Sirtuin family members protect cardiomyocyte function against ischemia and reperfusion injury. C57BL/6J wild type mice, inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1-/-), and cardiomyocyte-specific SIRT3 knockout(cSIRT3-/-) mice are subjected to isolate cardiomyocytes. The deletion of SIRT1 or SIRT3 in cardiomyocytes impairs cardiac contractility during ischemic stress. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 in aging leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to stress.

A novel stress-inducible protein Sesn2 declines with aging in the heart that contributes to an age-related intolerance to ischemic insults. This study characterizes the role of Sesn2 in maintaining mitochondrial functional integrity during ischemia and reperfusion in aging. The study reveals that ischemia reperfusion stress triggers Sesn2 accumulation in mitochondria. The association of Sesn2 with OXPHOS Complex I and Complex II altered with aging that results in alterations in mitochondria respiratory function and TCA related enzyme activities. Sesn2 plays a key role in an adaptive metabolic response to ischemia reperfusion stress through maintaining mitochondrial integrity. The results could advance our understanding of Sesn2 serving as a stress inducible scaffold protein to modulate adaptive signaling pathways in the heart under stress conditions. The study will provide a basis that Sesn2 could be a target for increasing heart’s resistance to ischemic insults in the elderly.

Empagliflozin (EMPA) and metformin have been revealed to benefit cardiac function in heart failure besides their anti-diabetes activity in some clinical trials. However, the pharmacological mechanisms of Empagliflozin and/or metformin on obesity-related cardiac dysfunction are incompletely understood. We characterize the role of Sestrn2-AMPK-mTOR signaling cascade in mediating the beneficial effects of EMPA and/or metformin on high fat diet (HFD)-induced obesity related cardiac functions. Intriguingly, EMPA can ameliorate obesity related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling pathway. We also attempt to understand the roles and mechanism of metformin improve metabolic syndrome heart from ischemic insults by modulating substrate metabolism, leading to determine a future drug as a target of ischemic injury in the setting of metabolic syndrome.