The Antiapoptotic Action of 17beta-Estradiol in Skeletal Muscle Cells Involves ERK 1/2, p38 MAPK, ASK-1 and HSP27

ANA C RONDA; NOELIA ZANETTI; ANDREA VASCONSUELO; LORENA MILANESI; ANA RUSSO DE BOLAND; RICARDO BOLAND

Canada

Congreso; 30th Annual Meeting of the American Society for Bone and Mineral research.; 2008

ASBMR

SU185 The Antiapoptotic Action of 17â-Estradiol in Skeletal Muscle Cells Involves ERK 1/2, p38 MAPK, ASK-1 and HSP27. A. C. Ronda*, N. Zanetti*, A. Vasconsuelo*, L. Milanesi*, A. Russo de Boland*, R. L. Boland. Dept. Biologia, Bioquimica & Farmacia, Universidad Nacional del Sur, Bahia Blanca, Argentina. Estrogens exert antiapoptotic effects in various cell types, e.g. vascular endothelial, smooth muscle and breast cancer cells. We have previously reported that 17â-estradiol inhibits apoptosis through estrogen receptors with non-nuclear localization, e.g. mitochondria and endoplasmic reticulum, in the mouse skeletal muscle C2C12 cell line. The steroid hormone abrogates DNA damage, PARP cleavage and cytochrome c release induced by H2O2 or etoposide. This mechanism involves fast activation of the PI3K/Akt/ Bad pathway. It was demonstrated that the estrogen also triggers rapid phosphorylation of ERK 1/2 and p38 MAPK. Using specific inhibitors it was shown that both MAPKs mediate the effects of estradiol on Akt and Bad phosphorylation, cytochrome c and Smac/Diablo release, caspase 3 and PARP cleavage, and morphological changes of the cells. Interestingly, we found that ERK1/2 activated by 17â-estradiol is located mainly in mitochondria. Parallel studies showed that the interaction between proapoptotic kinase ASK-1 with phospho-Akt increases in presence of estrogen. This fact suggests another possible point of negative regulation of the apoptotic cascade by Akt. Furthermore, evidence was obtained that 17â-estradiol at longer exposure times increases the expression of HSP27. Assays under apoptotic conditions linked this chaperone to the protective action of the hormone, specifically regulating caspase-3 activity. Immunocytochemistry and coimmunoprecipitation assays revealed interaction of HSP27 and ER â in mitochondria. Altogether, these data imply that ERK 1/2, p38 MAPK, ASK-1 and HSP27 play a role in the mechanism underlying the antiapoptotic action of 17â-estradiol in skeletal muscle cells. Disclosures: R.L. Boland, None.