Protein imbalance in the development of skeletal muscle wasting in tumour-bearing mice.
Protein imbalance in the development of skeletal muscle wasting in tumour-bearing mice.
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DOI：
10.1002/jcsm.12354
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Greene NP
中科院分区：
文献类型：
--
作者：
Brown JL;Lee DE;Rosa-Caldwell ME;Brown LA;Perry RA;Haynie WS;Huseman K;Sataranatarajan K;Van Remmen H;Washington TA;Wiggs MP;Greene NP
癌症恶病质发生在大约80%的癌症患者中，是癌症相关死亡的关键因素。控制肿瘤诱导的肌肉萎缩发展的机制尚未完全阐明。具体而言，癌症恶病质的进展和发展还未充分研究。因此，我们检查了荷瘤小鼠癌症恶病质发展过程中的骨骼肌蛋白质周转。将刘易斯肺癌（LLC）注射到8周龄的C57 BL 6/J小鼠的后胁腹中，使肿瘤发展1、2、3或4周，并与注射PBS的对照进行比较。通过苏木精和伊红染色的胫骨前肌的横截面积分析测量肌肉大小。2 H2O用于评估癌症恶病质发展过程中的蛋白质合成。免疫印迹和RT-qPCR用于测量蛋白质周转的调节剂。TUNEL染色检测凋亡细胞核。LLC条件培养基（LCM）处理C2 C12肌管用于体外分析癌症恶病质。肿瘤植入后4周，肌肉横截面积减少约40%。与对照动物相比，肿瘤植入后1周，荷瘤小鼠中的生肌信号传导即被抑制，包括Pax 7、MyoD、CyclinD 1和Myogenin的mRNA含量较低。AchRδ和AchRε mRNA含量在肿瘤植入后3周下调约50%。与PBS对照组相比，4周荷瘤小鼠的混合部分合成率蛋白质合成降低约40%。肿瘤植入后4周，蛋白质泛素化升高约50%。此外，在肿瘤生长4周后，自噬机制增加。最后，ERK和p38 MAPK磷酸化的四倍和三倍以上，分别比对照肌肉肿瘤植入后4周。抑制p38 MAPK，而不是ERK MAPK，在体外部分挽救LCM诱导的肌管直径损失。我们的研究结果致力于了解癌症恶病质最初发展过程中骨骼肌的病理生理信号。荷瘤状态发生后不久，肌源性调节因子的改变是明显的，表明肌源性诱导能力的早期发生改变。癌症恶病质表现为蛋白质合成损失和蛋白质分解标志物增加的组合，特别是在泛素-蛋白酶体系统中。此外，p38 MAPK可能是通过p38-FOX 01-atrogene-ubiquitin-proteasome机制对抗癌症恶病质的潜在治疗靶点。
Cancer cachexia occurs in approximately 80% of cancer patients and is a key contributor to cancer‐related death. The mechanisms controlling development of tumour‐induced muscle wasting are not fully elucidated. Specifically, the progression and development of cancer cachexia are underexplored. Therefore, we examined skeletal muscle protein turnover throughout the development of cancer cachexia in tumour‐bearing mice. Lewis lung carcinoma (LLC) was injected into the hind flank of C57BL6/J mice at 8 weeks age with tumour allowed to develop for 1, 2, 3, or 4 weeks and compared with PBS injected control. Muscle size was measured by cross‐sectional area analysis of haematoxylin and eosin stained tibialis anterior muscle. 2H2O was used to assess protein synthesis throughout the development of cancer cachexia. Immunoblot and RT‐qPCR were used to measure regulators of protein turnover. TUNEL staining was utilized to measure apoptotic nuclei. LLC conditioned media (LCM) treatment of C2C12 myotubes was used to analyse cancer cachexia in vitro. Muscle cross‐sectional area decreased ~40% 4 weeks following tumour implantation. Myogenic signalling was suppressed in tumour‐bearing mice as soon as 1 week following tumour implantation, including lower mRNA contents of Pax7, MyoD, CyclinD1, and Myogenin, when compared with control animals. AchRδ and AchRε mRNA contents were down‐regulated by ~50% 3 weeks following tumour implantation. Mixed fractional synthesis rate protein synthesis was ~40% lower in 4 week tumour‐bearing mice when compared with PBS controls. Protein ubiquitination was elevated by ~50% 4 weeks after tumour implantation. Moreover, there was an increase in autophagy machinery after 4 weeks of tumour growth. Finally, ERK and p38 MAPK phosphorylations were fourfold and threefold greater than control muscle 4 weeks following tumour implantation, respectively. Inhibition of p38 MAPK, but not ERK MAPK, in vitro partially rescued LCM‐induced loss of myotube diameter. Our findings work towards understanding the pathophysiological signalling in skeletal muscle in the initial development of cancer cachexia. Shortly following the onset of the tumour‐bearing state alterations in myogenic regulatory factors are apparent, suggesting early onset alterations in the capacity for myogenic induction. Cancer cachexia presents with a combination of a loss of protein synthesis and increased markers of protein breakdown, specifically in the ubiquitin‐proteasome system. Also, p38 MAPK may be a potential therapeutic target to combat cancer cachexia via a p38‐FOX01‐atrogene‐ubiquitin‐proteasome mechanism.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
DOI：
10.1002/jcsm.12126
发表时间：
2016-06
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Stewart Coats AJ;Ho GF;Prabhash K;von Haehling S;Tilson J;Brown R;Beadle J;Anker SD;for and on behalf of the ACT‐ONE study group
通讯作者：
for and on behalf of the ACT‐ONE study group
DOI：
10.1002/jcsm.12232
发表时间：
2017-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Brown JL;Rosa-Caldwell ME;Lee DE;Blackwell TA;Brown LA;Perry RA;Haynie WS;Hardee JP;Carson JA;Wiggs MP;Washington TA;Greene NP
通讯作者：
Greene NP
DOI：
10.1002/jcsm.12233
发表时间：
2017-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Bowen TS;Adams V;Werner S;Fischer T;Vinke P;Brogger MN;Mangner N;Linke A;Sehr P;Lewis J;Labeit D;Gasch A;Labeit S
通讯作者：
Labeit S
DOI：
10.1152/ajpendo.90872.2008
发表时间：
2009-07-01
影响因子：
5.1
作者：
Gasier, Heath G.;Riechman, Steven E.;Fluckey, James D.
通讯作者：
Fluckey, James D.