Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway

Altamirano F.; oyarce c; Silva P.; Toyos, M; Wilson, C; Lavandero S.; Uhlen, P; Estrada, M

Abstract

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 the hypertrophic effects of testosterone are mediated by mTORC1 signaling in cultured cardiomyocytes. Testosterone increases the phosphorylation of mTOR and its downstream targets 40S ribosomal protein S6 kinase 1 (S6K1; also known as RPS6KB1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The S6K1 phosphorylation induced by testosterone was blocked by rapamycin and small interfering RNA to mTOR. Moreover, the hormone increased both extracellular-regulated kinase (ERK1/2) and protein kinase B (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 increases were blocked by either 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethylester or by inhibitors of inositol 1,4,5-trisphosphate (IP3) pathway: U-73122 and 2-aminoethyl diphenylborate. Finally, cardiomyocyte hypertrophy was evaluated by, the expression of ß-myosin heavy chain, a-skeletal actin, cell size, and amino acid incorporation. Testosterone increased all four parameters and the increase being blocked by mTOR inhibition. Our findings suggest that testosterone activates the mTORC1/S6K1 axis through IP3/Ca2+ and MEK/ERK1/2 to induce cardiomyocyte hypertrophy. © 2009 Society for Endocrinology.

Más información

Título según WOS: Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway
Título según SCOPUS: Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway
Título de la Revista: JOURNAL OF ENDOCRINOLOGY
Volumen: 202
Número: 2
Editorial: BioScientifica Ltd.
Fecha de publicación: 2009
Página de inicio: 299
Página final: 307
Idioma: English
URL: http://joe.endocrinology-journals.org/cgi/doi/10.1677/JOE-09-0044
DOI:

10.1677/JOE-09-0044

Notas: ISI, SCOPUS