posted on 2020-05-04, 17:02authored byAda AdminAda Admin, Adam R. Wende, John C. Schell, Chae-Myeong Ha, Mark E. Pepin, Oleh Khalimonchuk, Hansjörg Schwertz, Renata O. Pereira, Manoja K. Brahma, Joseph Tuinei, Ariel Contreras-Ferrat, Li Wang, Chase A. Andrizzi, Curtis D. Olsen, Wayne E. Bradley, Louis J. Dell’Italia, Wolfgang H. Dillmann, Sheldon E. Litwin, E. Dale Abel
Cardiac glucose uptake and oxidation are reduced in
diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart
failure in diabetes. It is unclear if these changes are adaptive or
maladaptive. To directly evaluate the relationship between
glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we
generated transgenic mice with inducible cardiomyocyte-specific expression of
the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following
low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by
transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased
mitochondrial ATP generation and was associated with echocardiographic evidence
of diastolic dysfunction. Increasing myocardial glucose delivery after short-term
diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic
analysis revealed that the largest changes, driven by glucose and diabetes, were
in genes involved in mitochondrial function. This glucose-dependent
transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose
uptake induced direct O-GlcNAcylation
of many electron transport chain subunits and other mitochondrial proteins.These
findings identify mitochondria as a major target of glucotoxicity. They also
suggest reduced glucose utilization in diabetic cardiomyopathy might defend
against glucotoxicity and caution that restoring glucose delivery to the heart
in the context of diabetes could accelerate mitochondrial dysfunction by disrupting
protective metabolic adaptations.
Funding
This work was supported by National Institutes of Health (NIH) grants R00 HL111322, R01 HL133011, and JDRF Advanced Postdoctoral Fellowship 10-2009-267 to A.R.W., M.E.P. was supported by an NIH grant F30 HL137240, R.O.P. and M.K.B. were both supported by postdoctoral fellowships from the American Heart Association (AHA), O.K. was supported by NIH grant R01 GM108975, and E.D.A. was supported by NIH grants R01 DK092065, R01 HL108379, U01 HL087947, and is an established investigator of the AHA.