DataSheet1_The Mitochondria-Targeting Agent MitoQ Improves Muscle Atrophy, Weakness and Oxidative Metabolism in C26 Tumor-Bearing Mice.pdf

Cancer cachexia is a debilitating syndrome characterized by skeletal muscle wasting, weakness and fatigue. Several pathogenetic mechanisms can contribute to these muscle derangements. Mitochondrial alterations, altered metabolism and increased oxidative stress are known to promote muscle weakness and muscle catabolism. To the extent of improving cachexia, several drugs have been tested to stimulate mitochondrial function and normalize the redox balance. The aim of this study was to test the potential beneficial anti-cachectic effects of Mitoquinone Q (MitoQ), one of the most widely-used mitochondria-targeting antioxidant. Here we show that MitoQ administration (25 mg/kg in drinking water, daily) in vivo was able to improve body weight loss in Colon-26 (C26) bearers, without affecting tumor size. Consistently, the C26 hosts displayed ameliorated skeletal muscle and strength upon treatment with MitoQ. In line with improved skeletal muscle mass, the treatment with MitoQ was able to partially correct the expression of the E3 ubiquitin ligases Atrogin-1 and Murf1. Contrarily, the anabolic signaling was not improved by the treatment, as showed by unchanged AKT, mTOR and 4EBP1 phosphorylation. Assessment of gene expression showed altered levels of markers of mitochondrial biogenesis and homeostasis in the tumor hosts, although only Mitofusin-2 levels were significantly affected by the treatment. Interestingly, the levels of Pdk4 and CytB, genes involved in the regulation of mitochondrial function and metabolism, were also partially increased by MitoQ, in line with the modulation of hexokinase (HK), pyruvate dehydrogenase (PDH) and succinate dehydrogenase (SDH) enzymatic activities. The improvement of the oxidative metabolism was associated with reduced myosteatosis (i.e., intramuscular fat infiltration) in the C26 bearers receiving MitoQ, despite unchanged muscle LDL receptor expression, therefore suggesting that MitoQ could boost β-oxidation in the muscle tissue and promote a glycolytic-to-oxidative shift in muscle metabolism and fiber composition. Overall, our data identify MitoQ as an effective treatment to improve skeletal muscle mass and function in tumor hosts and further support studies aimed at testing the anti-cachectic properties of mitochondria-targeting antioxidants also in combination with routinely administered chemotherapy agents.

癌症恶病质是一种导致骨骼肌萎缩、衰弱及疲乏的耗竭性综合征。多种致病机制可导致这些肌肉病变。线粒体改变、代谢紊乱及氧化应激增加均被认为是促进肌肉衰弱和肌肉分解代谢的因素。为了改善恶病质症状，已有多项药物试验旨在刺激线粒体功能并恢复正常氧化还原平衡。本研究旨在测试Mitoquinone Q（MitoQ），一种广泛使用的靶向线粒体的抗氧化剂，潜在的益处抗恶病质作用。本研究结果显示，MitoQ的体内给药（25 mg/kg，溶于饮用水，每日一次）能够改善Colon-26（C26）肿瘤携带者的体重减轻，且不影响肿瘤大小。一致地，接受MitoQ治疗的C26宿主表现出骨骼肌和力量的改善。与骨骼肌质量的改善相一致，MitoQ治疗能够部分纠正E3泛素连接酶Atrogin-1和Murf1的表达。相反，治疗并未改善合成代谢信号通路，如AKT、mTOR和4EBP1磷酸化水平未发生变化。基因表达评估显示，肿瘤宿主体内线粒体生物发生和稳态的标志物水平发生改变，尽管只有Mitofusin-2的水平受到治疗的显著影响。有趣的是，Pdk4和CytB，这两种基因参与线粒体功能和代谢的调控，其水平也部分由MitoQ升高，这与己糖激酶（HK）、丙酮酸脱氢酶（PDH）和琥珀酸脱氢酶（SDH）的酶促活性调节相一致。氧化代谢的改善与接受MitoQ治疗的C26携带者的肌脂肪浸润（即肌内脂肪浸润）减少相关，尽管肌肉LDL受体表达未发生变化，因此提示MitoQ可能增强肌肉组织的β-氧化作用，并促进肌肉代谢和纤维组成的糖酵解至氧化代谢的转变。总体而言，我们的数据将MitoQ鉴定为一种有效的治疗手段，能够改善肿瘤宿主的骨骼肌质量和功能，并进一步支持旨在测试靶向线粒体抗氧化剂抗恶病质特性的研究，这些研究旨在与常规使用的化疗药物联合应用。