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Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia
Science Translational Medicine ( IF 17.1 ) Pub Date : 2021-08-04 , DOI: 10.1126/scitranslmed.aay9592
Roberta Sartori 1, 2, 3 , Adam Hagg 1, 4, 5 , Sandra Zampieri 3, 6, 7 , Andrea Armani 2, 3 , Catherine E Winbanks 1 , Laís R Viana 4, 8 , Mouna Haidar 9 , Kevin I Watt 1, 4 , Hongwei Qian 1, 4 , Camilla Pezzini 2, 3 , Pardis Zanganeh 9 , Bradley J Turner 9 , Anna Larsson 10 , Gianpietro Zanchettin 6 , Elisa S Pierobon 6 , Lucia Moletta 6 , Michele Valmasoni 6 , Alberto Ponzoni 11 , Shady Attar 12 , Gianfranco Da Dalt 6 , Cosimo Sperti 6 , Monika Kustermann 13 , Rachel E Thomson 1, 4 , Lars Larsson 14, 15, 16 , Kate L Loveland 17, 18 , Paola Costelli 19 , Aram Megighian 3 , Stefano Merigliano 6 , Fabio Penna 19 , Paul Gregorevic 1, 4, 20, 21 , Marco Sandri 2, 3, 7, 22
Affiliation  

Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle, which blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction (NMJ), denervation, and muscle wasting. Increasing BMP signaling in the muscles of tumor-bearing mice by gene delivery or pharmacological means can prevent muscle wasting and preserve measures of NMJ function. The data identify perturbed BMP signaling and denervation of muscle fibers as important pathogenic mechanisms of muscle wasting associated with tumor growth. Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer.



中文翻译:

扰乱的 BMP 信号传导和去神经支配促进癌症恶病质中的肌肉萎缩

大多数晚期实体癌患者表现出恶病质的特征,这是一种以骨骼肌质量和力量进行性丧失为特征的衰弱综合征。由于这种多因素综合征的潜在机制尚未完全确定,因此尚未开发出有效的治疗方法。在这里,我们表明,在小鼠模型和癌症患者中,在与癌症恶病质相关的骨骼肌萎缩发生的早期观察到骨形态发生蛋白 (BMP) 信号减弱。包括激活素 A 和 IL-6 在内的癌症介导因子触发 BMP 抑制剂 Noggin 在肌肉中的表达,从而阻断 BMP 对肌肉纤维和运动神经的作用,随后导致神经肌肉接头 (NMJ) 的破坏、去神经支配和肌肉浪费。通过基因传递或药理学手段增加荷瘤小鼠肌肉中的 BMP 信号传导,可以防止肌肉萎缩并保持 NMJ 功能的测量。数据确定扰动的 BMP 信号和肌肉纤维去神经支配是与肿瘤生长相关的肌肉萎缩的重要致病机制。总的来说,这些发现提出了促进 BMP 介导的信号传导的干预措施,作为抵消癌症患者功能性肌肉组织丧失的有吸引力的策略。

更新日期:2021-08-05
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