Department of Medicine, Division of Geriatric Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Steroids. 2019 Jun;146:43-49. doi: 10.1016/j.steroids.2019.03.008. Epub 2019 Mar 27.
Menopause and decline in estradiol (E) may contribute to sarcopenia (i.e., age-related decline in muscle mass and strength) in women. E may directly impact skeletal muscle protein breakdown via estrogen receptor (ER) signaling, primarily ERα. It is not yet known whether: 1) E regulates pathways of skeletal muscle protein breakdown; 2) E-mediated changes in protein breakdown markers are associated with ERα activation and insulin sensitivity; and 3) the effects of E on protein breakdown markers differ by increasing time since menopause.
We studied 27 women who were ≤6 years past menopause (early postmenopausal, EPM; n = 13) or ≥10 years past menopause (late postmenopausal, LPM; n = 14). Fasted skeletal muscle samples were collected following 1 week of transdermal E or placebo treatment in a randomized cross-over design.
We analyzed for cytosolic protein content of the: 1) structural proteins myosin heavy chain (MHC) and tropomyosin; and 2) protein regulatory markers: protein kinase B (Akt), muscle-specific ring finger protein1 (MuRF1), atrogin1, and forkhead box O3 (FOXO3) using Western blot.
In response to acute E, FOXO3 activation (dephosphorylation) and MuRF1 protein expression decreased in EPM but increased in LPM women (p < 0.05). ERα activation was not associated with these protein breakdown markers, but FOXO3 activation tended to be inversely correlated (r = -0.318, p = 0.065) to insulin sensitivity.
These preliminary studies suggest the effects of E on skeletal muscle protein breakdown markers were dependent on time since menopause, which is consistent with our previous study on insulin sensitivity.
绝经和雌二醇（E）水平下降可能导致女性的肌肉减少症（即与年龄相关的肌肉质量和力量下降）。E 可能通过雌激素受体（ER）信号转导，主要是 ERα，直接影响骨骼肌蛋白分解。目前尚不清楚：1）E 是否调节骨骼肌蛋白分解途径；2）E 介导的蛋白分解标志物变化与 ERα 激活和胰岛素敏感性相关；3）E 对蛋白分解标志物的影响是否因绝经后时间的不同而不同。
我们研究了 27 名绝经后 ≤6 年（早绝经后，EPM；n=13）或 ≥10 年（晚绝经后，LPM；n=14）的女性。在随机交叉设计中，经过 1 周的透皮 E 或安慰剂治疗后，采集空腹骨骼肌样本。
我们分析了细胞质蛋白含量：1）结构蛋白肌球蛋白重链（MHC）和原肌球蛋白；2）蛋白调节标志物：蛋白激酶 B（Akt）、肌特异性环指蛋白 1（MuRF1）、atrogin1 和叉头框蛋白 O3（FOXO3），采用 Western blot 法。
急性 E 反应中，FOXO3 激活（去磷酸化）和 MuRF1 蛋白表达在 EPM 中降低，但在 LPM 女性中增加（p<0.05）。ERα 激活与这些蛋白分解标志物无关，但 FOXO3 激活与胰岛素敏感性呈负相关趋势（r=-0.318，p=0.065）。
这些初步研究表明，E 对骨骼肌蛋白分解标志物的影响取决于绝经后时间，这与我们之前关于胰岛素敏感性的研究一致。
