Research ArticleISCHEMIA/REPERFUSION INJURY

Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury

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Science Translational Medicine  29 Nov 2017:
Vol. 9, Issue 418, eaao6298
DOI: 10.1126/scitranslmed.aao6298

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Protecting the lungs with irisin

Limb remote ischemic preconditioning, or subjecting a limb to temporary periods of brief ischemia, is a method that can be used to protect the lungs from ischemia/reperfusion damage due to an expected stressor such as surgery. Chen et al. investigated the mechanism by which this occurs and determined that remote ischemic preconditioning releases irisin, a myokine that targets mitochondria and blocks some of the deleterious effects of oxidative stress. The authors showed that this can occur naturally, as when infants with neonatal respiratory distress syndrome show transfer of endogenous irisin from the circulation into the lungs, or it can be induced therapeutically, as the authors demonstrated by treating mouse models with exogenous irisin, which protected their lungs from ischemia/reperfusion injury.

Abstract

Limb remote ischemic preconditioning (RIPC) is an effective means of protection against ischemia/reperfusion (IR)–induced injury to multiple organs. Many studies are focused on identifying endocrine mechanisms that underlie the cross-talk between muscle and RIPC-mediated organ protection. We report that RIPC releases irisin, a myokine derived from the extracellular portion of fibronectin domain–containing 5 protein (FNDC5) in skeletal muscle, to protect against injury to the lung. Human patients with neonatal respiratory distress syndrome show reduced concentrations of irisin in the serum and increased irisin concentrations in the bronchoalveolar lavage fluid, suggesting transfer of irisin from circulation to the lung under physiologic stress. In mice, application of brief periods of ischemia preconditioning stimulates release of irisin into circulation and transfer of irisin to the lung subjected to IR injury. Irisin, via lipid raft–mediated endocytosis, enters alveolar cells and targets mitochondria. Interaction between irisin and mitochondrial uncoupling protein 2 (UCP2) allows for prevention of IR-induced oxidative stress and preservation of mitochondrial function. Animal model studies show that intravenous administration of exogenous irisin protects against IR-induced injury to the lung via improvement of mitochondrial function, whereas in UCP2-deficient mice or in the presence of a UCP2 inhibitor, the protective effect of irisin is compromised. These results demonstrate that irisin is a myokine that facilitates RIPC-mediated lung protection. Targeting the action of irisin in mitochondria presents a potential therapeutic intervention for pulmonary IR injury.

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