title: Thyroid hormone receptor-beta-selective agonist GC-24 spares skeletal muscle type I to II fiber shift.
abstract: Triiodothyronine (T3) is known to play a key role in the function of several tissues/organs via the thyroid hormone receptor isoforms alpha (TRalpha) and beta (TRbeta). We have investigated the effects of GC-24, a novel synthetic TRbeta-selective compound, on skeletal muscle fiber-type determination, cross-sectional area, and gene expression in rat skeletal muscles. For fiber typing, cross sections of soleus and extensor digitorum longus (EDL) muscles were stained for myosin ATPase activity at various pHs. Serum T3, T4, and cholesterol levels were also determined. Analysis of highly T3-responsive genes, viz., myosin heavy chain IIa (MHCIIa) and sarcoendoplasmic reticulum adenosine triphosphatase (SERCA1), was performed by quantitative real-time polymerase chain reaction. Equimolar doses of T3 and GC-24 had a similar cholesterol-lowering effect. T3, but not GC-24, decreased fiber type I and increased fiber type II abundance in soleus and EDL muscles. Conversely, in EDL, both T3 and GC-24 decreased the mean cross-sectional area of type I fibers. MHCIIa gene expression was reduced (approximately 50%) by T3 and unchanged by GC-24. SERCA1 gene expression was strongly induced by T3 (approximately 20-fold) and mildly induced by GC-24 (approximately two-fold). These results show that GC-24 does not significantly alter the composition of skeletal muscle fiber type and further strengthens the putative use of GC compounds as therapeutic agents.
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
authors.forename: Elen H
authors.initials: EH
authors.lastname: Miyabara
authors.forename: Marcelo S
authors.initials: MS
authors.lastname: Aoki
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Soares
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Saltao
authors.forename: Cassio M
authors.initials: CM
authors.lastname: Vilicev
authors.forename: Marisa
authors.initials: M
authors.lastname: Passarelli
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
authors.forename: Cecilia H
authors.initials: CH
authors.lastname: Gouveia
authors.forename: Anselmo S
authors.initials: AS
authors.lastname: Moriscot
mesh_terms: D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000252:Calcium-Transporting ATPases / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects* / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D037042:Thyroid Hormone Receptors beta / Q000819:agonists* / Q000378:metabolism; D014284:Triiodothyronine / Q000009:adverse effects
chemical_list: D000085:Acetates; C506945:Atp2a1 protein, rat; D001559:Benzhydryl Compounds; C483767:GC 24 compound; D012333:RNA, Messenger; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D002784:Cholesterol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases