We investigated the effects of 14 d of cyclosporine A (CsA) administration on skeletal muscle mitochondrial respiration and submaximal running endurance time in rats. Eight experimental (CsA) and eight control rats followed a 14-d feeding protocol of CsA (20 mg/kg/d) oral administration or placebo. Submaximal endurance exercise time (EET) was measured on a treadmill on Day 13 and mitochondria were isolated from the hind limb muscles homogenate on Day 15. The results showed (1) a significant decrease of EET in CsA versus control rats (29 +/- 8 min versus 60 +/- min, p < 0.001), (2) significantly lower state 3 and uncoupled mitochondrial respiration in CsA compared with control rats with pyruvate plus malate (p < 0.001, p < 0.01) as well as succinate plus rotenone (p < 0.01) as substrates, (3) no differences in coupling efficiency (ADP/O ratios), and (4) significant linear correlation between EET and state 3 respiration (r = 0.71, p < 0.05; r = 0.92, p < 0.001), and strong curvilinear relationship between EET and CsA state 3/mean control state 3 (r2 = 0.81, p < 0.001; r2 = 0.82, p < 0.001), respectively, with pyruvate plus malate and succinate plus rotenone. We conclude that 14 d of CsA oral administration decreases skeletal muscle mitochondrial electron chain capacity without changing coupling efficiency in rats. Results suggest that immunosuppressive therapy is responsible, in part, for poor exercise performance in transplant patients.
The pronghorn antelope (Antilocapra americana) has an alleged top speed of 100 km h-1, second only to the cheetah (Acionyx jubatus) among land vertebrates, a possible response to predation in the exposed habitat of the North American prairie. Unlike cheetahs, however, pronghorn antelope are distance runners rather than sprinters, and can run 11 km in 10 min, an average speed of 65 km h-1. We measured maximum oxygen uptake in pronghorn antelope to distinguish between two potential explanations for this ability: either they have evolved a uniquely high muscular efficiency (low cost of transport) or they can supply oxygen to the muscles at unusually high levels. Because the cost of transport (energy per unit distance covered per unit body mass) varies as a predictable function of body mass among terrestrial vertebrates, we can calculate the predicted cost to maintain speeds of 65 and 100 km h-1 in an average 32-kg animal. The resulting range of predicted values, 3.2-5.1 ml O2 kg-1 s-1, far surpasses the predicted maximum aerobic capacity of a 32-kg mammal (1.5 ml O2 kg-1 s-1). We conclude that their performance is achieved by an extraordinary capacity to consume and process enough oxygen to support a predicted running speed greater than 20 ms-1 (70 km h-1), attained without unique respiratory-system structures.
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.
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