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Myofibrillar myopathy. III. Abnormal expression of cyclin-dependent kinases and nuclear proteins
S Nakano1, A G Engel, I Akiguchi
1Department of Neurology, Kyoto University Hospital, Japan.
Abstract:
The pathological process in myofibrillar myopathy (MFM) (previously also referred to as "desmin storage" or "intermediate filament myopathy") results in dissolution of myofibrils, accumulation of products of the degradative process, and abnormal ectopic expression of desmin, dystrophin, gelsolin, NCAM, and N-terminal components of beta-amyloid precursor protein. We now demonstrate that the abnormal fiber regions in MFM immunoreact strongly for (a) CDC2 kinase, the mitotic kinase that phosphorylates and disassembles intermediate filaments; (b) cyclin-dependent kinases CDK2, CDK4, and CDK7, which are involved in regulation of the cell cycle; (c) lamin B, which normally supports the inner nuclear membrane; and (d) the nuclear matrix associated protein. The normal muscle fiber lies in a terminally differentiated state and is refractory to reentry into the cell cycle. The abnormal expression of multiple cyclin-dependent kinases in the terminally differentiated muscle fiber implies inappropriate activation of positive regulators of mitosis and may signal a mitotic catastrophe. The dissolution of myofibrils may be due to hyperphosphorylation occurring during this event.
Insights
Myofibrillar myopathy (MFM) involves abnormal protein expression and cell cycle dysregulation. This suggests a potential mitotic catastrophe, leading to myofibril dissolution in muscle fibers.
Area of Science:
- Muscle Biology
- Cellular Pathology
- Molecular Myology
Background:
- Myofibrillar myopathy (MFM) is characterized by myofibril dissolution and abnormal protein accumulation.
- Previous understanding linked MFM to desmin and intermediate filament abnormalities.
Purpose of the Study:
- To investigate the expression of cell cycle-related proteins in MFM.
- To explore the potential role of mitotic dysregulation in MFM pathogenesis.
Main Methods:
- Immunohistochemical analysis of MFM muscle fibers.
- Detection of specific kinases, nuclear proteins, and matrix-associated proteins.
Main Results:
- Abnormal fiber regions in MFM showed strong immunoreactivity for CDC2 kinase, CDK2, CDK4, and CDK7.
- Increased expression of lamin B and nuclear matrix-associated protein was observed.
- Terminally differentiated muscle fibers exhibited inappropriate cell cycle activation markers.
Conclusions:
- The abnormal expression of cyclin-dependent kinases suggests inappropriate activation of mitosis regulators in MFM.
- This aberrant cell cycle activity may lead to mitotic catastrophe and myofibril dissolution via hyperphosphorylation.