The responsiveness of mature regenerated soleus (SOL) muscles to cyclosporin A (CsA) administration was studied in rats. Forty-two days after notexin-induced degeneration of left SOL muscles, rats were treated with CsA (25 mg/kg · day) or vehicle daily for 3 weeks. CsA administration decreased by eightfold the level of transcription of MCIP-1, a well-known calcineurin-induced gene, in intact as well as in regenerated muscles (P < 0.001). In response to CsA-administration we observed a slow-to-fast transition in the MHC profile, more marked in regenerated than in intact muscles (P < 0.05), but mainly restricted to MHC-Iβ toward MHC-IIA. Immunohistochemical analysis showed that MHC-IIA was often co-expressed with MHC-Iβ within myofibers of intact muscles, whereas it was mainly expressed within pure fast fibers of regenerated muscles. MHC-Iβ mRNA levels were lower in regenerated than in intact muscles, but did not change in response to CsA-administration. CsA administration induced a significant increase in MHC-IIA mRNA levels (P < 0.001) similar in both intact and regenerated muscles. Present results suggest that in vivo in intact SOL muscles, calcineurin blocks the upregulation of the MHC-IIA isoform at the transcriptional level. On the other hand, the higher response of regenerated muscles to CsA administration cannot be explained by transcriptional events, and may result from either a more rapid turnover of MHC proteins in regenerated muscles than in intact ones, or translational events. This study further suggests that the developmental history of myofibers could play a role in the adaptability of skeletal muscle to variations in neuromuscular activity. © 2006 Wiley-Liss, Inc.