title: Non-pathogenic protein aggregates in skeletal muscle in MLF1 transgenic mice.
abstract: Protein aggregate formation in muscle is thought to be pathogenic and associated with clinical weakness. Over-expression of either wild type or a mutant form of myeloid leukemia factor 1 (MLF1) in transgenic mouse skeletal muscle and in cultured cells resulted in aggregate formation. Aggregates were detected in MLF1 transgenic mice at 6 weeks of age, and increased in size with age. However, histological examination of skeletal muscles of MLF1 transgenic mice revealed no pathological changes other than the aggregates, and RotaRod testing did not detect functional deficits. MLF1 has recently been identified as a protein that could neutralize the toxicity of intracellular protein aggregates in a Drosophila model of Huntington's disease (HD). We also demonstrate that MLF1 interacts with MRJ, a heat shock protein, which can independently neutralize the toxicity of intracellular protein aggregates in the Drosophila HD model. Our data suggest that over-expression of MLF1 has no significant impact on skeletal muscle function in mice; that progressive formation of protein aggregates in muscle are not necessarily pathogenic; and that MLF1 and MRJ may function together to ameliorate the toxic effects of polyglutamine or mutant proteins in myodegenerative diseases such as inclusion body myositis and oculopharyngeal muscular dystrophy, as well as neurodegenerative disease.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, United States.
authors.forename: Zhi-Fang
authors.initials: ZF
authors.lastname: Li
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.forename: Yun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Liu
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.forename: Masaki
authors.initials: M
authors.lastname: Inagaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Izawa
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mizisin
authors.forename: Eva
authors.initials: E
authors.lastname: Engvall
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D018832:Molecular Chaperones / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; C100852:MLF1 protein, human; D018832:Molecular Chaperones; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011506:Proteins; C097188:polyglutamine