Aberrant cell cycle reentry in human and experimental inclusion body myositis and polymyositis

摘要

Inclusion body myositis (IBM), a degenerative and inflammatory disorder of skeletal muscle, and Alzheimer's disease share protein derangements and attrition of postmitotic cells. Overexpression of cyclins and proliferating cell nuclear antigen (PCNA) and evidence for DNA replication is reported in Alzheimer's disease brain, possibly contributing to neuronal death. It is unknown whether aberrant cell cycle reentry also occurs in IBM. We examinedcell cyclemarkersinIBMcomparedwith normalcontrol, polymyositis (PM)andnon-inflammatorydystrophy sample sets. Next, we tested for evidence of reentry and DNA synthesis in C2C12 myotubes induced to express b-amyloid (Ab42). We observed increased levels of Ki-67, PCNA and cyclins E/D1 in IBM compared with normals and non-inflammatory conditions. Interestingly, PM samples displayed similar increases. Satellite cell markers did not correlatewith Ki-67-affected myofiber nuclei.DNAsynthesis and cell cycle markers were induced inAb-bearing myotubes. Cell cycle marker and cyclin protein expressions were also induced in an experimental allergic myositis-like model of PM in mice. Levels of p21 (Cip1/WAF1), a cyclin-dependent kinase inhibitor, were decreased in affected myotubes. However, overexpression of p21 did not rescue cells from Abinduced toxicity. This is the first report of cell cycle reentry in human myositis. The absence of rescue and evidence for reentry in separate models of myodegeneration and inflammation suggest that new DNA synthesis may be a reactive response to either or both stressors.