TUG Mediates GLUT4 Translocation by AMP‐Activated Protein Kinase in the Heart

Abstract

IntroductionIschemic heart disease, is mainly caused by reduced nutrient availability. Increasing nutrient uptake becomes a key approach to improve cardiomyocyte survival during the ischemia and reperfusion (I/R) period. TUG (tether containing a UBX domain, for GLUT4, 60 KDa) is a regulator of GLUT4 trafficking, which is cleaved to mobilize GLUT4 from intracellular compartments to the cell surface. The energy sensor AMP‐activated protein kinase (AMPK) is known to play an important cardioprotective role during myocardial I/R by regulating GLUT4 translocation. Antithrombin (AT) exhibits a cardioprotective function severed as AMPK activator. 
HypothesisTUG is one of the downstream targets of AMPK, which can be phosphorylated by hypoxia/ischemia‐induced as well as AT‐induced AMPK activation. 
MethodsIn vitro hypoxia chamber and in vivo I/R models were used to analyze AMPK/TUG interactions. Ex vivo isolated mouse heart perfusion Langendorff system was used to measure glucose metabolism. 
ResultsIn HL‐1 cardiomyocytes, TUG proteins were phosphorylated by activated AMPK during hypoxia. Moreover, TUG siRNA knockdown the TUG of HL‐1 cells caused significantly increased cell surface GLUT4 and glucose uptake. The ex vivo heart perfusion data demonstrated that AT triggered AMPK activation and significantly increase glucose uptake and GLUT4 translocation during I/R. Moreover, AT treatment increased abundance of a TUG cleavage product (42KDa) in response to I/R. All of these glucose transporter events are blunted in the AMPK kinase dead transgenic hearts. 
ConclusionsCardiac AMPK activation via AT during the I/R period stimulates TUG cleavage and causes the dissociation between TUG and GLUT4, followed by the enhanced glucose uptake.