Cellular adaptations of skeletal muscles to cyclosporine.
The aim of this study was to evaluate the cellular response of the diaphragm, extensor digitorum longus (EDL), and soleus (Sol) muscles to clinically relevant doses of cyclosporine administered to male rats over 4 wk. Control rats were provided with vehicle only. Muscle fiber types, cross-sectional areas, indexes of capillarity, and succinate dehydrogenase (SDH) activity were determined by quantitative histochemistry. Myosin heavy chain isoforms were identified by SDS-PAGE, and their proportions were measured by scanning densitometry. Serum cyclosporine level, 20-24 h after the last dose of cyclosporine, was 145 +/- 81 ng/ml. Final body weight and muscle mass were similar between the cyclosporine and control groups. In the diaphragm, EDL, and Sol, no differences were observed between the groups with regard to fiber type proportions, fiber cross-sectional areas, and proportions of myosin heavy chain isoforms. In the EDL, reductions, both in SDH activity in type I, IIx, and IIb fibers (-26 to -37%) and in indexes of capillarity (-18 to -37%), were noted. In the Sol, SDH activity and capillarity were similar between the groups. In the diaphragm of cyclosporine-treated rats, there was significant reduction in the number of capillaries around individual fibers (-5%), whereas levels of SDH activity tended to be lower. This suggests that activation history may in part determine muscle-specific responses to cyclosporine. We speculate that reduced oxidative activity and capillarity of some limb muscles contribute to reduced exercise capacity and the "deconditioned state" observed in patients receiving cyclosporine after successful solid-organ transplantation.
Biring
M S
MS
Division of Pulmonary/Critical Care Medicine, Department of Medicine, The Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Fournier
M
M
Ross
D J
DJ
Lewis
M I
MI
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology*; D006651:Histocytochemistry; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D013385:Succinate Dehydrogenase / Q000378:metabolism
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D013385:Succinate Dehydrogenase; D018995:Myosin Heavy Chains