Background: Changes in phosphorylation status of sarcomeric proteins allows rapid alteration of cardiac function. Results: Tropomyosin dephosphorylation results in myocyte hypertrophy with increases in SERCA2a (sarcoplasmic reticulum Ca 2ϩ ATPase 2a) expression and phospholamban phosphorylation but without functional changes. Conclusion: Tropomyosin phosphorylation can influence calcium regulatory proteins and cardiac remodeling in response to stress. Significance: This is the first report detailing that altering tropomyosin phosphorylation affects calcium handling proteins.

Studies indicate that tropomyosin (Tm) phosphorylation status varies in different mouse models of cardiac disease. Investigation of basal and acute cardiac function utilizing a mouse model expressing an α-Tm protein that cannot be phosphorylated (S283A) shows a compensated hypertrophic phenotype with significant increases in SERCA2a expression and phosphorylation of phospholamban Ser-16 (Schulz, E. M., Correll, R. N., Sheikh, H. N., Lofrano-Alves, M. S., Engel, P. L., Newman, G., Schultz Jel, J., Molkentin, J. D., Wolska, B. M., Solaro, R. J., and Wieczorek, D. F. (2012) J. Biol. Chem. 287, 44478-44489). With these results, we hypothesized that decreasing α-Tm phosphorylation may be beneficial in the context of a chronic, intrinsic stressor. To test this hypothesis, we utilized the familial hypertrophic cardiomyopathy (FHC) α-Tm E180G model (Prabhakar, R., Boivin, G. P., Grupp, I. L., Hoit, B., Arteaga, G., Solaro, R. J., and Wieczorek, D. F. (2001) J. Mol. Cell. Cardiol. 33, 1815-1828). These FHC hearts are characterized by increased heart:body weight ratios, fibrosis, increased myofilament Ca(2+) sensitivity, and contractile defects. The FHC mice die by 6-8 months of age. We generated mice expressing both the E180G and S283A mutations and found that the hypertrophic phenotype was rescued in the α-Tm E180G/S283A double mutant transgenic animals; these mice exhibited no signs of cardiac hypertrophy and displayed improved cardiac function. These double mutant transgenic hearts showed increased phosphorylation of phospholamban Ser-16 and Thr-17 compared with the α-Tm E180G mice. This is the first study to demonstrate that decreasing phosphorylation of tropomyosin can rescue a hypertrophic cardiomyopathic phenotype.

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Tropomyosin (Tm) is an alpha‐helical coiled coil dimer involved in regulating striated muscle contraction. Although sarcomeric Tm is known to be phosphorylated at the penultimate amino acid Ser‐283, little is known regarding its phosphorylation levels in healthy and cardiac diseased states. The objective of this study was to study Tm phosphorylation levels with respect to age in wild type mice and in mice with familial hypertrophic cardiomyopathy (FHC). Phosphorylation levels were determined by western blotting of 2‐D gel electrophoresis of myofibrillar protein preparations. Results show that cardiac Tm phosphorylation is high during the perinatal period and decreases throughout adulthood in wild type mice. We also found that walls of the different cardiac chambers exhibit differential Tm phosphorylation.Two transgenic mouse models harboring FHC mutations in alpha‐Tm (Glu180Gly, and Asp175Asn) were studied to determine the effect of this disease on cardiac Tm phosphorylation. Results show that Tm phosphorylation is altered in both FHC models. Unlike in wild type mice, Tm phosphorylation levels do not decrease after birth, but rather remain constant. Depending on the role of Tm phosphorylation, modulation of phosphorylation levels in FHC patients may be potentially of therapeutic value.This project was funded by NHLBI HL81680 grant to DFW. HNS was supported by a fellowship from Dubai Medical College.