Age-Dependent Cardiac Function during Experimental Sepsis: Effect of Pharmacological Activation of AMP-Activated Protein Kinase by AICAR

Age represents a major risk factor of multiple organ failure, including cardiac dysfunction, in patients with sepsis. AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis, which controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-γ co-activator-α and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation contributes to age-dependent cardiac injury in young (2-3 months) and mature adult (11-13 months) male mice subjected to sepsis by cecal ligation and puncture, and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) affords cardioprotective effects. Plasma pro-inflammatory cytokines and myokine follistatin were similarly elevated in vehicle-treated young and mature adult mice at 18 hours after sepsis. However, despite equivalent troponin I and T levels, compared to similarly treated young mice, vehicle-treated mature adult mice exhibited more severe cardiac damage by light and electron microscopy analyses with more marked intercellular edema, inflammatory cell infiltration, and mitochondrial derangement. Echocardiography revealed that vehicle-treated young mice exhibited left ventricular dysfunction after sepsis, whereas mature adult mice exhibited reduction in stroke volume without apparent changes in load-dependent indexes of cardiac function. At molecular analysis, phosphorylation of the catalytic subunits AMPKα1/2 was associated with nuclear translocation of peroxisome proliferator-activated receptor-γ co-activator-α in vehicle-treated young, but not mature adult mice. Treatment with AICAR ameliorated cardiac architecture derangement in mice of both ages. These cardioprotective were associated with attenuation of the systemic inflammatory response and amelioration of cardiac dysfunction in young mice only, but not in mature adult animals.