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J. Biol. Chem., Vol. 281, Issue 30, 20666-20672, July 28, 2006

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Thyroid Hormone Stimulates Protein Synthesis in the Cardiomyocyte by Activating the Akt-mTOR and p70^S6K Pathways^*

Agnes Kenessey and Kaie Ojamaa¹

From the The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030 and the Departments of Cell Biology and Medicine, New York University School of Medicine, New York, New York 10016

Thyroid hormones affect cardiac growth and phenotype; however, the mechanisms by which the hormones induce cardiomyocyte hypertrophy remain uncharacterized. Tri-iodo-L-thyronine (T3) treatment of cultured cardiomyocytes for 24 h resulted in a 41 ± 5% (p < 0.001) increase in [³H]leucine incorporation into total cellular protein. This response was abrogated by the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Co-immunoprecipitation studies showed a direct interaction of cytosol-localized thyroid hormone receptor TR1 and the p85 subunit of PI3K. T3 treatment rapidly increased PI3K activity by 52 ± 3% (p < 0.005), which resulted in increased phosphorylation of downstream kinases Akt and mammalian target of rapamycin (mTOR). This effect was abrogated by pretreatment with wortmannin or LY294002. Phosphorylation of p70^S6K, a known target of mTOR, occurred rapidly following T3 treatment and was inhibited by rapamycin and wortmannin. In contrast, phosphorylation of the p85 variant of S6K in response to T3 was not blocked by LY294002, wortmannin, or rapamycin, thus supporting a T3-activated pathway independent of PI3K and mTOR. 40 S ribosomal protein S6, a target of p70^S6K, and 4E-BP1, a target of mTOR, were both phosphorylated within 15–25 min of T3 treatment and could be inhibited by wortmannin and rapamycin. Thus, rapid T3-mediated activation of PI3K by cytosolic TR1 and subsequent activation of the Akt-mTOR-S6K signaling pathway may underlie one of the mechanisms by which thyroid hormone regulates physiological cardiac growth.

Received for publication, November 28, 2005 , and in revised form, May 2, 2006.

^* This work was supported by NHLBI, National Institutes of Health Grant HL-071623. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: The Feinstein Inst. for Medical Research, 350 Community Dr., Manhasset, NY 11030. Tel.: 516-562-1591; Fax: 516-562-1022; E-mail: kojamaa{at}nshs.edu.

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