title: Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients.
abstract: BACKGROUND
  Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy.
  
  
  RESULTS
  Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A1C, but neither body mass index nor the insulin resistance index (homeostasis model assessment-insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A1C.
  
  
  CONCLUSIONS
  Worsening of intrinsic myocardial contraction in the transition from obesity to diabetes mellitus is likely related to worsening of cardiac mitochondrial function because impaired mitochondrial function and dynamics and contractile dysfunction are observed in diabetic patients but not in "metabolically healthy" obese patients at early stage in insulin resistance.
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.). davidmontaigne@hotmail.com bart.staels@pasteur-lille.fr.
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Augustin
authors.initials: A
authors.lastname: Coisne
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Debry
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Modine
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Georges
authors.initials: G
authors.lastname: Fayad
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Charlotte
authors.initials: C
authors.lastname: Potelle
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: El Arid
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Mouton
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Sebti
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Hélène
authors.initials: H
authors.lastname: Duez
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Sébastien
authors.initials: S
authors.lastname: Preau
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Remy-Jouet
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Farid
authors.initials: F
authors.lastname: Zerimech
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Mohamed
authors.initials: M
authors.lastname: Koussa
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Edme
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.affiliation: From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D000368:Aged; D016280:Atrial Function, Right / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D009765:Obesity / Q000097:blood / Q000503:physiopathology*; D009924:Organ Culture Techniques; D011446:Prospective Studies
chemical_list: D001786:Blood Glucose
keywords: autophagy; diabetes mellitus, type 2; mitochondria; mitochondrial dynamics; obesity