Physiological and pathological cardiac hypertrophy have directionally opposite 
changes in transcription of thyroid hormone (TH)-responsive genes, including 
alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum 
Ca(2+)-ATPase (SERCA), and TH treatment can reverse molecular and functional 
abnormalities in pathological hypertrophy, such as pressure overload. These 
findings suggest relative hypothyroidism in pathological hypertrophy, but serum 
levels of TH are usually normal. We studied the regulation of TH receptors (TRs) 
beta1, alpha1, and alpha2 in pathological and physiological rat cardiac 
hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH 
target genes, alpha- and beta-MyHC and SERCA. All 3 TR subtypes in myocytes were 
downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, 
phenylephrine in culture and pressure overload in vivo. Myocyte TRbeta1 was 
upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, 
T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or 
excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and 
promoters. In addition, TR cotransfection and treatment with the 
TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR 
isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and 
TRalpha1 to alpha-MyHC transcription and increased myocyte size. We conclude 
that TR isoforms have distinct regulation and function in rat cardiac myocytes. 
Changes in myocyte TR levels can explain in part the characteristic molecular 
phenotypes in physiological and pathological cardiac hypertrophy.