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 (T-3) and insulin treatment on rodent cardiac myosin heavy chain (MMC) 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 T-3 treatment (3 mu g/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 T-3 treatment, failed to exert any significant influence on the pattern of isomyosin expression in the the thyroid-deficient diabetic rat model. Furthermore, when exogenous T-3 was administered in conjunction with insulin, the effect on MHC mRNA expression was greater than that of T-3 alone, thus suggesting the existence of interaction between T-3 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 T-3 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 T-3. This interaction is disrupted in the absence of sufficient thyroid hormone. (C) 1997 Academic Press Limited.