A comparison of LKB1/AMPK/mTOR metabolic axis response to global ischaemia in brain, heart, liver and kidney in a rat model of cardiac arrest

Abstract

BackgroundCellular energy failure in high metabolic rate organs is one of the underlying causes for many disorders such as neurodegenerative diseases, cardiomyopathies, liver and renal failures. In the past decade, numerous studies have discovered the cellular axis of LKB1/AMPK/mTOR as an essential modulator of cell homeostasis in response to energy stress. Through regulating adaptive mechanisms, this axis adjusts the energy availability to its demand by a systematized control on metabolism. Energy stress, however, could be sensed at different levels in various tissues, leading to applying different strategies in response to hypoxic insults.MethodsHere the immediate strategies of high metabolic rate organs to time-dependent short episodes of ischaemia were studied by using a rat model (n = 6/group) of cardiac arrest (CA) (15 and 30 s, 1, 2, 4 and 8 min CA). Using western blot analysis, we examined the responses of LKB1/AMPK/mTOR pathway in brain, heart, liver and kidney from 15 s up to 8 min of global ischaemia. The ratio of ADP/ATP was assessed in all ischemic and control groups, using ApoSENSOR bioluminescent assay kit.ResultsBrain, followed by kidney showed the early dephosphorylation response in AMPK (Thr172) and LKB1 (Ser431); in the absence of ATP decline (ADP/ATP elevation). Dephosphorylation of AMPK was followed by rephosphorylation and hyperphosphorylation, which was associated with a significant ATP decline. While heart’s activity of AMPK and LKB1 remained at the same level during short episodes of ischaemia, liver’s LKB1 was dephosphorylated after 2 min. AMPK response to ischaemia in liver was mainly based on an early alternative and a late constant hyperphosphorylation. No significant changes was observed in mTOR activity in all groups.ConclusionTogether our results suggest that early AMPK dephosphorylation followed by late hyperphosphorylation is the strategy of brain and kidney in response to ischaemia. While the liver seemed to get benefit of its AMPK system in early ischameia, possibly to stabilize ATP, the level of LKB1/AMPK activity in heart remained unchanged in short ischaemic episodes up to 8 min. Further researches must be conducted to elucidate the molecular mechanism underlying LKB1/AMPK response to oxygen supply.

Activation of AMPK under Hypoxia: Many Roads Leading to Rome

“…Beyond differences between cancer and normal cells, the effects of AMPK might generally be tissue-specific due to different metabolic profiles and needs. Majd et al [113] reported varying time courses and intensities of AMPK activation under short-term ischemia in rat brain, liver, kidney and heart that coincide with the individual tissue sensitivities to ischemic insults. This tissue specificity might be mediated by the different combinations of AMPK subunit isoforms [8] whose specific roles remain elusive for the most part to date [114] and might mirror the metabolic specificities of different tissues.…”

Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice

“…The AMPK pathway is considered to be the master regulator of cellular energy during conditions of metabolic stress because it can establish ATP homeostasis by both inhibiting ATP-consuming anabolic pathways and switching on catabolic pathways [25,26]. LKB1 is the upstream signal of AMPK and is one of the most important kinases mediating AMPK phosphorylation [7]. While the mTOR pathway is also an upstream signal of AMPK, the LKB1/AMPK pathway can negatively regulate the phosphorylation of the mTOR pathway [7].…”

“…LKB1 is the upstream signal of AMPK and is one of the most important kinases mediating AMPK phosphorylation [7]. While the mTOR pathway is also an upstream signal of AMPK, the LKB1/AMPK pathway can negatively regulate the phosphorylation of the mTOR pathway [7]. Considering the regulation of energy metabolism also reported in a recent study [7], we measured the effects of thyroxine on the phos-phorylation of the LKB1/AMPK/mTOR axis to determine the mechanisms by which thyroxine alleviates DOX-induced cardiac injury, and the results showed that thyroxine increased LKB1/AMPK phosphorylation but reduced mTOR phosphorylation in DOX-treated mice.…”

“…While the mTOR pathway is also an upstream signal of AMPK, the LKB1/AMPK pathway can negatively regulate the phosphorylation of the mTOR pathway [7]. Considering the regulation of energy metabolism also reported in a recent study [7], we measured the effects of thyroxine on the phos-phorylation of the LKB1/AMPK/mTOR axis to determine the mechanisms by which thyroxine alleviates DOX-induced cardiac injury, and the results showed that thyroxine increased LKB1/AMPK phosphorylation but reduced mTOR phosphorylation in DOX-treated mice. The LKB1/AMPK/m-TOR axis has been reported to regulate multiple biological processes, such as apoptosis and tumor growth; therefore, we can conclude only that thyroxine may reduce DOXinduced cardiac injury by regulating energy metabolism.…”

“…The human body is a complex metabolic factory, and a normal energy supply is essential to the proper functioning of all organs, especially the heart and brain [4]. Growing evidence has demonstrated that decreases in energy production from various causes are closely related to the occurrence of cardiac injury, including PIMT/NCOA6IP gene deletioninduced delayed cardiomyopathy, diabetic cardiomyopathy, and global ischemia-induced cardiac injury [5][6][7]. The underlying mechanisms may be related to excessive apoptosis caused by the energy generation of cardiac cells [8].…”