Role of thyroid hormone and insulin in control of cardiac isomyosin expression.

Previous studies show that both diabetes and thyroid state exert a strong regulatory influence on the pattern of rodent cardiac isomyosin expression. Therefore, we determined the separate and combined effects of thyroid hormone (T3) and insulin treatment on rodent cardiac myosin heavy chain (MHC) expression using a model of combined thyroid deficiency (Tx) and diabetes (D). The combination of Tx and D completely transformed cardiac isomyosin expression such that the fast alpha-myosin heavy chain (MHC) was completely repressed at both the protein and mRNA level of expression; whereas, the slow beta-MHC was upregulated to constitute 100% of the total MHC pool, based on both protein and mRNA analyses. Daily low doses of exogenous T3 treatment (3 micrograms/kg b.w. i.p.). in the absence of insulin treatment, partially restored expression of the alpha-MHC, while inhibiting expression of the beta-isoform. In contrast daily insulin treatment (4 U/rat), in the absence of exogenous T3 treatment, failed to exert any significant influence on the pattern of isomyosin expression in the thyroid-deficient diabetic rat model. Furthermore, when exogenous T3 was administered in conjunction with insulin, the effect on MHC mRNA expression was greater than that of T3 alone, thus suggesting the existence of interaction between T3 and insulin action in the regulation of MHC mRNA expression. Collectively, these findings suggest that: (a) thyroid state is a dominant regulator of cardiac isomyosin phenotype: and (b) insulin does not exert any regulatory influence on cardiac MHC expression in a severe thyroid deficient state, instead it requires a critical level of circulating T3 in order to be effective in blunting MHC transformation associated with diabetes. It is thus concluded that the regulation of cardiac MHC by insulin is a complex mechanism involving interaction of insulin with subcellular factors likely to have impact on the specific action of T3. This interaction is disrupted in the absence of sufficient thyroid hormone.