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Decreased NADPH oxidase expression and antioxidant activity in cachectic skeletal muscle
Abstract:
BACKGROUND: Cancer cachexia is the progressive loss of skeletal muscle protein that contributes significantly to cancer morbidity and mortality. Evidence of antioxidant attenuation and the presence of oxidised proteins in patients with cancer cachexia indicate a role for oxidative stress. The level of oxidative stress in tissues is determined by an imbalance between reactive oxygen species production and antioxidant activity. This study aimed to investigate the superoxide generating NADPH oxidase (NOX) enzyme and antioxidant enzyme systems in murine adenocarcinoma tumour-bearing cachectic mice. METHODS: Superoxide levels, mRNA levels of NOX enzyme subunits and the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidise (GPx) and catalase was measured in the skeletal muscle of mice with cancer and cancer cachexia. Protein expression levels of NOX enzyme subunits and antioxidant enzyme activity was also measured in the same muscle samples. RESULTS: Superoxide levels increased 1.4-fold in the muscle of mice with cancer cachexia, and this was associated with a decrease in mRNA of NOX enzyme subunits, NOX2, p40(phox) and p67(phox) along with the antioxidant enzymes SOD1, SOD2 and GPx. Cancer cachexia was also associated with a 1.3-fold decrease in SOD1 and 2.0-fold decrease in GPx enzyme activity. CONCLUSION: Despite increased superoxide levels in cachectic skeletal muscle, NOX enzyme subunits, NOX2, p40(phox) and p67(phox), were downregulated along with the expression and activity of the antioxidant enzymes. Therefore, the increased superoxide levels in cachectic skeletal muscle may be attributed to the reduction in the activity of endogenous antioxidant enzymes.
Insights
Oxidative stress increases in cancer cachexia, despite reduced antioxidant enzyme activity and NADPH oxidase (NOX) enzyme expression in skeletal muscle. This suggests decreased antioxidant defenses contribute to elevated superoxide levels in cachectic muscle.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer cachexia involves significant skeletal muscle protein loss, a major contributor to cancer morbidity and mortality.
- Evidence suggests oxidative stress, characterized by an imbalance between reactive oxygen species and antioxidant activity, plays a role in cancer cachexia.
- Oxidized proteins and antioxidant attenuation are observed in cancer cachexia patients.
Purpose of the Study:
- To investigate the role of superoxide-generating NADPH oxidase (NOX) enzymes and antioxidant enzyme systems in murine adenocarcinoma tumor-bearing cachectic mice.
- To analyze superoxide levels, NOX enzyme subunit mRNA and protein expression, and antioxidant enzyme (superoxide dismutase, glutathione peroxidase, catalase) expression and activity in skeletal muscle.
Main Methods:
- Measurement of superoxide levels in skeletal muscle of cachectic and non-cachectic tumor-bearing mice.
- Quantification of mRNA and protein expression for NOX enzyme subunits (NOX2, p40phox, p67phox).
- Assay of antioxidant enzyme activity (superoxide dismutase [SOD], glutathione peroxidase [GPx], catalase) and expression (SOD1, SOD2).
Main Results:
- Superoxide levels were 1.4-fold higher in the skeletal muscle of cachectic mice.
- A decrease in mRNA levels for NOX subunits (NOX2, p40phox, p67phox) and antioxidant enzymes (SOD1, SOD2, GPx) was observed.
- Significant reductions in SOD1 (1.3-fold) and GPx (2.0-fold) enzyme activity were found in cachectic muscle.
Conclusions:
- Increased superoxide levels in cachectic skeletal muscle occur despite downregulation of NOX enzyme subunits.
- The expression and activity of key antioxidant enzymes (SOD, GPx) are reduced in cancer cachexia.
- Reduced activity of endogenous antioxidant enzymes is a likely contributor to elevated superoxide levels in cachectic skeletal muscle.
