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Published on: July 19, 2019
No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis
Graham R Campbell1, Amy K Reeve, Iryna Ziabreva
1Centre for Neuroregeneration, University of Edinburgh, Chancellor's Building, UK.
Background:
Mitochondrial dysfunction is an established feature of multiple sclerosis (MS). We recently described high levels of mitochondrial DNA (mtDNA) deletions within respiratory enzyme-deficient (lacking mitochondrial respiratory chain complex IV with intact complex II) neurons and choroid plexus epithelial cells in progressive MS.
Objectives:
The objective of this paper is to determine whether respiratory enzyme deficiency and mtDNA deletions in MS were in excess of age-related changes within muscle, which, like neurons, are post-mitotic cells that frequently harbour mtDNA deletions with ageing and in disease.
Methods:
In progressive MS cases (n=17), known to harbour an excess of mtDNA deletions in the central nervous system (CNS), and controls (n=15), we studied muscle (paraspinal) and explored mitochondria in single fibres. Histochemistry, immunohistochemistry, laser microdissection, real-time polymerase chain reaction (PCR), long-range PCR and sequencing were used to resolve the single muscle fibres.
Results:
The percentage of respiratory enzyme-deficient muscle fibres, mtDNA deletion level and percentage of muscle fibres harbouring high levels of mtDNA deletions were not significantly different in MS compared with controls.
Conclusion:
Our findings do not provide support to the existence of a diffuse mitochondrial abnormality involving multiple systems in MS. Understanding the cause(s) of the CNS mitochondrial dysfunction in progressive MS remains a research priority.
Insights
Mitochondrial DNA deletions and respiratory enzyme deficiency were not elevated in the muscles of multiple sclerosis (MS) patients compared to controls. This suggests mitochondrial issues in MS may be specific to the central nervous system.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mitochondrial dysfunction is a known characteristic of multiple sclerosis (MS).
- Previous research identified high levels of mitochondrial DNA (mtDNA) deletions in neurons and choroid plexus epithelial cells in progressive MS.
- These cells showed deficiency in respiratory enzyme complex IV.
Purpose of the Study:
- To investigate if respiratory enzyme deficiency and mtDNA deletions in MS muscles exceed age-related changes.
- To compare muscle tissue, which like neurons are post-mitotic, between MS patients and controls.
- To determine if mitochondrial abnormalities in MS are systemic or confined to the central nervous system (CNS).
Main Methods:
- Studied paraspinal muscle tissue from 17 progressive MS cases and 15 controls.
- Utilized histochemistry, immunohistochemistry, and laser microdissection to analyze single muscle fibers.
- Employed real-time PCR, long-range PCR, and sequencing to quantify mtDNA deletions and assess enzyme activity.
Main Results:
- No significant difference was found in the percentage of respiratory enzyme-deficient muscle fibers between MS patients and controls.
- The level of mtDNA deletions in muscle fibers did not differ significantly between the two groups.
- The percentage of muscle fibers with high levels of mtDNA deletions was also comparable in MS and control groups.
Conclusions:
- The study does not support a widespread mitochondrial abnormality across multiple systems in MS.
- The findings indicate that the observed mitochondrial dysfunction in the CNS of MS patients may be localized.
- Further research is needed to elucidate the specific causes of CNS mitochondrial dysfunction in progressive MS.
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