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 (<i>P</i> ≤ 0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis, and abated <i>Redd1</i> and <i>Atrogin</i> 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 <i>Ryr1</i>, <i>Serca1</i>, and <i>Serca2a</i> 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.<b>NEW & NOTEWORTHY</b> 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.