“AMP”(K)ed up recovery from ischemia-reperfusion injury

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Science Translational Medicine  21 Jun 2017:
Vol. 9, Issue 395, eaan6194
DOI: 10.1126/scitranslmed.aan6194


Aging decreases tolerance to ischemia-reperfusion injury, which is mitigated by sestrin2-driven substrate metabolism.

Regardless of how gracefully we age, our ability to recover from injury, including ischemic cardiac and skeletal muscle injury, substantially reduces as we grow old. Rather than searching for the fountain of youth, therapies to slow this decreased tolerance to ischemic muscle injury would prove more realistic. A recent study by Quan and colleagues demonstrates that modulation of glucose metabolism improves cardiac tolerance to ischemia-reperfusion (IR) injury. It is known that 5′ adenosine monophosphate –activated protein kinase (AMPK) activation stimulates glucose transport and that AMPK is central to activating glucose uptake after ischemic cardiac injury. However, the pathway by which AMPK mediates this process has not been identified.

Quan et al. first analyzed ischemic cardiac insults in mice of differing ages and demonstrated the importance of the age-related protein Sestrin 2 (Sesn2), which decreases with aging. They then hypothesized that Sesn2, a protein involved in cell survival and response to stress, modulates ischemic AMPK activation by acting as an ischemia-induced scaffold protein. Hearts from Sesn2 KO mice after cardiac IR had decreased contractile function and more severe myocardial injury than age-matched wild-type hearts. To tie this to glucose metabolism, they used an ex vivo labeling system that revealed that ischemic stress increased glucose transporter 4 (GLUT4) mobilization to the cell surface, which was blunted in Sesn2 KO and aged wild-type mice. Importantly, viral recovery of Sesn2 expression in aged hearts rescued the AMPK signaling and improved tolerance to ischemic stress.

This study further defines the important interaction between glucose metabolism, IR recovery, and myocardial infarction while defining the novel role of Sesn2. Based on these findings, researchers have a potential new target, Sesn2, to combat age-related decline in recovery from IR injury. Although this study focused specifically on myocardial injury, these findings will likely translate to other forms of IR injury including skeletal muscle trauma and post-tourniquet–induced IR injury. Thus, as we aim to improve muscle recovery and maintain a strong heart, it is time we “AMP”(K) up our Sesn2 signaling.

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