Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways.
Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways.
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DOI：
10.3389/fphys.2016.00472
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发表时间：
2016
影响因子：
4
通讯作者：
Bonetto A
中科院分区：
文献类型：
--
作者：
Barreto R;Mandili G;Witzmann FA;Novelli F;Zimmers TA;Bonetto A
恶病质是结直肠癌的主要并发症之一，因为它会消耗肌肉和脂肪。有证据表明，化疗方案（例如 Folfiri）会导致恶病质相关症状。本研究的目的是调查与严重肌肉萎缩相关的不同条件下的恶病质特征，即 Colon-26 (C26) 和 Folfiri 相关恶病质。使用定量 LC-MS/MS 方法，我们确定了 Folfiri 处理小鼠股四头肌中 386 个蛋白质的显着变化，以及 C26 宿主中差异表达的 269 个蛋白质（p < 0.05；-1.5 ≥ 倍数变化 ≥ +1.5）。比较分析分离出 240 种受到共同调节的蛋白质，其中大多数 (218) 在两种实验环境中均被下调。有趣的是，代谢蛋白（47.08%）和结构蛋白（21.25%）代表最多。通路分析揭示了两种实验条件下的线粒体功能障碍，也与线粒体融合（OPA-1、mitofusin-2）、裂变（DRP-1）和生物发生（细胞色素 C、PGC-1α）介质表达减少一致。还检测到 TCA 循环内氧化磷酸化、脂肪酸代谢和 Ca2+ 信号传导的变化。总体而言，化疗和癌症同时存在时的蛋白质组特征表明与运动障碍、坏死、肌肉细胞死亡、肌肉无力和肌肉损伤相关的机制的激活。相反，这与调节核苷酸和脂肪酸代谢、ATP 合成、肌肉和心脏功能以及 ROS 清除途径的抑制是一致的。有趣的是，与 Folfiri 处理的动物不同，在 C26 宿主的肌肉中观察到促炎急性期蛋白的强烈上调以及线粒体和脂质代谢的更协调的调节。总之，我们的结果表明癌症和化疗都通过激活共同的信号通路导致肌肉损失。这些数据支持采取旨在抵消肿瘤生长和减少化疗副作用的联合策略。
Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; −1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.
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影响因子：
4.8
作者：
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通讯作者：
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作者：
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DOI：
10.1016/j.bbrc.2009.12.123
发表时间：
2010-01-15
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10.1152/ajpregu.2001.280.5.r1518
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2001-05-01
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