dnRas stimulates autocrine-paracrine growth of regenerating muscle via calcineurin-NFAT-IL-4 pathway.
Ras and calcineurin are members of two independent pathways in muscle growth but their interaction is not known. This work shows that the transfection of about 1% of the muscle fibers with dominant negative Ras (dnRas) shows a wilder effect; it stimulates the fiber growth in the entire regenerating soleus muscle, including the nontransfected fibers. Co-transfection with the calcineurin inhibitor cain/cabin prevented the growth stimulation. Injection of antibody for interleukin-4 (IL-4) also abolished the growth ameliorating effect. These results suggest that the inactivation of Ras in 1% of the fibers upregulates the calcineurin-NFAT-IL-4 pathway and the secreted IL-4 triggers fiber growth stimulation in the whole regenerating soleus muscle of the rat. The results highlight the importance of the autocrine-paracrine regulation in muscle regeneration and hint to a novel method of gene theraphy of degenerative-regenerative muscle dystrophies.
Zádor
Erno
E
Institute of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Dóm tér 9, H-6720, Hungary. erno@biochem.szote.u.szeged.hu
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019898:Autocrine Communication; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000235:genetics; D015316:Genetic Therapy; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009136:Muscular Dystrophies / Q000628:therapy; D050778:NFATC Transcription Factors / Q000378:metabolism; D019899:Paracrine Communication; D051381:Rats; D011919:Rats, Inbred Strains; D012038:Regeneration / Q000235:genetics; D014162:Transfection; D018631:ras Proteins / Q000235:genetics* / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C113573:Cabin1 protein, rat; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D050778:NFATC Transcription Factors; D015847:Interleukin-4; D019703:Calcineurin; D018631:ras Proteins