Cardiomyocyte Contractility and Autophagy in a Premature Senescence Model of Cardiac Aging.

Steffen Häseli,Tobias Jung,Stefanie Deubel,Christiane Ott,Tilman Grune

doi:10.1155/2020/8141307

Abstract

Globally, cardiovascular diseases are the leading cause of death in the aging population. While the clinical pathology of the aging heart is thoroughly characterized, underlying molecular mechanisms are still insufficiently clarified. The aim of the present study was to establish an in vitro model system of cardiomyocyte premature senescence, culturing heart muscle cells derived from neonatal C57Bl/6J mice for 21 days. Premature senescence of neonatal cardiac myocytes was induced by prolonged culture time in an oxygen-rich postnatal environment. Age-related changes in cellular function were determined by senescence-associated β-galactosidase activity, increasing presence of cell cycle regulators, such as p16, p53, and p21, accumulation of protein aggregates, and restricted proteolysis in terms of decreasing (macro-)autophagy. Furthermore, the culture system was functionally characterized for alterations in cell morphology and contractility. An increase in cellular size associated with induced expression of atrial natriuretic peptides demonstrated a stress-induced hypertrophic phenotype in neonatal cardiomyocytes. Using the recently developed analytical software tool Myocyter, we were able to show a spatiotemporal constraint in spontaneous contraction behavior during cultivation. Within the present study, the 21-day culture of neonatal cardiomyocytes was defined as a functional model system of premature cardiac senescence to study age-related changes in cardiomyocyte contractility and autophagy.

Highlights

Aging is a time-dependent process with a progressive reduction in the physiological and functional capacity as well as in stress resilience [1]
Neonatal cardiomyocytes were cultured for a period of 21 days following primary cell isolation
At the following time points, heart muscle cells were partly overgrown by ACNT1-negative noncardiomyocytes which prevented the explicit microscopic examination of ACTN1-positive cardiac myocytes

Summary

Introduction

Aging is a time-dependent process with a progressive reduction in the physiological and functional capacity as well as in stress resilience [1]. The phenotype of the aging heart is characterized by a gradual loss of cardiac function [5]. A primary impairment of diastolic function emerges, which under increasing workload expands to a reduction of heart rate and systolic ejection capacity [6]. Acute hemodynamic stress can be compensated by (neuro-)hormonal systems and physiological hypertrophy [6]. The cardiacderived hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) fulfill a vasodilatory, natriuretic, and diuretic function [7]. The excessive secretion of ANP and BNP serves as a clinical marker of ventricular hypertrophy, hypertension, heart failure, and myocardial infarction [7]

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Conclusion