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Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing
Published on: February 10, 2023
Pleomorphic mitochondrial and different filamentous inclusions in inflammatory myopathies associated with mtDNA
1Institut für Neuropathologie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen, Germany. neupath@amsd.imib.rwth-aachen.de
Abstract:
Mitochondrial changes are frequently observed in muscle fibers of patients with inclusion body myositis (IBM) and polymyositis (PM), suggesting that mitochondrial function may be especially impaired in these forms of inflammatory myopathies. Intranuclear and cytoplasmic tubulofilamentous inclusions are characteristic, although not totally specific for IBM. In the present cases, the inclusions were strikingly pleomorphic when chloroquine had been given for long periods. The nuclear inclusions were always tubular, whereas the cytoplasmic filaments had either a tubular, a helical, or a cross-striated structure with different diameters and arrangements in association with myelin-like figures, and vacuoles. Abnormal mitochondria containing paracrystalline, globoid, and other inclusions, noted in IBM, were occasionally also seen in PM or vasculitis. By contrast, in the latter, no intranuclear or cytoplasmic tubulofilamentous inclusions were apparent in muscle fibers. This study reports for the first time the presence of membrane-bound crystalloid inclusions in a muscle fiber with numerous abnormal mitochondria; similar structures have thus far only been observed in macrophages. The identity and function of these inclusions remains unknown. Using PCR analysis we detected different mtDNA deletions not only in IBM, but also in PM and vasculitis, indicating at least some degree of association between the structural mitochondrial abnormalities and the mtDNA mutations. There was no topographical correlation between the presence of tubular or helical filaments and the mitochondrial abnormalities. As already noted by others, the mitochondrial changes in IBM were more frequent than expected in this age group. It is suggested that the presence of the mtDNA deletions in IBM and PM are not primary, but rather the result of the underlying, presumably immunological disorder causing nuclear and secondary or simultaneous mitochondrial changes.
Insights
Mitochondrial changes and DNA deletions are common in inclusion body myositis (IBM) and polymyositis (PM). These changes, along with unique inclusions, may stem from an underlying immunological disorder affecting muscle fibers.
Area of Science:
- Neurology
- Pathology
- Molecular Biology
Background:
- Mitochondrial dysfunction and characteristic inclusions are noted in inflammatory myopathies like inclusion body myositis (IBM) and polymyositis (PM).
- The precise nature and origin of these cellular changes, particularly in relation to mitochondrial DNA (mtDNA) and potential triggers like chloroquine, require further elucidation.
Purpose of the Study:
- To investigate the spectrum of mitochondrial abnormalities and inclusions in IBM, polymyositis (PM), and vasculitis.
- To explore the association between mtDNA deletions and observed structural changes in muscle fibers.
- To characterize novel membrane-bound crystalloid inclusions in muscle fibers.
Main Methods:
- Histopathological examination of muscle biopsies from patients with IBM, PM, and vasculitis.
- Analysis of intranuclear and cytoplasmic inclusions, including their morphology and association with other organelles.
- Polymerase Chain Reaction (PCR) analysis to detect mtDNA deletions in affected muscle tissues.
Main Results:
- Mitochondrial abnormalities and mtDNA deletions were detected in IBM, PM, and vasculitis, with IBM showing more frequent changes than expected for age.
- Intranuclear and cytoplasmic inclusions, including tubular and helical filaments, were observed, with pleomorphism noted after long-term chloroquine use.
- Novel membrane-bound crystalloid inclusions were identified in a muscle fiber with abnormal mitochondria, a finding previously seen only in macrophages.
Conclusions:
- Mitochondrial changes and mtDNA deletions in IBM and PM are likely secondary to an underlying immunological disorder, rather than primary events.
- The observed structural abnormalities in muscle fibers, including inclusions and mitochondrial alterations, are associated with mtDNA deletions.
- Further research is needed to determine the identity and function of the newly identified crystalloid inclusions in muscle fibers.
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