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Experimental data indicate that apoptosis is activated in the aged skeletal muscle, contributing to sarcopenia. We have previously demonstrated that testosterone protects against hydrogen peroxide (H 2 O 2 )-induced apoptosis in C2C12 muscle cells. Here we identified molecular events involved in the antiapoptotic effect of testosterone. At short times of exposure to H 2 O 2 cells exhibit a defense response but at longer treatment times cells undergo apoptosis. Incubation with testosterone prior to H 2 O 2 induces BAD inactivation, inhibition of poly(ADP-ribose) polymerase cleavage, and a decrease in BAX levels, and impedes the loss of mitochondrial membrane potential, suggesting that the hormone participates in the regulation of the apoptotic intrinsic pathway. Simultaneous treatment with testosterone, H 2 O 2 , and the androgen receptor (AR) antagonist, flutamide, reduces the effects of the hormone, pointing to a possible participation of the AR in the antiapoptotic effect. The data presented allow us to begin to elucidate the mechanism by which the hormone prevents apoptosis in skeletal muscle.

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17β-Estradiol (E ) protects several nonreproductive tissues from apoptosis, including skeletal muscle. Previously, we showed that E at physiological concentrations prevented apoptosis induced by H O in skeletal myoblasts, reverting PKCδ, JNK, and p66Shc activation and exerting a beneficial action over mitochondria. Since genomic actions underlying the regulation of nuclear gene transcription are a common property of this steroid, the present work characterizes the transcriptional activity modulated by E to exert its antiapoptotic effect. We report that E protects skeletal myoblasts against apoptosis induced by H O modulating p53 and FoxO transcription factors and then their target genes Bcl-2, Bim, Puma, PERP, and MDM2, without affecting Noxa gene. The results presented in this work support the notion that the transcription factors FoxO and p53 coordinate apoptosis in C2C12 cells, and deepens our knowledge about a putative molecular mechanism by which E exerts beneficial effects against oxidative stress in skeletal myoblasts. J. Cell. Biochem. 118: 104-115, 2017. © 2016 Wiley Periodicals, Inc.

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