Immunosuppressive treatment affects cardiac and skeletal muscle mitochondria by the toxic effect of vehicle.
In order to examine whether immunosuppressive treatment could be responsible for the reduced exercise capacity of heart transplant recipients (HTR), we studied the effects of long-term immunosuppressive treatment with cyclosporin A (CsA) and its vehicle (2/3 cremophor and 1/3 alcohol diluted in olive oil) on in situ mitochondrial respiration of different muscles. Rats were fed for 3 weeks with 10 or 25 mg/kg/day CsA in its vehicle (CsA10 and CsA25 groups), or vehicle or H(2)O. Oxygen consumption rate was measured in saponin skinned fibers without (V(0)) and with ADP until maximal respiration (V(max)) was reached and K(M)for ADP as well as V(max)were calculated using non-linear fit of the Michaelis-Menten equation. In the cardiac muscle of the CsA25 group, V(0)and V(max)were decreased by immunosuppressive treatment respectively from 6.33+/-0.51 to 3.18+/-0.3micromol O(2)/min/g dw (P<0.001) and from 29.0+/-1.5 to 18.1+/-1.6micromol O(2)/min/g dw (P<0.001), an effect which could be entirely attributed to the vehicle itself, with no difference between CsA10 and CsA25. Regulation of cardiac mitochondrial respiration by ADP was altered by vehicle with the K(M)for ADP decreasing from 371+/-37 to 180+/-21microm(P<0.001). A similar trend was observed in the diaphragm or soleus, although to a lesser extent. In contrast, V(0)and V(max)decreased in glycolytic gastrocnemius muscle respectively from 1.7+/-0.2 to 0.94+/-0.14 (P<0. 01) and from 6.8+/-0.3 to 5.1+/-0.4micromol O(2)/min/g dw (P<0.001) in the CsA25 group, but the main effects could be attributed to CsA itself. It was concluded that immunosuppressive treatment induces a deleterious effect on cardiac and skeletal muscle oxidative capacities, mainly due to cremophor, the main component of vehicle.
Sanchez
H
H
Unité de Bioénergétique et Environnement, Centre de Recherches du Service de Santé des Armées, Ave du Maquis du Grésivaudan, 38702, La Tronche Cedex, France.
Bigard
X
X
Veksler
V
V
Mettauer
B
B
Lampert
E
E
Lonsdorfer
J
J
Ventura-Clapier
R
R
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000633:toxicity*; D003964:Diaphragm / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005221:Fatigue / Q000139:chemically induced; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects*; D008931:Mitochondria, Muscle / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects; D000069463:Olive Oil; D009928:Organ Specificity; D010101:Oxygen Consumption / Q000187:drug effects; D014677:Pharmaceutical Vehicles / Q000633:toxicity*; D010938:Plant Oils / Q000008:administration & dosage / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000633:toxicity*; D011183:Postoperative Complications / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar
D007166:Immunosuppressive Agents; D000069463:Olive Oil; D014677:Pharmaceutical Vehicles; D010938:Plant Oils; C022131:cremophor; D000431:Ethanol; D011092:Polyethylene Glycols; D000244:Adenosine Diphosphate; D016572:Cyclosporine