A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1

Abstract

This editorial refers to 'Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury' by L. Wang et al., Myocardial injury is increased in aged hearts during ischaemia-reperfusion (IR) and accelerates the transition to post-infarct heart failure. 1Although many therapeutic interventions can effectively decrease cardiac injury in younger adult hearts, strategies to decrease cardiac injury in aged hearts are still limited.1 Therefore, understanding the mechanisms of injury in the aged heart during IR is critical to develop potential strategies to protect the high-risk aged heart. 2The impairment of substrate flexibility (balance between glucose usage and fatty acid oxidation) contributes to cardiac injury during IR as well as heart failure development.3 Limitation of glucose utilization and oxidation with concomitant increased fatty acid oxidation during reperfusion enhances cardiac injury. 3 Dr Li et al. found that the substrate flexibility was markedly impaired in aged hearts following IR compared with young hearts. 4 They further found that the decreased substrate flexibility was due in part to impairment of the AMPK (AMP-activated protein kinase) signalling pathway activation. Glucose uptake and utilization was decreased in parallel with enhanced fatty acid oxidation. 4 AMPK contributes an essential role in the regulation of glucose and lipid metabolism. Activation of the AMPK leads to increased glucose uptake and enhances insulin sensitivity. 5 Liver kinase B1 (LKB1) is an AMP-activated kinase that activates AMPK through phosphorylation of the alpha subunit of AMPK. 6The activity of LKB1 is regulated by SIRT1 (sirtuin 1), a member of the sirtuin (NAD-dependent deacetylase) family. 7 Activation of SIRT1 leads to deacetylation and activation of LKB1 that increases AMPK phosphorylation and activity. Thus, SIRT1-dependent activation of LKB1 stimulates AMPK activity. Dr Li's study clearly showed that the impaired AMPK activation in aged hearts was at least in part due to decreased SIRT1 activity.

Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

“…Accumulating evidence suggests that the activation of AMPK signaling pathway can significantly reduce myocardial injury in aging hearts. Li et al found that AMPK activation is markedly impaired in aged hearts following IR compared to young hearts [65]. They further found that cardiac SIRT1 mediates AMPK activation via LKB1(Liver kinase B1, LKB1) deacetylation, and AMPK modulates SIRT1 activity via regulation of NAD + level during MI.…”

“…Importantly, the SIRT1 protein level and activity decline in aging heart, resulting in the impairment of the AMPK signaling. This suggests that SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease [65]. It has been shown that autophagy plays an active role in MI.…”

“…One study reported that aging affects the cardioprotective AMPK signaling pathway, which plays a pivotal role in the increased susceptibility to myocardial ischemia observed in older cardiac patients [64]. Recently, compelling evidence has indicated that AMPK is a potential target that improves the function of aging heart and delay the aging process [46,65]. Accumulating evidence suggests that the activation of AMPK signaling pathway can significantly reduce myocardial injury in aging hearts.…”

Whole body vibration activates AMPK/CPT1 signaling pathway of skeletal muscle in young and aging mice based on metabolomics study

“…Activation of the AMPK signaling pathway can significantly reduce myocardial injury in the elderly heart. AMPK can delay aging [32,33]. Exercise can activate the expression of AMPK in skeletal muscle and induce energy imbalance in muscles, leading to increased intracellular AMP and ADP concentrations.…”