The responsiveness of regenerated soleus muscle to pharmacological calcineurin inhibition.
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 x 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-Ibeta toward MHC-IIA. Immunohistochemical analysis showed that MHC-IIA was often co-expressed with MHC-Ibeta within myofibers of intact muscles, whereas it was mainly expressed within pure fast fibers of regenerated muscles. MHC-Ibeta 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.
Koulmann
Nathalie
N
Département des facteurs humains, Centre de Recherches du Service de Santé des Armées, La Tronche Cedex, France. nkoulmann@crssa.net
Sanchez
Hervé
H
N'Guessan
Benoît
B
Chapot
Rachel
R
Serrurier
Bernard
B
Peinnequin
André
A
Ventura-Clapier
Renée
R
Bigard
Xavier
X
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000032:analysis / Q000235:genetics; D009929:Organ Size; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C000594638:MYH7 protein, rat; D020033:Protein Isoforms; C548050:RCAN1 protein, rat; D012333:RNA, Messenger; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin; D018995:Myosin Heavy Chains