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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 Ca2+ 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 Ca2+ 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 Ca2+ 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. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to evaluate the interaction between aging and obesity on cardiac contractile and intracellular Ca2+ properties. Methods: Cardiomyocytes from young (4-mo) and aging (12- and 18-mo) male lean and the leptin deficient ob/ob obese mice were treated with leptin (0.5, 1.0 and 50 nM) for 4 hrs in vitro. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obesity models at young and older age were used for comparison. Cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), intracellular Ca2+ levels and decay. O2− levels were measured by dihydroethidium fluorescence. Results: Our results revealed reduced survival in ob/ob mice. Aging and obesity reduced PS, ± dL/dt, intracellular Ca2+ rise, prolonged TR90 and intracellular Ca2+ decay, enhanced O2− production and p47phox expression without an additive effect of the two, with the exception of intracellular Ca2+ rise. Western blot analysis exhibited reduced Ob-R expression and STAT-3 phosphorylation in both young and aging ob/ob mice, which was restored by leptin. Aging and obesity reduced phosphorylation of Akt, eNOS and p38 while promoting pJNK and pIκB. Low levels of leptin reconciled contractile, intracellular Ca2+ and cell signaling defects as well as O2− production and p47phox upregulation in young but not aging ob/ ob mice. High level of leptin (50 nM) compromised contractile and intracellular Ca2+ response as well as O2− production and stress signaling in all groups. High fat diet-induced and db/db obesity displayed somewhat comparable aging-induced mechanical but not leptin response. Conclusions: Taken together, our data suggest that aging and obesity compromise cardiac contractile function possibly via phosphorylation of Akt, eNOS and stress signaling-associated O2− release. [ABSTRACT FROM AUTHOR]

Provides information on a study which examined the role of antioxidant metallothionein on cardiomyocyte function, superoxide generation, the oxidative stress biomarker aconitase activity, cytochrome c release and expression of oxidative stress-related proteins. Discussion on the capability of metallothionein to prevent aging-induced cardiac contractile defects; Conclusions and significance.