title: MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction.
abstract: Heart disease remains a major complication of diabetes, and the identification of new therapeutic targets is essential. This study investigates the role of the protein kinase MK2, a p38 mitogen-activated protein kinase downstream target, in the development of diabetes-induced cardiomyopathy. Diabetes was induced in control (MK2(+/+)) and MK2-null (MK2(-/-)) mice using repeated injections of a low dose of streptozotocin (STZ). This protocol generated in MK2(+/+) mice a model of diabetes characterized by a 50% decrease in plasma insulin, hyperglycemia, and insulin resistance (IR), as well as major contractile dysfunction, which was associated with alterations in proteins involved in calcium handling. While MK2(-/-)-STZ mice remained hyperglycemic, they showed improved IR and none of the cardiac functional or molecular alterations. Further analyses highlighted marked lipid perturbations in MK2(+/+)-STZ mice, which encompass increased 1) circulating levels of free fatty acid, ketone bodies, and long-chain acylcarnitines and 2) cardiac triglyceride accumulation and ex vivo palmitate β-oxidation. MK2(-/-)-STZ mice were also protected against all these diabetes-induced lipid alterations. Our results demonstrate the benefits of MK2 deletion on diabetes-induced cardiac molecular and lipid metabolic changes, as well as contractile dysfunction. As a result, MK2 represents a new potential therapeutic target to prevent diabetes-induced cardiac dysfunction.
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Lise
authors.initials: L
authors.lastname: Coderre
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Dominic
authors.initials: D
authors.lastname: Lachance
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Houde
authors.affiliation: Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Cécile
authors.initials: C
authors.lastname: Martel
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Thompson Legault
authors.affiliation: Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bouchard
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Daneault
authors.affiliation: Department of Medicine, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: André C
authors.initials: AC
authors.lastname: Carpentier
authors.affiliation: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Research Center, Montreal Heart Institute, Montréal, Québec, Canada Department of Medicine, Université de Montréal, Montréal, Québec, Canada Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada christine.des.rosiers@umontreal.ca bruce.g.allen@umontreal.ca.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Allen
authors.affiliation: Department of Nutrition, Université de Montréal, Montréal, Québec, Canada Research Center, Montreal Heart Institute, Montréal, Québec, Canada Department of Medicine, Université de Montréal, Montréal, Québec, Canada christine.des.rosiers@umontreal.ca bruce.g.allen@umontreal.ca.
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
mesh_terms: D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D017353:Gene Deletion; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007657:Ketone Bodies / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D009119:Muscle Contraction / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013311:Streptozocin; D014280:Triglycerides / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D002331:Carnitine; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D007657:Ketone Bodies; D017346:Protein Serine-Threonine Kinases; D013311:Streptozocin; D014280:Triglycerides; D000099190:MAP-Kinase-Activated Kinase 2; C116917:acylcarnitine