Testosterone induces skeletal muscle hypertrophy via Akt/mTOR/S6K1 pathway and the androgen receptor

Abstract

The anabolic hormone testosterone is associated with muscle hypertrophy, but the intracellular mechanisms involved are poorly known. We studied whether signal transduction pathways and the androgen receptor are necessary to elicit hypertrophy in skeletal muscle myotubes. Testosterone induced an increase in myotube cross sectional area (control=134,5±10,2 μm2; testosterone=181,9±14,4 μm2) and in α‐actin protein levels at 12 hours. Morphological development of myotube sarcomerisation was more clearly established in testosterone stimulated myotubes at this time. Earlier times of testosterone stimulation showed increased transcription of α‐actin gene, concomitantly with no changes in atrogenes (MAFfbx and MuRF‐1) activity at 6 hours. Characteristic hypertrophy pathways were studied at short times: ERK1/2 and Akt showed an increase in phosphorylation status after testosterone at 5 and 15 minutes, respectively. S6K1 was phosphorilated at 60 minutes. This response was inhibited with LY294002, Akt‐inhibitor‐VIII and Rapamycin but not by PD98059. Similarly, the hypertrophic response at 12 hours was abolished with these inhibitors as well as partly by a siRNA against androgen receptor but not by PD98059. These results suggest interlink between pathways involving intracellular signal cascades and the classical genomic actions of androgens for testosterone‐induced skeletal muscle hypertrophy.FONDECYT 1090276, FONDAP 15010006