Hokanson J F, Mercier J G, Brooks G A
Department of Human Biodynamics, University of California, Berkeley, USA.
Am J Respir Crit Care Med. 1995 Jun;151(6):1848-51. doi: 10.1164/ajrccm.151.6.7767529.
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.
环孢素A（CsA）是一种强效免疫抑制剂，用于降低移植手术后的器官排斥反应。据报道，CsA使用的局限性在于肝毒性和肾毒性。此外，即使动脉氧运输能力得到修复，移植后的运动能力仍远低于预期。本研究的目的是确定CsA对体外骨骼肌线粒体呼吸的影响，并确定CsA骨骼肌线粒体损伤的部位。通过差速离心从大鼠后肢肌肉匀浆中分离出线粒体。在37℃下，使用Rank氧极谱仪在蔗糖和甘露醇呼吸介质中测定线粒体呼吸。在琥珀酸和鱼藤酮存在的情况下，CsA抑制最大呼吸（ADP刺激）18.3%，在苹果酸和丙酮酸存在的情况下抑制34.7%。对于琥珀酸和鱼藤酮或丙酮酸加苹果酸，CsA分别使解偶联呼吸速率（添加羰基氰化物对三氟甲氧基苯腙）降低19.6%和32.0%。未观察到CsA对任何一种底物的ADP/O有显著影响。我们得出结论，CsA在体外抑制最大偶联和非偶联的骨骼肌线粒体呼吸。此外，尽管CsA对通过复合体I的电子通量影响更大，但CsA引起的线粒体损伤并非特异性针对电子传递链（ETC）的复合体I或复合体II。移植患者尽管动脉氧合充足以及全身和局部氧输送正常，但运动能力较差，这可能部分归因于免疫抑制治疗对骨骼肌线粒体ETC能力的影响。
