线粒体抗氧化剂 SkQ1 可减轻 C26 癌症诱发的雄性小鼠肌肉萎缩,并改善雌性肿瘤小鼠的肌肉收缩力。

IF 5 2区 生物学 Q2 CELL BIOLOGY American journal of physiology. Cell physiology Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI:10.1152/ajpcell.00497.2024
Stavroula Tsitkanou, Francielly Morena da Silva, Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Pieter J Koopmans, Sabin Khadgi, Seongkyun Lim, Luca J Delfinis, Tyrone A Washington, Kevin A Murach, Christopher G R Perry, Nicholas P Greene
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引用次数: 0

摘要

线粒体功能障碍是癌症恶病质(CC)的一个特征。肿瘤发生后不久,肌肉中的线粒体活性氧(ROS)就会升高。靶向线粒体 ROS 可能是预防癌症恶病质的可行方案。本研究的目的是评估线粒体靶向抗氧化剂 SkQ1 对缓解雌雄 CC 的疗效。给雌雄 Balb/c 小鼠双侧注射结肠 26 腺癌(C26)细胞(共 1x106 个细胞)或 PBS(等体积对照)。将 SkQ1 溶于饮用水中(约 250 nmol/kg体重/天),在诱导肿瘤七天后开始给小鼠注射,而对照组则饮用普通饮用水。在终点(肿瘤诱导后 25 天)评估背屈肌的体内肌肉收缩力、基于氧化氘的蛋白质合成、线粒体呼吸以及线粒体、蛋白质周转和钙通道相关标记物的 mRNA 含量。进行了双向方差分析,如果交互作用显著(p≤0.05),则进行 Tukey 后检验。SkQ1减轻了癌症诱导的萎缩,促进了蛋白质合成,并减少了C26雄性小鼠腓肠肌中Redd1和Atrogin的诱导。在雌性小鼠中,无论是否患有肿瘤,SkQ1都会降低肌肉质量,增加肿瘤小鼠跖跗关节的分解代谢信号,并降低线粒体耗氧量。然而,在雌性小鼠中,SkQ1 可增强背屈肌的肌肉收缩力,同时诱导 TA 中的 Ryr1、Serca1 和 Serca2a。总之,线粒体靶向抗氧化剂 SkQ1 可减轻雄性小鼠 CC 诱导的肌肉损失,同时改善雌性肿瘤小鼠的肌肉收缩功能。
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Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.

Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1 × 106 cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (∼250 nmol/kg body wt/day) and administered to mice beginning 7 days following tumor induction, whereas control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover, and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post hoc test when interactions were significant (P ≤ 0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis, and abated Redd1 and Atrogin induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females, SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of Ryr1, Serca1, and Serca2a in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC.NEW & NOTEWORTHY Herein, we assess the efficacy of the mitochondria-targeted antioxidant SkQ1 to mitigate cancer cachexia (CC) in both biological sexes. We demonstrate that SkQ1 administration attenuates muscle wasting induced by C26 tumors in male, but not female, mice. Conversely, we identify that in females, SkQ1 improves muscle contractility. These phenotypic adaptations to SkQ1 are aligned with respective responses in muscle protein synthesis, mitochondrial respiration, and mRNA content of protein turnover, as well as mitochondrial and calcium handling-related markers.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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