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

Author： Sanchez H. Bigard X. Veksler V. Mettauer B. Lampert E. Lonsdorfer J. Ventura-Clapier R.

ISSN： 0022-2828

Source： Journal of Molecular and Cellular Cardiology, Vol.32, Iss.2, 2000-02, pp. : 323-331

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

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 (V_max) was reached and K_Mfor ADP as well as V_maxwere calculated using non-linear fit of the Michaelis–Menten equation. In the cardiac muscle of the CsA25 group, V₀and V_maxwere 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 K_Mfor 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 V_maxdecreased 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.