The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage.

Ramy K A Sayed,José Fernández-Martínez,Germaine Escames,Ibtissem Rahim,Reem M Alsaadawy,Laura Martínez-Ruiz,Marisol Fernández-Ortiz,Paula Aranda-Martínez,Darío Acuña-Castroviejo,Iryna Rusanova

doi:10.3390/antiox10081269

Abstract

To investigate the role of NLRP3 inflammasome in cardiac aging, we evaluate here morphological and ultrastructural age-related changes of cardiac muscles fibers in wild-type and NLRP3-knockout mice, as well as studying the beneficial effect of melatonin therapy. The results clarified the beginning of the cardiac sarcopenia at the age of 12 months, with hypertrophy of cardiac myocytes, increased expression of β-MHC, appearance of small necrotic fibers, decline of cadiomyocyte number, destruction of mitochondrial cristae, appearance of small-sized residual bodies, and increased apoptotic nuclei ratio. These changes were progressed in the cardiac myocytes of 24 old mice, accompanied by excessive collagen deposition, higher expressions of IL-1α, IL-6, and TNFα, complete mitochondrial vacuolation and damage, myofibrils disorganization, multivesicular bodies formation, and nuclear fragmentation. Interestingly, cardiac myocytes of NLRP3−/− mice showed less detectable age-related changes compared with WT mice. Oral melatonin therapy preserved the normal cardiomyocytes structure, restored cardiomyocytes number, and reduced β-MHC expression of cardiac hypertrophy. In addition, melatonin recovered mitochondrial architecture, reduced apoptosis and multivesicular bodies’ formation, and decreased expressions of β-MHC, IL-1α, and IL-6. Fewer cardiac sarcopenic changes and highly remarkable protective effects of melatonin treatment detected in aged cardiomyocytes of NLRP3−/− mice compared with aged WT animals, confirming implication of the NLRP3 inflammasome in cardiac aging. Thus, NLRP3 suppression and melatonin therapy may be therapeutic approaches for age-related cardiac sarcopenia.

Highlights

Aging is a complex process that depends on diverse factors including environmental, cellular, and genetic ones, resulting in accumulation of cellular and molecular defects, and displaying dysfunctional impacts on tissues, organs, and systems [1]
Progressive impairments of diverse metabolic pathways were reported including inflammation and mitochondrial and autophagy dysfunction [5]; a considerable amount of these changes are implicated in cardiac aging and age-accompanied cardiovascular diseases [6]
This increase in the left ventricular wall thickness was countered in the OA animals by melatonin therapy, which revealed a more detectable beneficial effect on NLRP3−/− mice (Table 1, Figure 1M)

Summary

Introduction

Aging is a complex process that depends on diverse factors including environmental, cellular, and genetic ones, resulting in accumulation of cellular and molecular defects, and displaying dysfunctional impacts on tissues, organs, and systems [1]. Antioxidants 2021, 10, 1269 accompanied with morphological and biochemical changes, yielding a progressive and irreversible decline of all functions of the body [2]. Progressive impairments of diverse metabolic pathways were reported including inflammation and mitochondrial and autophagy dysfunction [5]; a considerable amount of these changes are implicated in cardiac aging and age-accompanied cardiovascular diseases [6]. Muscle mass and strength are progressively lost, a phenomenon defined as sarcopenia, which is characterized by a set of biochemical and morphological changes that deteriorate muscle function [7]. Sarcopenia has been considered one of the most essential reasons for reduced physical performance and declined cardiorespiratory fitness in older individuals with heart failure [8]

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Discussion

Conclusion