Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function
Trevor P. Fidler,
Robert A. Campbell,
Trevor Funari,
Nicholas Dunne,
Enrique Balderas Angeles,
Elizabeth A. Middleton,
Dipayan Chaudhuri,
Andrew S. Weyrch,
E. Dale Abel
Affiliations
Trevor P. Fidler
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA
Robert A. Campbell
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA
Trevor Funari
Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Nicholas Dunne
Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Enrique Balderas Angeles
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA
Elizabeth A. Middleton
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA
Dipayan Chaudhuri
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA
Andrew S. Weyrch
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA
E. Dale Abel
Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA
Anucleate platelets circulate in the blood to facilitate thrombosis and diverse immune functions. Platelet activation leading to clot formation correlates with increased glycogenolysis, glucose uptake, glucose oxidation, and lactic acid production. Simultaneous deletion of glucose transporter (GLUT) 1 and GLUT3 (double knockout [DKO]) specifically in platelets completely abolished glucose uptake. In DKO platelets, mitochondrial oxidative metabolism of non-glycolytic substrates, such as glutamate, increased. Thrombosis and platelet activation were decreased through impairment at multiple activation nodes, including Ca2+ signaling, degranulation, and integrin activation. DKO mice developed thrombocytopenia, secondary to impaired pro-platelet formation from megakaryocytes, and increased platelet clearance resulting from cytosolic calcium overload and calpain activation. Systemic treatment with oligomycin, inhibiting mitochondrial metabolism, induced rapid clearance of platelets, with circulating counts dropping to zero in DKO mice, but not wild-type mice, demonstrating an essential role for energy metabolism in platelet viability. Thus, substrate metabolism is essential for platelet production, activation, and survival.
