In a randomized cross-over study by Park et al., the expression of structural proteins and protein regulatory markers was measured in muscle samples collected from women who had received transdermal estradiol (E2) or placebo the preceding week and were either in the early postmenopause (EPM, ≤6 years since menopause, n=13) or late postmenopause (LPM, >10 years since menopause, n=14) stages . In response to acute E2 treatment, dephosphorylation (activation) of forkhead box O3 (FOXO3) protein, that triggers apoptosis, and expression of muscle-specific ring finger protein (MuRF1), that triggers muscle protein degradation, were found to decrease in EPM but not in LPM women. This suggests that the beneficial effects of E2 on muscle protein breakdown may be dependent on the time after menopause.
Sarcopenia is defined as age-related loss in muscle mass and strength . Its prevalence has been reported to increase from 37% in women in their forties to 57% in women in their fifties, suggesting a link between menopause and the pathogenesis of this disease . Although the mechanism underlying the possible negative effect(s) of estrogen deficiency on the loss of muscle mass and strength are yet to be elucidated, both direct (through estrogen receptors [ER] expressed on skeletal muscle cells) and indirect (via increase in pro-inflammatory cytokines induced by a rapid decrease in estrogen) pathways could be involved . In line with this concept, menopausal hormone therapy has been supposed to protect postmenopausal women from muscle loss. For example, the Women’s Health Initiative trial assessed body composition and found that women on estrogen-progestin treatment did not lose lean body mass, compared to those on placebo who did . In their previous paper , Park et al. compared muscle biopsy samples from EPM and LPM women, and found that: (1) compared with EPM, LPM women had reduced expression of ERα and ERβ in the nuclei of skeletal muscle cells; (2) short-term E2 treatment did not change nuclear ERα or ERβ expression, but decreased cytosolic ERα, so the proportion of ERα in the nucleus compared with the cytosol tended to increase; (3) acute E2 treatment increased the expression of master regulators of cellular bioenergetics pathways, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC-1α] and phosphorylated adenosine monophosphate-activated protein kinase (AMPK) in EPM, but not in LPM women . Collectively, these findings suggest that the expression of ERs decreases in proportion to the time after menopause and that E2 treatment regulates energy homeostasis only in EPM women. In their new study, Park et al. investigated the effects of E2 treatment on skeletal muscle protein metabolism with a protocol similar to the previous one by sampling the muscles from EPM and LPM women who were previously administered E2 for one week to measure the expression of structural proteins and protein regulatory markers . They found that the FOXO3/pFOXO3 ratio and expression of MuRF1 decreased in EPM women treated with E2, meaning that estrogen deactivates Akt, protein kinase B, which leads to the inactivation of FOXO3, and to the reduced expression of MuRF1, without affecting the expression of structural proteins. In LMP women, E2 treatment, on the contrary, activates FOXO3 and increases the expression of MuRF1. As MuRF1 is a marker for protein degradation, the study implies that estrogen administration could prevent muscle loss in EPM and worsen it in LPM women. The “timing hypothesis” on the prevention of atherosclerotic cardiovascular diseases due to menopausal hormone therapy (MHT) has been proven by the Early vs Late Intervention Trial with Estradiol (ELITE). Women starting MHT in EMP may also benefit from a lower risk of sarcopenia. However, the reason for a difference in the effect of estrogen on muscle breakdown in EPM and LPM women remains unknown. Furthermore, the authors’ finding that the activation/inactivation of FOXO3 (ratio of FOXO3 to pFOXO3) is not related to E2-mediated ERα activation makes the relationship between estrogen treatment of postmenopausal women and muscle catabolism more complex. The sequel of the study is much anticipated.
Tokyo Medical and Dental University, Tokyo, Japan
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