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Oxidative damage to skeletal muscle DNA from patients with mitochondrial encephalomyopathies
T Mitsui1, H Kawai, M Nagasawa
1First Department of Internal Medicine, School of Medicine, University of Tokushima, Japan.
Abstract:
To estimate the oxidative damage to skeletal muscle DNA in mitochondrial encephalomyopathies, we studied the amount of 8-hydroxy-deoxyguanosine (8-OH-dG) and the localization of superoxide dismutase (SOD) in the skeletal muscles of patients with progressive external ophthalmoplegia (PEO) or Kearns-Sayre syndrome (KSS). The molar ratio of 8-OH-dG/deoxyguanosine in skeletal muscle from PEO or KSS patients was significantly higher than the control value. The ratio from patients with polymyositis or Duchenne's muscular dystrophy was not significantly elevated. Immunohistochemical staining for both Mn-SOD and Cu,Zn-SOD showed pronounced staining in the subsarcolemmal and intermyofibrillar regions of cytochrome-oxidase-negative ragged red fibers of KSS or PEO muscles. Our findings suggest that overproduction of 8-OH-dG and mitochondrial dysfunction with gene deletions are associated with each other in muscle cells of patients with PEO or KSS, and that free radicals may play an important role in the pathophysiology of mitochondrial encephalomyopathies.
Insights
Oxidative damage to skeletal muscle DNA, measured by 8-hydroxy-deoxyguanosine (8-OH-dG), is elevated in mitochondrial encephalomyopathies like progressive external ophthalmoplegia (PEO) and Kearns-Sayre syndrome (KSS). Free radicals likely contribute to the pathophysiology of these conditions.
Area of Science:
- Mitochondrial Medicine
- Neurogenetics
- Muscle Biology
Background:
- Mitochondrial encephalomyopathies, including progressive external ophthalmoplegia (PEO) and Kearns-Sayre syndrome (KSS), are characterized by mitochondrial dysfunction.
- Oxidative stress and DNA damage are implicated in various neuromuscular disorders.
- The role of specific oxidative damage markers in PEO and KSS skeletal muscle requires further investigation.
Purpose of the Study:
- To quantify oxidative DNA damage, specifically 8-hydroxy-deoxyguanosine (8-OH-dG), in skeletal muscle of patients with PEO or KSS.
- To investigate the localization of superoxide dismutase (SOD) isoforms in affected muscle tissues.
- To explore the association between oxidative damage, mitochondrial dysfunction, and gene deletions in PEO and KSS.
Main Methods:
- Quantification of the molar ratio of 8-OH-dG/deoxyguanosine in skeletal muscle biopsies.
- Immunohistochemical staining for manganese superoxide dismutase (Mn-SOD) and copper-zinc superoxide dismutase (Cu,Zn-SOD).
- Comparison of marker levels between patients with PEO/KSS, polymyositis, Duchenne's muscular dystrophy, and controls.
Main Results:
- Skeletal muscle from PEO and KSS patients exhibited a significantly higher 8-OH-dG/deoxyguanosine molar ratio compared to controls.
- Elevated ratios were not observed in patients with polymyositis or Duchenne's muscular dystrophy.
- Pronounced staining for Mn-SOD and Cu,Zn-SOD was detected in cytochrome-oxidase-negative ragged red fibers of PEO/KSS muscles.
Conclusions:
- Overproduction of 8-OH-dG is associated with mitochondrial dysfunction and gene deletions in PEO and KSS muscle cells.
- Free radicals play a significant role in the pathophysiology of mitochondrial encephalomyopathies.
- These findings highlight oxidative stress as a key factor in the pathogenesis of PEO and KSS.