TY - JOUR
T1 - P62-positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy
AU - van der Klooster, Zoë Joy
AU - Sepehrkhouy, Shahrzad
AU - Dooijes, Dennis
AU - Te Rijdt, Wouter P
AU - Schuiringa, Frederique S A M
AU - Lingeman, Jolanthe
AU - van Tintelen, Johannes Peter
AU - Harakalova, Magdalena
AU - Goldschmeding, Roel
AU - Suurmeijer, Albert J H
AU - Asselbergs, Folkert W
AU - Vink, Aryan
N1 - © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Aged
KW - Biopsy
KW - Cardiomyopathies/diagnosis
KW - Female
KW - Fibrosis
KW - Genetic Association Studies
KW - Genetic Predisposition to Disease
KW - Humans
KW - Immunohistochemistry
KW - Male
KW - Middle Aged
KW - Mutation
KW - Myocardium/metabolism
KW - Phenotype
KW - Protein Aggregation, Pathological/metabolism
KW - RNA-Binding Proteins/metabolism
U2 - https://doi.org/10.1111/jcmm.16388
DO - https://doi.org/10.1111/jcmm.16388
M3 - Article
C2 - 33605084
SN - 1582-1838
VL - 25
SP - 3160
EP - 3166
JO - Journal of cellular and molecular medicine
JF - Journal of cellular and molecular medicine
IS - 6
ER -