P62-positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy

Zoë Joy van der Klooster, Shahrzad Sepehrkhouy, Dennis Dooijes, Wouter P Te Rijdt, Frederique S A M Schuiringa, Jolanthe Lingeman, Johannes Peter van Tintelen, Magdalena Harakalova, Roel Goldschmeding, Albert J H Suurmeijer, Folkert W Asselbergs, Aryan Vink

Research output: Contribution to journalArticleAcademicpeer-review

9 Downloads (Pure)

Abstract

Genetic cardiomyopathy is caused by mutations in various genes. The accumulation of potentially proteotoxic mutant protein aggregates due to insufficient autophagy is a possible mechanism of disease development. The objective of this study was to investigate the distribution in the myocardium of such aggregates in relation to specific pathogenic genetic mutations in cardiomyopathy hearts. Hearts from 32 genetic cardiomyopathy patients, 4 non-genetic cardiomyopathy patients and 5 controls were studied. Microscopic slices from an entire midventricular heart slice were stained for p62 (sequestosome-1, marker for aggregated proteins destined for autophagy). The percentage of cardiomyocytes with p62 accumulation was higher in cardiomyopathy hearts (median 3.3%) than in healthy controls (0.3%; P < .0001). p62 accumulation was highest in the desmin (15.6%) and phospholamban (7.2%) groups. P62 accumulation was homogeneously distributed in the myocardium. Fibrosis was not associated with p62 accumulation in subgroup analysis of phospholamban hearts. In conclusion, accumulation of p62-positive protein aggregates is homogeneously distributed in the myocardium independently of fibrosis distribution and associated with desmin and phospholamban cardiomyopathy. Proteotoxic protein accumulation is a diffuse process in the myocardium while a more localized second hit, such as local strain during exercise, might determine whether this leads to regional myocyte decay.

Original languageEnglish
Pages (from-to)3160-3166
Number of pages7
JournalJournal of Cellular and Molecular Medicine
Volume25
Issue number6
Early online date18 Feb 2021
DOIs
Publication statusPublished - Mar 2021

Keywords

  • autophagy
  • cardiomyopathy
  • desminopathy
  • genetic
  • histology
  • P62
  • pathology
  • phospholamban
  • senescence
  • sequestosome-1

Fingerprint

Dive into the research topics of 'P62-positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy'. Together they form a unique fingerprint.

Cite this