The Mitochondria-Targeting Agent MitoQ Improves Muscle Atrophy, Weakness and Oxidative Metabolism in C26 Tumor-Bearing Mice
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 an...
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| Vydáno v: | Frontiers in cell and developmental biology Ročník 10; s. 861622 |
|---|---|
| Hlavní autoři: | , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
Switzerland
Frontiers Media SA
22.03.2022
Frontiers Media S.A |
| Témata: | |
| ISSN: | 2296-634X, 2296-634X |
| On-line přístup: | Získat plný text |
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| Shrnutí: | 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. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Reviewed by: Brandon VanderVeen, University of South Carolina, United States Edited by: Laura Mangiavini, University of Milan, Italy This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Cell and Developmental Biology Craig Andrew Goodman, The University of Melbourne, Australia |
| ISSN: | 2296-634X 2296-634X |
| DOI: | 10.3389/fcell.2022.861622 |