Examining Cardiomyocyte Dysfunction Using Acute Chemical Induction of an Ageing Phenotype

Said Masoud,Fraser Mcdonald,Martin D Bootman,Dirk Bister,Claire Kotecki,Katja Rietdorf

doi:10.3390/ijms21010197

Said Masoud, Fraser Mcdonald + Show 4 more

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https://doi.org/10.3390/ijms21010197

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Abstract

Much effort is focussed on understanding the structural and functional changes in the heart that underlie age-dependent deterioration of cardiac performance. Longitudinal studies, using aged animals, have pinpointed changes occurring to the contractile myocytes within the heart. However, whilst longitudinal studies are important, other experimental approaches are being advanced that can recapitulate the phenotypic changes seen during ageing. This study investigated the induction of an ageing cardiomyocyte phenotypic change by incubation of cells with hydroxyurea for several days ex vivo. Hydroxyurea incubation has been demonstrated to phenocopy age- and senescence-induced changes in neurons, but its utility for ageing studies with cardiac cells has not been examined. Incubation of neonatal rat ventricular myocytes with hydroxyurea for up to 7 days replicated specific aspects of cardiac ageing including reduced systolic calcium responses, increased alternans and a lesser ability of the cells to follow electrical pacing. Additional functional and structural changes were observed within the myocytes that pointed to ageing-like remodelling, including lipofuscin granule accumulation, reduced mitochondrial membrane potential, increased production of reactive oxygen species, and altered ultrastructure, such as mitochondria with disrupted cristae and disorganised myofibres. These data highlight the utility of alternative approaches for exploring cellular ageing whilst avoiding the costs and co-morbid factors that can affect longitudinal studies.

Highlights

Ageing studies are typically conducted via protracted longitudinal experiments that compare cells, tissues or samples from young and old animals, or by using progeroid models
Altered Reactive Oxygen Species (ROS) Production in HU-Treated Neonatal rat ventricular myocytes (NRVMs) The results presented above indicate that HU incubation led to reduced mitochondrial membrane potential
An alternative approach that has been used for some cell types is ageing of cells from young and old animals in vitro [40]

Summary

Introduction

Ageing studies are typically conducted via protracted longitudinal experiments that compare cells, tissues or samples from young and old animals, or by using progeroid models. It may be difficult to ensure that the environment, nutrition and condition of animals are exactly alike over protracted periods, and that co-morbid factors do not impinge the presumed ageing phenotypes observed [1] For these reasons, it would be useful to establish acute models of ageing that do not require aged cells or animals. A plausible alternative to protracted longitudinal experiments is to acutely induce changes in cellular form and function that replicate those seen in aged tissues This can be achieved, for example, by culturing cells ex vivo for prolonged periods, using iPSC-derived cells from patient samples, or via chemically-induced cellular remodelling [1,3,4,5,6]

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