Twist1 Activation in Muscle Progenitor Cells Causes Muscle Loss Akin to Cancer Cachexia.
Twist1 Activation in Muscle Progenitor Cells Causes Muscle Loss Akin to Cancer Cachexia.
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DOI：
10.1016/j.devcel.2018.05.026
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发表时间：
2018-06-18
影响因子：
11.8
通讯作者：
Atfi A
中科院分区：
文献类型：
--
作者：
Parajuli P;Kumar S;Loumaye A;Singh P;Eragamreddy S;Nguyen TL;Ozkan S;Razzaque MS;Prunier C;Thissen JP;Atfi A
癌症恶病质的特征在于导致高发病率和死亡率的极端骨骼肌损失。恶病质的发生率在肿瘤类型之间变化，在肉瘤中最低，而90%的胰腺导管腺癌（PDAC）患者经历严重的体重减轻。这些肿瘤如何引发肌肉耗竭仍在展开。偶然地，我们发现Twist 1在小鼠肌肉祖细胞中的过度表达，无论是在发育过程中的组成性表达还是在成年动物中的诱导性表达，都会引起严重的肌肉萎缩，并伴有恶病质的特征。使用几种PDAC的遗传小鼠模型，我们检测到恶病质肌肉中Twist 1表达显著增加。在癌症患者中，Twist 1水平升高与更大程度的肌肉萎缩相关。最后，肌肉祖细胞中Twist 1的遗传和药理学失活提供了针对癌症介导的恶病质的实质性保护，这转化为有意义的生存益处，暗示Twist 1可能是减轻癌症患者肌肉恶病质的靶点。Parajuli等人表明，Twist 1的遗传和药理学抑制在几种癌症恶病质小鼠模型中保留了肌肉质量并延长了寿命，突出了Twist 1作为减轻晚期癌症患者肌肉恶病质和相关发病率和死亡率的有吸引力的治疗靶点。
Cancer cachexia is characterized by extreme skeletal muscle loss that results in high morbidity and mortality. The incidence of cachexia varies among tumor types, being lowest in sarcomas, whereas 90% of pancreatic ductal adenocarcinoma (PDAC) patients experience severe weight loss. How these tumors trigger muscle depletion is still unfolding. Serendipitously, we found that overexpression of Twist1 in mouse muscle progenitor cells, either constitutively during development or inducibly in adult animals, caused severe muscle atrophy with features reminiscent of cachexia. Using several genetic mouse models of PDAC, we detected a marked increase in Twist1 expression in muscle undergoing cachexia. In cancer patients, elevated levels of Twist1 are associated with greater degrees of muscle wasting. Finally, both genetic and pharmacological inactivation of Twist1 in muscle progenitor cells afforded substantial protection against cancer-mediated cachexia, which translated into meaningful survival benefits, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients. Parajuli et al. show that both genetic and pharmacological inhibition of Twist1 preserves muscle mass and extends lifespan in several mouse models of cancer cachexia, highlighting Twist1 as an attractive therapeutic target for attenuating muscle cachexia and associated morbidity and mortality in advanced cancer patients.
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影响因子：
64.5
作者：
Burd CE;Sorrentino JA;Clark KS;Darr DB;Krishnamurthy J;Deal AM;Bardeesy N;Castrillon DH;Beach DH;Sharpless NE
通讯作者：
Sharpless NE
影响因子：
50.3
作者：
Lee KE;Bar-Sagi D
通讯作者：
Bar-Sagi D
DOI：
10.1152/ajpendo.2001.281.6.e1128
发表时间：
2001-12-01
影响因子：
5.1
作者：
Ma, K;Mallidis, C;Bhasin, S
通讯作者：
Bhasin, S
影响因子：
11.4
作者：
Lagirand-Cantaloube, Julie;Offner, Nicolas;Leibovitch, Serge A.
通讯作者：
Leibovitch, Serge A.
影响因子：
11.2
作者：
Gallot, Yann S.;Durieux, Anne-Cecile;Freyssenet, Damien G.
通讯作者：
Freyssenet, Damien G.