Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy

• Published in: Basic research in cardiology Vol. 106; no. 6; pp. 1173 - 1191
• Main Authors: Hua, Yinan, Zhang, Yingmei, Ceylan-Isik, Asli F., Wold, Loren E., Nunn, Jennifer M., Ren, Jun
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-11-2011; Springer Nature B.V
• Subjects: Aging - metabolism; Aging - pathology; Animals; Autophagy - physiology; Blotting, Western; Cardiology; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Echocardiography; Enzyme Activation; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Myocardial Contraction - physiology; Original Contribution; Proto-Oncogene Proteins c-akt - metabolism; Aging; Akt; Cardiac geometry; Autophagy; Contractile function; Insulin signaling
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-011-0222-8

Aging is often accompanied with geometric and functional changes in the heart, although the underlying mechanisms remain unclear. Recent evidence has described a potential role of Akt and autophagy in aging-associated organ deterioration. This study was to examine the impact of cardiac-specific Akt activation on aging-induced cardiac geometric and functional changes and underlying mechanisms involved. Cardiac geometry, contractile and intracellular Ca
2+
properties were evaluated using echocardiography, edge-detection and fura-2 techniques. Level of insulin signaling and autophagy was evaluated by western blot. Our results revealed cardiac hypertrophy (enlarged chamber size, wall thickness, myocyte cross-sectional area), fibrosis, decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca
2+
release and clearance in aged (24–26 month-old) mice compared with young (3–4 month-old) mice, the effects of which were accentuated by chronic Akt activation. Aging enhanced Akt and mTOR phosphorylation while reducing that of PTEN, AMPK and ACC with a more pronounced response in Akt transgenic mice. GSK3β phosphorylation and eNOS levels were unaffected by aging or Akt overexpression. Levels of beclin-1, Atg5 and LC3-II-to-LC3-I ratio were decreased in aged hearts, the effect of which with the exception of Atg 5 was exacerbated by Akt overactivation. Levels of p62 were significantly enhanced in aged mice with a more pronounced increase in Akt mice. Neither aging nor Akt altered β-glucuronidase activity and cathepsin B although aging reduced LAMP1 level. In addition, rapamycin reduced aging-induced cardiomyocyte contractile and intracellular Ca
2+
dysfunction while Akt activation suppressed autophagy in young but not aged cardiomyocytes. In conclusion, our data suggest that Akt may accentuate aging-induced cardiac geometric and contractile defects through a loss of autophagic regulation.