NON-GENOMIC MECHANISM INVOLVED IN THE ANTIAPOPTOTIC ACTION OF 17B-ESTRADIOL IN SKELETAL MUSCLE CELLS

BOLAND R; MILANESI L,; RONDA; VASCONSUELO A.

ConcepciOn Chile

Congreso; Second Workshop of Signal Transduction Mechanism Mediating Steroid non-genomic Action; 2008

  In this study we report that 17b-estradiol, through estrogen receptors with non-nuclear localization, e.g. mitochondria, endoplasmic reticulum and Golgi, can regulate apoptosis in mouse skeletal muscle C2C12 cells. 17b-estradiol, at physiological concentrations, abrogates DNA damage, PARP cleavage and cytochrome c release induced by H2O2 or etoposide. This protective action of the steroid involves fast activation of the PI3K/Akt/Bad pathway. Within the same short time interval 17b-estradiol increases phosphorylation of ERK 1/2 and p38 MAPK. Interestingly the main localization of phosphorylated ERK 1/2 is mitochondrial. In addition the effect of the hormone on cytochrome c release was blocked in presence of inhibitors of MAPKs. Evidence was obtained suggesting that the ERK 1/2 and PI3K/Akt/Bad pathways play a role in the antiapoptotic effects of 17b-estradiol at the level of mitochondria. Blocking experiments with specific antibodies and siRNAs against the estrogen receptors a (ER a) and â (ER â) isoforms, revealed that ER â mediates to a greater extent than ER a the antiapoptotic effects of 17b-estradiol in mitochondria. Furthermore, it was shown that the protective role of the hormone requires the participation of heat shock protein 27 (HSP27). 17â-estradiol rapidly induced phosphorylation of HSP27. Immunocytochemistry and co-immunoprecipitation assays demonstrated co-localization and interaction of the chaperone with ER â in mitochondria. Altogether, these results suggest that the antiapoptotic signal triggered by 17â-estradiol in muscle cells involves a non-genomic mechanism mediated by ER â and rapid activation of Akt and MAPKs, and the participation of HSP27.