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Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering
Elizabeth Duggan1, Jordan D Fuqua1, Bo Hagy1
1Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Background:
Cancer cachexia is a muscle wasting syndrome that occurs in ~80% of cancer patients and is the primary cause of death for 22%-30% of cancer patients. The primary challenge associated with cancer cachexia is that effective therapies to treat the associated muscle loss and dysfunction are lacking. Research exploring whether reactive oxygen species (ROS, i.e., superoxide anion and hydrogen peroxide) contributes to cancer cachexia has had mixed results. Lipid peroxidation is an underexplored component of oxidative stress that may contribute to cancer cachexia as markers of lipid peroxidation such as 4-hydroxyneoneal (4-HNE) and MDA (Malondialdehyde) are higher in muscle from tumour-bearing mice when compared to controls. Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an antioxidant enzyme that reduces lipid hydroperoxides. We hypothesized that reducing lipid peroxidation via GPx4 overexpression would mitigate cancer cachexia in tumour-bearing mice.
Methods:
One million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline was injected into the hind flank of wildtype or GPx4 transgenic (Tg) mice at 6 months of age and the tumour developed for 4 weeks. Muscle mass, contractile function, mitochondrial respiration, RNA-sequencing, inflammation and the oxylipin profile were assessed.
Results:
Muscle mass and myofiber cross-sectional area were reduced ~25% in wildtype tumour-bearing mice compared to control mice but not changed in GPx4 Tg tumour-bearing mice. GPx4 overexpression (~3-fold) did not raise maximal or specific muscle force generation in LLC-tumour-bearing mice. Muscle mitochondrial respiration was reduced in wildtype tumour-bearing mice by ~40% when compared to control mice but not altered in tumour-bearing GPx4 Tg mice. Quadricep RNA seq analysis revealed that expression of inflammatory genes was elevated in wildtype tumour-bearing mice when compared to control mice, and the expression of these genes was reduced in tumour-bearing GPx4 Tg mice compared to wildtype tumour-bearing mice. Next, we found that protein content of IL-6 was ~5-fold greater in muscle from wildtype tumour-bearing mice compared to control mice, and GPx4 overexpression prevented this increase in IL-6. We assessed the muscle oxylipin profile and found that many oxylipins generated by 12/15-Lox were elevated in tumour-bearing mice but not impacted by GPx4 overexpression.
Conclusions:
Our results show that GPx4 overexpression protected muscle mass and mitochondrial respiration in tumour-bearing mice, possibly by reducing muscle inflammation. Future studies will explore the potential mechanisms for the protective effect of GPx4 in cancer cachexia.
Insights
Overexpressing the antioxidant enzyme GPx4 protected against muscle wasting and mitochondrial dysfunction in cancer cachexia models. This suggests GPx4 may be a therapeutic target for this debilitating condition.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer cachexia affects 80% of cancer patients, causing muscle wasting and death, with limited effective therapies.
- Oxidative stress, particularly lipid peroxidation, is implicated in cancer cachexia, but its mechanisms are not fully understood.
- Phospholipid hydroperoxide glutathione peroxidase 4 (GPx4) is an antioxidant enzyme that neutralizes lipid hydroperoxides.
Purpose of the Study:
- To investigate the role of lipid peroxidation in cancer cachexia.
- To determine if GPx4 overexpression can mitigate cancer cachexia-associated muscle loss and dysfunction.
- To explore the impact of GPx4 on muscle inflammation and mitochondrial respiration in cancer cachexia.
Main Methods:
- Lewis lung carcinoma (LLC) cells were injected into wildtype and GPx4 transgenic (Tg) mice.
- Muscle mass, contractile function, mitochondrial respiration, RNA sequencing, and inflammation were assessed.
- Oxylipin profiles were analyzed to evaluate lipid peroxidation markers.
Main Results:
- GPx4 overexpression prevented muscle mass loss and preserved myofiber cross-sectional area in tumor-bearing mice.
- Mitochondrial respiration was maintained in GPx4 Tg mice, unlike in wildtype tumor-bearing mice.
- GPx4 overexpression reduced inflammatory gene expression and IL-6 protein levels in muscle.
Conclusions:
- GPx4 overexpression protects against muscle mass reduction and mitochondrial dysfunction in cancer cachexia.
- The protective effects of GPx4 may be mediated by the reduction of muscle inflammation.
- Further research is warranted to elucidate the precise mechanisms of GPx4's protective role in cancer cachexia.
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