Phosphorylation of Dynamin-Related Protein 1 (DRP1) Regulates Mitochondrial Dynamics and Skeletal Muscle Wasting in Cancer Cachexia.
Phosphorylation of Dynamin-Related Protein 1 (DRP1) Regulates Mitochondrial Dynamics and Skeletal Muscle Wasting in Cancer Cachexia.
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发动蛋白相关蛋白1（DRP1）的磷酸化调节癌症恶病质中的线粒体动力学和骨骼肌消耗
DOI：
10.3389/fcell.2021.673618
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wu G
中科院分区：
文献类型：
--
作者：
Mao X;Gu Y;Sui X;Shen L;Han J;Wang H;Xi Q;Zhuang Q;Meng Q;Wu G
癌症相关恶病质（CAC）是一种以骨骼肌萎缩为特征的综合征，其潜在机制仍不清楚。近期的研究揭示了线粒体动力学与肌肉生理学之间值得注意的联系。在本研究中，我们探讨了线粒体动力学的关键因子动力相关蛋白1（DRP1）在癌症相关恶病质期间肌管萎缩中的作用。
76名手术患者，包括胃肠道肿瘤患者和良性疾病患者，参与了该研究并被分为三组：对照组、非恶病质组和癌症相关恶病质组。收集了人口统计学数据。术中获取了他们的腹直肌样本。测定了肌纤维大小、泛素 - 蛋白酶体系统（UPS）标志物、线粒体超微结构以及线粒体功能和动力学标志物。通过将C2C12肌管与C26结肠癌细胞的培养基共培养，建立了体外恶病质模型。使用一种特异性的DRP1抑制剂Mdivi - 1以及DRP1敲低/过表达的慢病毒来调节DRP1的表达。测定了肌肉直径、线粒体形态、质量、活性氧（ROS）、膜电位以及UPS、线粒体功能和动力学的标志物。
与其他组患者相比，恶病质患者的营养状况明显恶化且肌肉流失严重。观察到严重的线粒体肿胀和面积增大，并且发现肌肉中的线粒体功能有部分改变。对线粒体动力学的分析表明，丝氨酸616位点磷酸化的DRP1上调。在体外，癌细胞培养基导致肌管萎缩。这伴随着线粒体动力学的显著失衡，以及线粒体ROS增加和线粒体功能及膜电位下降。然而，一定浓度的Mdivi - 1和DRP1敲低使线粒体动力学重新平衡，减轻了恶病质导致的这种不良表型。此外，DRP1的过表达加剧了这些现象。
在临床患者中，恶病质导致萎缩肌肉的线粒体异常变化以及可能的分裂激活。我们的体外恶病质模型进一步表明，线粒体动力学失衡导致了这种萎缩和线粒体损伤，并且通过调节DRP1重建平衡可以改善这些改变。
Cancer-associated cachexia (CAC) is a syndrome characterized by skeletal muscle atrophy, and the underlying mechanisms are still unclear. Recent research studies have shed light on a noteworthy link between mitochondrial dynamics and muscle physiology. In the present study, we investigate the role of dynamin-related protein 1 (DRP1), a pivotal factor of mitochondrial dynamics, in myotube atrophy during cancer-associated cachexia. Seventy-six surgical patients, including gastrointestinal tumor and benign disease, were enrolled in the study and divided to three groups: control, non-cachexia, and cancer-associated cachexia. Demographic data were collected. Their rectus abdominis samples were acquired intraoperatively. Muscle fiber size, markers of ubiquitin proteasome system (UPS), mitochondrial ultrastructure, and markers of mitochondrial function and dynamics were assayed. A cachexia model in vitro was established via coculturing a C2C12 myotube with media from C26 colon cancer cells. A specific DRP1 inhibitor, Mdivi-1, and a lentivirus of DRP1 knockdown/overexpression were used to regulate the expression of DRP1. Muscle diameter, mitochondrial morphology, mass, reactive oxygen species (ROS), membrane potential, and markers of UPS, mitochondrial function, and dynamics were determined. Patients of cachexia suffered from a conspicuous worsened nutrition status and muscle loss compared to patients of other groups. Severe mitochondrial swelling and enlarged area were observed, and partial alterations in mitochondrial function were found in muscle. Analysis of mitochondrial dynamics indicated an upregulation of phosphorylated DRP1 at the ser616 site. In vitro, cancer media resulted in the atrophy of myotube. This was accompanied with a prominent unbalance of mitochondrial dynamics, as well as enhanced mitochondrial ROS and decreased mitochondrial function and membrane potential. However, certain concentrations of Mdivi-1 and DRP1 knockdown rebalanced the mitochondrial dynamics, mitigating this negative phenotype caused by cachexia. Moreover, overexpression of DRP1 aggravated these phenomena. In clinical patients, cachexia induces abnormal mitochondrial changes and possible fission activation for the atrophied muscle. Our cachexia model in vitro further demonstrates that unbalanced mitochondrial dynamics contributes to this atrophy and mitochondrial impairment, and rebuilding the balance by regulating of DRP1 could ameliorate these alterations.
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影响因子：
6.3
作者：
Arends, Jann;Bachmann, Patrick;Preiser, Jean-Charles
通讯作者：
Preiser, Jean-Charles
影响因子：
3.3
作者：
Goodpaster, BH;Carlson, CL;Newman, AB
通讯作者：
Newman, AB
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：
10.1097/01.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：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC