Abstract
Ageing is associated with an increase in the incidence of heart failure, even if the existence of a real age-related cardiomyopathy remains controversial. Effective contraction and relaxation of cardiomyocytes depend on efficient production of ATP (handled by mitochondria) and on proper Ca2+ supply to myofibrils during excitation–contraction (EC) coupling (handled by Ca2+ release units, CRUs). Here, we analyzed mitochondria and CRUs in hearts of adult (4 months old) and aged (≥24 months old) mice. Analysis by confocal and electron microscopy (CM and EM, respectively) revealed an age-related loss of proper organization and disposition of both mitochondria and EC coupling units: (a) mitochondria are improperly disposed and often damaged (percentage of severely damaged mitochondria: adults 3.5 ± 1.1%; aged 16.5 ± 3.5%); (b) CRUs that are often misoriented (longitudinal) and/or misplaced from the correct position at the Z line. Immunolabeling with antibodies that mark either the SR or T-tubules indicates that in aged cardiomyocytes the sarcotubular system displays an extensive disarray. This disarray could be in part caused by the decreased expression of Cav-3 and JP-2 detected by western blot (WB), two proteins involved in formation of T-tubules and in docking SR to T-tubules in dyads. By WB analysis, we also detected increased levels of 3-NT in whole hearts homogenates of aged mice, a product of nitration of protein tyrosine residues, recognized as marker of oxidative stress. Finally, a detailed EM analysis of CRUs (formed by association of SR with T-tubules) points to ultrastructural modifications, i.e., a decrease in their frequency (adult: 5.1 ± 0.5; aged: 3.9 ± 0.4 n./50 μm2) and size (adult: 362 ± 40 nm; aged: 254 ± 60 nm). The changes in morphology and disposition of mitochondria and CRUs highlighted by our results may underlie an inefficient supply of Ca2+ ions and ATP to the contractile elements, and possibly contribute to cardiac dysfunction in ageing.
Highlights
The cardiovascular system, as many of the others vital systems of the human body, is a target of age-related cellular insults.Statistics indicate that the risk of heart failure (HF) doubles with each decade of life in individuals aged over 50 [1], making HF the major cause of mortality in the elderlies [2]. 4.0/).even if the increased incidence of HF in ageing is undeniable, the existence of a real age-related cardiomyopathy remains controversial [3]
We immunostained cardiomyocytes with antibodies marking the position of mitochondria (TOM20) and the position of membrane elements involved in EC coupling, i.e., sarcoplasmic reticulum (SR) and T-tubules (RYR2 and JP-2 to mark the position of the SR; wheat germgerm agglutinin (WGA) and antibodies against Cav-3 to mark the position T-tubules) (Figures 1 and 2)
By western blot (WB) we evaluated the expression levels of either JP-2 or Cav-3 and verified that both were reduced in samples from aged mice (Figure 2G,H), providing a possible molecular mechanism underlying the age-related disarray of the T-tubule network
Summary
The cardiovascular system, as many of the others vital systems of the human body, is a target of age-related cellular insults.Statistics indicate that the risk of heart failure (HF) doubles with each decade of life in individuals aged over 50 [1], making HF the major cause of mortality in the elderlies [2]. 4.0/).even if the increased incidence of HF in ageing is undeniable, the existence of a real age-related cardiomyopathy remains controversial [3]. The cardiovascular system, as many of the others vital systems of the human body, is a target of age-related cellular insults. Statistics indicate that the risk of heart failure (HF) doubles with each decade of life in individuals aged over 50 [1], making HF the major cause of mortality in the elderlies [2]. In the past years a tremendous effort has been made to unravel the causes of age-related HF [4], the need to fully understand the mechanisms underlying cardiac decline is becoming increasingly urgent as the elderly population continues to grow [5]. ATP is provided by mitochondria during cellular respiration, and the myocardium is well known to be heavily dependent on the oxidative metabolism [6,7]. Ca2+ needed for contraction is released by the sarcoplasmic reticulum (SR) during excitation–contraction (EC) coupling, the mechanism that allows transduction of the action potential of transverse (T)-tubules into release of Ca2+
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