Regular Article
Immunosuppressive Treatment Affects Cardiac and Skeletal Muscle Mitochondria by the Toxic Effect of Vehicle

https://doi.org/10.1006/jmcc.1999.1078Get rights and content

Abstract

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 H2O. Oxygen consumption rate was measured in saponin skinned fibers without (V0) and with ADP until maximal respiration (Vmax) was reached and KMfor ADP as well as Vmaxwere calculated using non-linear fit of the Michaelis–Menten equation. In the cardiac muscle of the CsA25 group, V0and Vmaxwere decreased by immunosuppressive treatment respectively from 6.33±0.51 to 3.18±0.3μmol O2/min/g dw (P<0.001) and from 29.0±1.5 to 18.1±1.6μmol O2/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 KMfor ADP decreasing from 371±37 to 180±21μm(P<0.001). A similar trend was observed in the diaphragm or soleus, although to a lesser extent. In contrast, V0and Vmaxdecreased 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±0.4μmol O2/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.

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    Please address all correspondence to: R. Ventura-Clapier, U-446 INSERM, Cardiologie Cellulaire et Moléculaire, Université Paris-Sud, 92296 Châtenay-Malabry, France. Fax: (+331) 46 83 54 75; E-mail: [email protected]

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