Basic Research in Cardiology

, 107:235

Defective proteolytic systems in Mybpc3-targeted mice with cardiac hypertrophy

  • Saskia Schlossarek
  • Daniel R. Englmann
  • Karim R. Sultan
  • Markus Sauer
  • Thomas Eschenhagen
  • Lucie Carrier
Original Contribution

DOI: 10.1007/s00395-011-0235-3

Cite this article as:
Schlossarek, S., Englmann, D.R., Sultan, K.R. et al. Basic Res Cardiol (2012) 107: 235. doi:10.1007/s00395-011-0235-3

Abstract

Several lines of evidence suggest that alterations of the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) may be involved in cardiac diseases. Little is known, however, in hypertrophic cardiomyopathy (HCM). This study studied these pathways in two mouse models of HCM that mainly differ by the presence or absence of truncated mutant proteins. Analyses were performed in homozygous Mybpc3-targeted knock-in (KI) mice, carrying a HCM mutation and exhibiting low levels of mutant cardiac myosin-binding protein C (cMyBP-C), and in Mybpc3-targeted knock-out (KO) mice expressing no cMyBP-C, thus serving as a model of pure cMyBP-C insufficiency. In the early postnatal development of cardiac hypertrophy, both models showed higher levels of ubiquitinated proteins and greater proteasomal activities. To specifically monitor the degradation capacity of the UPS with age, mice were crossed with transgenic mice that overexpress UbG76V-GFP. UbG76V-GFP protein levels were fourfold higher in 1-year-old KI, but not KO mice, suggesting a specific UPS impairment in mice expressing truncated cMyBP-C. Whereas protein levels of key ALP markers were higher, suggesting ALP activation in both mutant mice, their mRNA levels did not differ between the groups, underlying rather defective ALP-mediated degradation. Analysis of key proteins regulated in heart failure did not reveal specific alterations in KI and KO mice. Our data suggest (1) UPS activation in early postnatal development of cardiac hypertrophy, (2) specific UPS impairment in old KI mice carrying a HCM mutation, and (3) defective ALP as a common mechanism in genetically engineered mice with cardiac hypertrophy.

Keywords

AutophagyHypertrophyLysosomeProteasomeTransgenic miceUbiquitin

Supplementary material

395_2011_235_MOESM1_ESM.pdf (64 kb)
Supplementary material 1 (PDF 64 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Saskia Schlossarek
    • 1
  • Daniel R. Englmann
    • 1
  • Karim R. Sultan
    • 1
  • Markus Sauer
    • 1
  • Thomas Eschenhagen
    • 1
  • Lucie Carrier
    • 1
    • 2
    • 3
  1. 1.Department of Experimental Pharmacology and Toxicology, Cardiovascular Research CenterUniversity Medical Center Hamburg EppendorfHamburgGermany
  2. 2.Inserm U974ParisFrance
  3. 3.UMR-S974, CNRS UMR7215, Institut de Myologie, IFR14University Pierre et Marie Curie-Paris6ParisFrance