title: Aberrant cell cycle reentry in human and experimental inclusion body myositis and polymyositis.
abstract: 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 examined cell cycle markers in IBM compared with normal control, polymyositis (PM) and non-inflammatory dystrophy sample sets. Next, we tested for evidence of reentry and DNA synthesis in C2C12 myotubes induced to express β-amyloid (Aβ42). 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 correlate with Ki-67-affected myofiber nuclei. DNA synthesis and cell cycle markers were induced in Aβ-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 Aβ-induced 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.
authors.affiliation: Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Bumsup
authors.initials: B
authors.lastname: Kwon
authors.affiliation: Department of Biotechnology, Delhi Technological University, New Delhi 110042, India.
authors.forename: Pravir
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Han-Kyu
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02135, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02135, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
authors.forename: Amey
authors.initials: A
authors.lastname: Barakat
authors.affiliation: Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA Molecular Cardiology and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02135, USA henry_querfurth@brown.edu.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Querfurth
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D017285:Polymyositis / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D018797:Cell Cycle Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004247:DNA