JF Hokanson, JG Mercier and GA Brooks
Department of Human Biodynamics, University of California, Berkeley, USA.

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.

This article has been cited by other articles:

				S. Mathur, W D. Reid, and R. D Levy Exercise Limitation in Recipients of Lung Transplants Physical Therapy, December 1, 2004; 84(12): 1178 - 1187. [Full Text] [PDF]

				S.M. Studer, R.D. Levy, K. McNeil, and J.B. Orens Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness Eur. Respir. J., October 1, 2004; 24(4): 674 - 685. [Abstract] [Full Text] [PDF]

				P. J. Schaeffer, A. R. Wende, C. J. Magee, J. R. Neilson, T. C. Leone, F. Chen, and D. P. Kelly Calcineurin and Calcium/Calmodulin-dependent Protein Kinase Activate Distinct Metabolic Gene Regulatory Programs in Cardiac Muscle J. Biol. Chem., September 17, 2004; 279(38): 39593 - 39603. [Abstract] [Full Text] [PDF]

				C Pinet, P Scillia, M Cassart, M Lamotte, C Knoop, C Melot, and M Estenne Preferential reduction of quadriceps over respiratory muscle strength and bulk after lung transplantation for cystic fibrosis Thorax, September 1, 2004; 59(9): 783 - 789. [Abstract] [Full Text] [PDF]

				J. Zoll, B. N'Guessan, F. Ribera, E. Lampert, D. Fortin, V. Veksler, X. Bigard, B. Geny, J. Lonsdorfer, R. Ventura-Clapier, et al. Preserved response of mitochondrial function to short-term endurance training in skeletal muscle of heart transplant recipients J. Am. Coll. Cardiol., July 2, 2003; 42(1): 126 - 132. [Abstract] [Full Text] [PDF]

				S. J. Swoap, R. B. Hunter, E. J. Stevenson, H. M. Felton, N. V. Kansagra, J. M. Lang, K. A. Esser, and S. C. Kandarian The calcineurin-NFAT pathway and muscle fiber-type gene expression Am J Physiol Cell Physiol, October 1, 2000; 279(4): C915 - C924. [Abstract] [Full Text] [PDF]

				R. Casaburi Skeletal Muscle Function in COPD Chest, May 1, 2000; 117(5_suppl_1): 267S - 271S. [Abstract] [Full Text] [PDF]

				X. N. WANG, T. J. WILLIAMS, M. J. MCKENNA, J. L. LI, S. F. FRASER, E. A. SIDE, G. I. SNELL, E. H. WALTERS, and M. F. CAREY Skeletal Muscle Oxidative Capacity, Fiber Type, and Metabolites after Lung Transplantation Am. J. Respir. Crit. Care Med., July 1, 1999; 160(1): 57 - 63. [Abstract] [Full Text]

				S. M. Arcasoy and R. M. Kotloff Lung Transplantation N. Engl. J. Med., April 8, 1999; 340(14): 1081 - 1091. [Full Text] [PDF]

				Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease . A Statement of the American Thoracic Society and European Respiratory Society Am. J. Respir. Crit. Care Med., April 1, 1999; 159(4): S2 - 40. [Full Text] [PDF]

				K. L. Abbott, B. B. Friday, D. Thaloor, T.J. Murphy, and G. K. Pavlath Activation and Cellular Localization of the Cyclosporine A-sensitive Transcription Factor NF-AT in Skeletal Muscle Cells Mol. Biol. Cell, October 1, 1998; 9(10): 2905 - 2916. [Abstract] [Full Text]

				E. Lampert, B. Mettauer, H. Hoppeler, A. Charloux, A. Charpentier, and J. Lonsdorfer Skeletal muscle response to short endurance training in heart transplant recipients J. Am. Coll. Cardiol., August 1, 1998; 32(2): 420 - 426. [Abstract] [Full Text] [PDF]

				M. S. Biring, M. Fournier, D. J. Ross, and M. I. Lewis Cellular adaptations of skeletal muscles to cyclosporine J Appl Physiol, June 1, 1998; 84(6): 1967 - 1975. [Abstract] [Full Text] [PDF]

				F. Yajid, J. G. Mercier, B. M. Mercier, H. Dubouchaud, and C. Prefaut Effects of 4 wk of hindlimb suspension on skeletal muscle mitochondrial respiration in rats J Appl Physiol, February 1, 1998; 84(2): 479 - 485. [Abstract] [Full Text] [PDF]