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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-09-0044v1 202/2/299    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Altamirano, F. Articles by Estrada, M. Search for Related Content PubMed PubMed Citation Articles by Altamirano, F. Articles by Estrada, M.

F Altamirano, Fisiologia y Biofisica, Universidad de Chile, Facultad de Medicina, Santiago, Chile
C Oyarce, Fisiologia y Biofisica, Universidad de Chile, Facultad de Medicina, Santiago, Chile
P Silva, Fisiologia y Biofisica, Universidad de Chile, Facultad de Medicina, Santiago, Chile
M Toyos, Fisiologia y Biofisica, Universidad de Chile, Facultad de Medicina, Santiago, Chile
C Wilson, Fisiologia y Biofisica, Universidad de Chile, Facultad de Medicina, Santiago, Chile
S Lavandero, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santiago, Chile
P Uhlen, Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
M Estrada, Fisiologia y Biofisica, Universidad de Chile, Facultad de Medicina, Santiago, Chile

Correspondence: Manuel Estrada, Email: iestrada{at}med.uchile.cl

Elevated testosterone concentrations induce cardiac hypertrophy but the molecular mechanisms are poorly understood. Anabolic properties of testosterone involve an increase in protein synthesis. The mammalian target of rapamycin complex 1 (mTORC1) pathway is a major regulator of cell growth, but the relationship between testosterone action and mTORC1 in cardiac cells remains unknown. Here, we investigated whether hypertrophy effects of testosterone are mediated by mTORC1 signaling in cultured cardiomyocytes. Testosterone increased phosphorylation of mTOR and its downstream targets 40S ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E BP1). The S6K1 phosphorylation induced by testosterone was blocked by rapamycin and siRNA to mTOR. Moreover, the hormone increased both ERK1/2 and Akt phosphorylation. ERK1/2 inhibitor PD98059 blocked the testosterone-induced S6K1 phosphorylation, whereas Akt inhibition (Akt inhibitor X) had no effect. Testosterone-induced ERK1/2 and S6K1 phosphorylation increase were blocked by either BAPTA-AM or by inhibitors of inositol 1,4,5-trisphosphate (IP3) pathway: U-73122 and 2-APB. Finally, cardiomyocyte hypertrophy was evaluated by expression of β myosin heavy chain, skeletal actin, cell size and aminoacid incorporation. Testosterone increased all four parameters and the increase being blocked by mTOR inhibition. Our findings suggest that testosterone activates mTORC1/S6K1 axis through IP3/Ca2+ and MEK/ERK1/2 to induce cardiomyocyte hypertrophy.