Cyclosporine A decreases rat skeletal muscle mitochondrial respiration in vitro.

Abstract

Cyclosporine A (CsA) is a potent immunosuppressant used to decrease organ rejection after transplantation surgery. Reported limitations to use of CsA have been hepatotoxicity and nephrotoxicity. Additionally, exercise capacity is much less than expected following transplantation even 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 CsA skeletal muscle mitochondrial lesion. Mitochondria were isolated from rat hind limb muscle homogenates after differential centrifugation. Mitochondrial respiration was determined using a Rank oxygen polarograph at 37 degrees C in a sucrose and mannitol respiration medium. CsA inhibited maximal respiration (ADP stimulated) in the presence of succinate and rotenone by 18.3% and in the presence of malate and pyruvate by 34.7%. CsA decreased the rate of uncoupled respiration (addition of carbonyl cyanide p-trifluoromethozyphenylhydrazone) by 19.6% and 32.0% for succinate and rotenone, or pyruvate plus malate, respectively. No 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 effects of CsA were greater on electron flux through Complex I, mitochondrial lesions caused by CsA were not specific to either Complex I or Complex II of the electron transport chain (ETC). Poor exercise performance despite adequate arterial oxygenation and systemic and regional oxygen deliveries in transplant patients may be attributed, in part, to the effects of immunosuppressive therapy on ETC capacity of skeletal muscle mitochondria.

Role of Oxidant Stress in the Permeability Transition Induced in Rat Hepatic Mitochondria by Hydrophobic Bile Acids

“…9). Higher concentrations of cyclosporin A had a mild inhibitory effect on ROS generation, possibly through direct inhibition of mitochondrial respiration (57). Thus, there was clearly a component of the ROS generated that was not dependent on opening of the permeability pore, although pore opening may have generated ROS to some …”

Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness

“…Cyclosporin, a calcineurin inhibitor, affects the ability of capillaries supplying skeletal muscle fibres to adequately dilate, thereby reducing oxygen delivery to working muscle [70,79], which could impair the oxidative capacity of exercising muscle. Mitochondrial function may also be impaired in transplant recipients due to a cyclosporin effect on mitochondrial respiration [80,81]. Corticosteroids can also result in muscle fibre atrophy and abnormalities in muscle fibre shape and size [82]; however, the morphological and biochemical changes associated with chronic corticosteroid use are not the same as those observed following LT, making this an unlikely culprit.…”

Exercise Limitation in Recipients of Lung Transplants

“…1 These medications have been shown to have profound effects on cellular features of skeletal muscle in patients with COPD 23,24 and in animals. 25,26 The histology of skeletal muscle and its relationship to muscle function has not been reported in recipients of lung transplants and warrants further examination.…”

“…Animal studies have shown that cyclosporine in therapeutic doses can decrease the capacity of the electron transport chain (a source of ATP production during oxidative metabolism) by blocking a calcium-dependent pore in the inner mitochondrial membrane, thus affecting calcium efflux from the mitochondria and impairing mitochondrial respiration. 25 This impairment in calcium transport may lead to an inability of working muscle to utilize oxygen and an early shift toward glycolytic metabolism, especially during exercise, resulting in limited exercise capacity. 25,26 Mercier et al 26 reported that the impairment in mitochondrial respiration was associated with reduced endurance time in treadmill running in rats given cyclosporine.…”