if arterial oxygen transport capacity is repaired. Purposes of the present study were to determine the effects of CsA on skeletal muscle mitochondrial respiration in vitro and to determine the site of the C sA skeletal muscle mitochondrial lesion. Mitochondria were isolated fr om rat hind limb muscle homogenates after differential centrifugation. Mitochondrial respiration was determined using a Rank oxygen polarogr aph at 37 degrees C in a sucrose and mannitol respiration medium. CsA inhibited maximal respiration (ADP stimulated) in the presence of succ inate and rotenone by 18.3% and in the presence of malate and pyruvate by 34.7%. CsA decreased the rate of uncoupled respiration (addition o f carbonyl cyanide p-trifluoromethozyphenylhydrazone) by 19.6% and 32. 0% for succinate and rotenone, or pyruvate plus malate, respectively N o significant effect of CsA on ADP/O for either substrate was observed . We conclude that CsA inhibits maximal coupled and uncoupled skeletal muscle mitochondrial respiration in vitro. Moreover, although the eff ects of CsA were greater on electron flux through Complex I, mitochond rial lesions caused by CsA were not specific to either Complex I or Co mplex II of the electron transport chain (ETC). Poor exercise performa nce despite adequate arterial oxygenation and systemic and regional ox ygen deliveries in transplant patients may be attributed, in part, to the effects of immunosuppressive therapy on FTC capacity of skeletal m uscle mitochondria.