Cyclosporine blocks muscle differentiation by inducing oxidative stress and by inhibiting the peptidylprolyl‐cistrans‐isomerase activity of cyclophilin A: cyclophilin A protects myoblasts from cyclosporine‐induced cytotoxicity

Abstract

Allogenic myoblast transplantation (AMT) is under investigation for treatment of severe genetic myopathies. Data regarding the role of cyclosporine (CsA) and FK-506 in AMT have shown that CsA is less effective than FK-506. For this study, we investigated mechanisms of CsA toxicity during AMT and showed that a high level of reactive oxygen species (ROS) generated by CsA, mediated partly by inhibition of the peptidylprolyl-cis-trans-isomerase (PPIase)-like activity of cyclophilin A (CypA), blocked differentiation and induced apoptosis at an early stage of muscle differentiation. Inhibition of the PPIase-like activity of CypA alone also blocked muscle differentiation. However, CsA toxicity did not depend on the inhibition of calcineurin activity during muscle differentiation. Together, these data suggest that CsA-mediated inhibition of the PPIase-like activity of CypA and the high level of ROS generation contributed to the low efficacy of CsA in AMT. In addition, we showed that a reduction of oxidative stress protected cells from CsA-induced apoptosis, and myoblasts that had survived after preexposure to CsA not only proliferated and differentiated reversibly but also gained resistance to subsequent CsA exposure. Thus, administration of antioxidants or overexpression of CypA either exogenously or endogenously during CsA treatment has the potential to improve the success of this treatment in AMT.