Open AccessP62‐positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy
Author(s) -
Klooster Zoë Joy,
Sepehrkhouy Shahrzad,
Dooijes Dennis,
te Rijdt Wouter P.,
Schuiringa Frederique S. A. M.,
Lingeman Jolanthe,
Tintelen Johannes Peter,
Harakalova Magdalena,
Goldschmeding Roel,
Suurmeijer Albert J. H.,
Asselbergs Folkert W.,
Vink Aryan
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16388
Subject(s) - phospholamban , desmin , cardiomyopathy , fibrosis , dilated cardiomyopathy , mutation , sequestosome 1 , biology , myocyte , medicine , autophagy , pathology , microbiology and biotechnology , heart failure , genetics , gene , immunohistochemistry , vimentin , apoptosis
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.