title: Autophagy and p62 in cardiac proteinopathy.
abstract: BACKGROUND
  Recent studies suggest an important role of autophagy in protection against αB-crystallin-based (CryAB(R120G)) desmin-related cardiomyopathies (DRC), but this has not been demonstrated in a different model of cardiac proteinopathy. Mechanisms underlying the response of cardiomyocytes to proteotoxic stress remain incompletely understood.
  
  
  OBJECTIVE
  Our first objective was to determine whether and how the autophagic activity is changed in a mouse model of desminopathy. We also investigated the role of p62 in the protein quality control of cardiomyocytes.
  
  
  RESULTS
  Using an autophagosome reporter and determining changes in LC3-II protein levels in response to lysosomal inhibition, we found significantly increased autophagic flux in mouse hearts with transgenic overexpression of a DRC-linked mutant desmin. Similarly, autophagic flux was increased in cultured neonatal rat ventricular myocytes (NRVMs) expressing a mutant desmin. Suppression of autophagy by 3-methyladenine increased, whereas enhancement of autophagy by rapamycin reduced the ability of a comparable level of mutant desmin overexpression to accumulate ubiquitinated proteins in NRVMs. Furthermore, p62 mRNA and protein expression was significantly up-regulated in cardiomyocytes by transgenic overexpression of the mutant desmin or CryAB(R120G) both in intact mice and in vitro. The p62 depletion impaired aggresome and autophagosome formation, exacerbated cell injury, and decreased cell viability in cultured NRVMs expressing the misfolded proteins.
  
  
  CONCLUSIONS
  Autophagic flux is increased in desminopathic hearts, and as previously suggested in CryAB(R120G)-based DRC, this increased autophagic flux serves as an adaptive response to overexpression of misfolded proteins. The p62 is up-regulated in mouse proteinopathic hearts. The p62 promotes aggresome formation and autophagy activation and protects cardiomyocytes against proteotoxic stress.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 East Clark Street, Vermillion, SD 57069, USA.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zheng
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ranek
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D003893:Desmin / Q000235:genetics* / Q000502:physiology; D017930:Genes, Reporter; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D016296:Mutagenesis / Q000502:physiology; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology* / Q000648:ultrastructure; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D013312:Stress, Physiological / Q000502:physiology; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination / Q000502:physiology; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000502:physiology
chemical_list: D003893:Desmin; C490981:Gtf2h1 protein, mouse; D014157:Transcription Factors; D038203:alpha-Crystallin B Chain; D051758:Transcription Factor TFIIH