Calcineurin plays a modulatory role in loading-induced regulation of type I myosin heavy chain gene expression in slow skeletal muscle.
The role of calcineurin (Cn) in skeletal muscle fiber-type expression has been a subject of great interest because of reports indicating that it controls the slow muscle phenotype. To delineate the role of Cn in phenotype remodeling, particularly its role in driving expression of the type I myosin heavy chain (MHC) gene, we used a novel strategy whereby a profound transition from fast to slow fiber type is induced and examined in the absence and presence of cyclosporin A (CsA), a Cn inhibitor. To induce the fast-to-slow transition, we first subjected rats to 7 days of hindlimb suspension (HS) + thyroid hormone [triiodothyronine (T(3))] to suppress nearly all expression of type I MHC mRNA in the soleus muscle. HS + T(3) was then withdrawn, and rats resumed normal ambulation and thyroid state, during which vehicle or CsA (30 mg x kg(-1) x day(-1)) was administered for 7 or 14 days. The findings demonstrate that, despite significant inhibition of Cn, pre-mRNA, mRNA, and protein abundance of type I MHC increased markedly during reloading relative to HS + T(3) (P < 0.05). Type I MHC expression was, however, attenuated by CsA compared with vehicle treatment. In addition, type IIa and IIx MHC pre-mRNA, mRNA, and relative protein levels were increased in Cn-treated compared with vehicle-treated rats. These findings indicate that Cn has a modulatory role in MHC transcription, rather than a role as a primary regulator of slow MHC gene expression.
Pandorf
Clay E
CE
Department of Physiology and Biophysics, University of California, Irvine, Irvine, California 92697, USA.
Jiang
Weihua H
WH
Qin
Anqi X
AX
Bodell
Paul W
PW
Baldwin
Kenneth M
KM
Haddad
Fadia
F
D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005838:Genotype; D019417:Hindlimb Suspension; D023421:Models, Animal; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000201:enzymology*; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D024461:Myosin Type I / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms; D012322:RNA Precursors / Q000378:metabolism; D016372:RNA, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000008:administration & dosage; D016474:Weight-Bearing
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D012322:RNA Precursors; D016372:RNA, Antisense; D012333:RNA, Messenger; D014284:Triiodothyronine; D016572:Cyclosporine; D019703:Calcineurin; D024461:Myosin Type I; D018995:Myosin Heavy Chains