Hormonally Regulated Myogenic miR-486 Influences Sex-specific Differences in Cancer-induced Skeletal Muscle Defects.
Hormonally Regulated Myogenic miR-486 Influences Sex-specific Differences in Cancer-induced Skeletal Muscle Defects.
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DOI：
10.1210/endocr/bqab142
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发表时间：
2021-10-01
期刊：
影响因子：
4.8
通讯作者：
Nakshatri H
中科院分区：
文献类型：
--
作者：
Wang R;Bhat-Nakshatri P;Zhong X;Zimmers T;Nakshatri H
癌症引起的骨骼肌缺陷在严重程度上显示出性别特异性差异，与女性相比，男性表现较差。激素和性染色体的差异被认为是介导这些差异的，但记录这些差异的功能性骨骼肌标志物尚不清楚。我们发现，肌源性microRNA miR-486是癌症诱导的骨骼肌缺陷中性别特异性差异的标志物。与患有相同癌症类型的女性相比，患有膀胱癌、肺癌和胰腺癌的男性中癌症诱导的循环miR-486损失更严重。在胰腺癌的同基因模型中，与雌性小鼠相比，雄性小鼠中miR-486的循环和骨骼肌损失更严重。雌激素（E2）和临床上使用的选择性雌激素受体调节剂托瑞米芬增加了未分化和分化成肌细胞系C2 C12中的miR-486，并且E2诱导的表达与雌激素受体α（ERα）与miR-486基因调控区的直接结合相关。E2和托瑞米芬降低了介导癌症诱导的骨骼肌萎缩的细胞因子如肌生长抑制素、TGFβ和TNFα的作用。E2和托瑞米芬处理的C2 C12成肌细胞/肌管细胞含有升高水平的活性AKT，其负调节因子PTEN（其是miR-486的靶标）的水平相应降低。我们提出了一个ERα：E2-miR-486-AKT信号传导轴，它可以减少癌症诱导的细胞因子/趋化因子对骨骼肌质量和/或功能的有害影响。
Cancer-induced skeletal muscle defects show sex-specific differences in severity with men performing poorly compared to women. Hormones and sex chromosomal differences are suggested to mediate these differences, but the functional skeletal muscle markers to document these differences are unknown. We show that the myogenic microRNA miR-486 is a marker of sex-specific differences in cancer-induced skeletal muscle defects. Cancer-induced loss of circulating miR-486 was more severe in men with bladder, lung and pancreatic cancers compared to women with the same cancer types. In syngeneic model of pancreatic cancer, circulating and skeletal muscle loss of miR-486 was more severe in male mice compared to female mice. Estradiol (E2) and the clinically used selective estrogen receptor modulator toremifene increased miR-486 in undifferentiated and differentiated myoblast cell line C2C12 and E2-inducible expression correlated with direct binding of estrogen receptor alpha (ERα) to the regulatory region of miR-486 gene. E2 and toremifene reduced the actions of cytokines such as myostatin, TGFβ and TNFα, which mediate cancer-induced skeletal muscle wasting. E2 and toremifene treated C2C12 myoblast/myotube cells contained elevated levels of active AKT with corresponding decrease in the levels of its negative regulator PTEN, which is a target of miR-486. We propose an ERα:E2-miR-486-AKT signaling axis, which reduces the deleterious effects of cancer-induced cytokines/chemokines on skeletal muscle mass and/or function.
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影响因子：
15.9
作者：
Alexander, Matthew S.;Carlos Casar, Juan;Kunkel, Louis M.
通讯作者：
Kunkel, Louis M.
DOI：
10.1097/01.mco.0000078983.18774.cc
发表时间：
2003-07-01
影响因子：
3.1
作者：
Argilés, JM;Busquets, S;López-Soriano, FJ
通讯作者：
López-Soriano, FJ
DOI：
10.1111/j.1365-2362.2008.01970.x
发表时间：
2008-07-01
影响因子：
5.5
作者：
Costelli, P.;Muscaritoli, M.;Fanelli, F. Rossi
通讯作者：
Fanelli, F. Rossi
影响因子：
4
作者：
Hitachi K;Tsuchida K
通讯作者：
Tsuchida K
影响因子：
8.9
作者：
Elkina, Yulia;von Haehling, Stephan;Anker, Stefan D.;Springer, Jochen
通讯作者：
Springer, Jochen