Time since menopause and skeletal muscle estrogen receptors, PGC-1α, and AMPK

OBJECTIVE: Short-term administration of estradiol (E(2)) improves insulin-stimulated glucose disposal rate in early postmenopausal (EPM) women compared with a reduction in late postmenopausal (LPM) women. The underlying mechanisms by which E(2) action on glucose disposal rate reversed from beneficial early to harmful late in menopause is unknown, but might include adverse changes in estrogen receptors (ERs) or other biomarkers of cellular energy metabolism with age or duration of estrogen deficiency. METHODS: We retrospectively analyzed skeletal muscle samples from 27 postmenopausal women who were 6 years or less past menopause (EPM; n = 13) or at least 10 years past menopause (LPM; n = 14). Fasted skeletal muscle (vastus lateralis) samples were collected after 1 week administration of transdermal E(2) or placebo, in random cross-over design. RESULTS: Compared with EPM, LPM had reduced skeletal muscle ERα and ERβ nuclear protein. Short-term E(2) treatment did not change nuclear ERα or ERβ, but decreased cytosolic ERα, so the proportion of ERα in the nucleus compared with the cytosol tended to increase. There was a group-by-treatment interaction (P < 0.05) for nuclear proliferator-activated receptor γ co-activator 1-α and phosphorylated adenosine monophosphate-activated protein kinase, such that E(2) increased these proteins in EPM, but decreased these proteins in LPM. CONCLUSIONS: These preliminary studies of skeletal muscle from early and late postmenopausal women treated with E(2) suggest there may be declines in skeletal muscle ER and changes in the E(2)-mediated regulation of cellular energy homeostasis with increasing time since menopause.