Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice.
Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice.
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DOI：
10.1002/jcsm.12232
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发表时间：
2017-12
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;Rosa-Caldwell ME;Lee DE;Blackwell TA;Brown LA;Perry RA;Haynie WS;Hardee JP;Carson JA;Wiggs MP;Washington TA;Greene NP
癌症恶病质在很大程度上是不可逆的，至少通过营养手段，并负责20-40%的癌症相关死亡。因此，预防措施是最重要的，然而，很少有人知道恶病质发作前的肌肉扰动。癌症恶病质与线粒体变性有关;然而，在癌症恶病质中线粒体变性是否先于肌肉萎缩仍有待确定。因此，我们的目的是确定在荷瘤小鼠中线粒体变性是否先于癌症诱导的肌肉萎缩。首先，将体重稳定（MinStable）和恶病质（MinCC）Apc Min/+小鼠与C57 B16/J对照小鼠的四头肌中线粒体质量调节因子的mRNA含量进行比较。接着，将刘易斯肺癌（LLC）细胞或PBS（对照）注射到8周龄的C57 B16/J小鼠的后胁腹中，并使肿瘤发展1、2、3或4周以检查恶病质发展的时间过程。琥珀酸脱氢酶染色测定胫骨前肌氧化表型。线粒体的质量和功能进行了评估，使用报告MitoTimer通过转染到屈趾短肌和线粒体功能/ROS排放透化成人肌纤维从跖。RT-qPCR和免疫印迹测量线粒体质量控制和抗氧化蛋白的表达。通过单向ANOVA和Student-Newman-Kuels事后检验分析数据。MinStable小鼠的Pgc-1α、Pparα和Mfn 2比C57 B16/J对照组低约50%，而MinCC小鼠的Bnip 3含量比C57 B16/J对照组高10倍。在LLC中，恶病质性肌肉损失仅在肿瘤植入后4周时明显。肿瘤植入后4周，氧化能力和线粒体含量降低约40%。肿瘤植入后3周，线粒体功能下降约25%。与PBS对照相比，通过2周LLC，线粒体变性是明显的，这通过MitoTimer红/绿色比率和纯红色斑点的数量来指示。肿瘤植入后1-3周，与PBS相比，线粒体ROS产生升高约50 - 100%。在荷瘤小鼠的癌症恶病质进展过程中，线粒体质量控制失调。相反，抗氧化蛋白质在恶病质肌肉萎缩中没有改变。在肌肉萎缩之前，LLC荷瘤小鼠中功能性线粒体变性明显。Apc Min/+和LLC小鼠中线粒体质量调节因子的含量表明线粒体质量控制受损是癌症恶病质临床前模型的共性。我们的数据为恶病质肌肉损失之前线粒体健康受损提供了新的证据，并为预防癌症恶病质提供了潜在的治疗靶点。
Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer‐related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer‐induced muscle wasting in tumour‐bearing mice. First, weight‐stable (MinStable) and cachectic (MinCC) Apc Min/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT‐qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one‐way ANOVA with Student–Newman–Kuels post hoc test. MinStable mice displayed ~50% lower Pgc‐1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10‐fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post‐tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post‐tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1–3 weeks post‐tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour‐bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting. Functional mitochondrial degeneration is evident in LLC tumour‐bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across Apc Min/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre‐clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia.
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