Ageing causes Severe Ultra-Structural Modification of Calcium Release Units and Mitochondria in Cardiomyocytes

Abstract

Ageing is associated to a dramatic increase in the incidence of heart failure, even if the existence of a real age-related cardiomyopathy remains controversial. In this study we performed a morphological study of cardiac cells in hearts from adult and old mice (4 and ≥ 24 months respectively) using confocal and electron microscopy. Our results indicates that the cross sectional areas (CSA) of cardiomyocytes is on the average increased in old hearts (adults: 191±105 μm2; old: 232 ± 147 μm2), with a greater variability in size indicating also the presence of several atrophic cells. The increased CSA may be the result of an increased presence of amorphic (apparently empty) cytoplasmic space between myofibrils (adults: 2.2 ± 3.1; old: 9.7 ± 5.7).As effective contraction and relaxation of cardiomyocytes also depends on Ca2+ supply to myofibrils (handled by calcium release units (CRUs) and sarcoplasmic reticulum (SR) and on efficient ATP production (provided by mitochondria), we have also analyzed in detail these intracellular organelles. The analysis of CRUs indicates that SR/transverse-tubules (TT) couplons become shorter with age and that the number of CRUs/50 μm2 is decreased of about 24% (adults: 5.1±3.3; old: 3.9±2.6). Also mitochondria present structural modifications, with a significant increase in the percentage of organelles presenting severe alterations (3.5% vs. 16.5%, respectively in adult vs. old). Importantly, both CRUs and mitochondria undergo a spatial re-organization with respect to sarcomeres/myofibrils: CRUs are may be miss-oriented (longitudinal) or miss-placed (found at the A band instead of being correctly placed in proximity of Z-lines), while mitochondria are often grouped in an abnormal fashion.These age-related ultra-structural changes may underlie an inefficient supply of Ca2+ and ATP to contractile elements, providing a possible structural explanation for heart dysfunction.