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Inclusion body myositis: expression of extracellular signal-regulated kinase and its substrate
S Nakano1, A Shinde, S Kawashima
1Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. snakano@isola.kuhp.kyoto-u.ac.jp
Objective:
To assess abnormal intracellular signal transduction in inclusion body myositis (IBM).
Background:
Mitogen-activated protein kinases (MAPKs) play pivotal roles in intracellular signal transduction and regulate cell growth and differentiation. Upon their activation, MAPKs translocate from the cytoplasm into the nucleus.
Design/Methods:
The authors investigated the localization of several forms of the MAPK family-extracellular signal-regulated kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 MAPK (p38)-in 10 patients with sporadic IBM and in 52 control subjects. The relationship between the localization of immunopositive deposits and nuclei was tested with bis-benzimide.
Results:
Vacuolated fibers in IBM displayed very strong focal immunoreactivity of ERK, but not of JNK or p38. The ERK-positive deposits in these vacuolated fibers colocalized with the nuclear substrate of ERK, Elk-1. ERK- and Elk-1-positive deposits were located frequently on the surface of the nuclei in vacuolated fibers in IBM. Similar findings to those of sporadic IBM were observed in three patients with distal myopathy with rimmed vacuoles, but not in eight normal or the other 41 disease controls.
Conclusion:
There is evidence for impaired molecular transport to the nucleus from the cytoplasm in the vacuolated fibers in IBM. This could be due to cytoplasmic aggregation of ERK and Elk-1 or to abnormal nuclear pore machinery involved in the transport of ERK and its substrate upon ERK activation.
Insights
Intracellular signal transduction is impaired in inclusion body myositis (IBM). Extracellular signal-regulated kinase (ERK) accumulates in the cytoplasm, preventing nuclear transport in affected muscle cells.
Area of Science:
- Cell biology
- Molecular biology
- Neuromuscular disorders
Background:
- Mitogen-activated protein kinases (MAPKs) are crucial for cell signaling, regulating growth and differentiation.
- Activated MAPKs normally move from the cytoplasm to the nucleus.
Purpose of the Study:
- To investigate abnormal intracellular signal transduction in inclusion body myositis (IBM).
- To assess the localization of MAPK family members in IBM.
Main Methods:
- Examined extracellular signal-regulated kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 MAPK localization in IBM patients and controls.
- Used bis-benzimide to test the relationship between immunopositive deposits and nuclei.
Main Results:
- Vacuolated muscle fibers in IBM showed strong ERK immunoreactivity, but not JNK or p38.
- ERK-positive deposits colocalized with Elk-1, an ERK nuclear substrate, on the nuclear surface in IBM vacuolated fibers.
- Similar findings were noted in distal myopathy with rimmed vacuoles, but not in controls.
Conclusions:
- Evidence suggests impaired transport of molecules to the nucleus in IBM vacuolated fibers.
- This impairment may result from cytoplasmic aggregation of ERK and Elk-1 or abnormal nuclear pore function.