title: Diaphragm muscle weakness in mice is early-onset post-myocardial infarction and associated with elevated protein oxidation.
abstract: Heart failure induced by myocardial infarction (MI) causes diaphragm muscle weakness, with elevated oxidants implicated. We aimed to determine whether diaphragm muscle weakness is 1) early-onset post-MI (i.e., within the early left ventricular remodeling phase of 72 h); and 2) associated with elevated protein oxidation. Ligation of the left coronary artery to induce MI (n = 10) or sham operation (n = 10) was performed on C57BL6 mice. In vitro contractile function of diaphragm muscle fiber bundles was assessed 72 h later. Diaphragm mRNA and protein expression, enzyme activity, and individual carbonylated proteins (by two-dimensional differential in-gel electrophoresis and mass spectrometry) were subsequently assessed. Infarct size averaged 57 ± 1%. Maximal diaphragm function was reduced (P < 0.01) by 20% post-MI, with the force-frequency relationship depressed (P < 0.01) between 80 and 300 Hz. The mRNA expression of inflammation, atrophy, and regulatory Ca(2+) proteins remained unchanged post-MI, as did the protein expression of key contractile proteins. However, enzyme activity of the oxidative sources NADPH oxidase and xanthine oxidase was increased (P < 0.01) by 45 and 33%, respectively. Compared with sham, a 57 and 45% increase (P < 0.05) was observed in the carbonylation of sarcomeric actin and creatine kinase post-MI, respectively. In conclusion, diaphragm muscle weakness was rapidly induced in mice during the early left ventricular remodeling phase of 72 h post-MI, which was associated with increased oxidation of contractile and energetic proteins. Collectively, these findings suggest diaphragm muscle weakness may be early onset in heart failure, which is likely mediated in part by posttranslational oxidative modifications at the myofibrillar level.
authors.affiliation: Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany; bows@med.uni-leipzig.de.
authors.forename: T Scott
authors.initials: TS
authors.lastname: Bowen
authors.affiliation: Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany;
authors.forename: Norman
authors.initials: N
authors.lastname: Mangner
authors.affiliation: Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Werner
authors.affiliation: Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Glaser
authors.affiliation: Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany;
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kullnick
authors.affiliation: Department of Cardiothoracic Surgery, University of Jena, Jena, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Schrepper
authors.affiliation: Department of Cardiothoracic Surgery, University of Jena, Jena, Germany;
authors.forename: Torsten
authors.initials: T
authors.lastname: Doenst
authors.affiliation: Department of Cardiac Surgery, Leipzig University-Heart Center, Leipzig, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Oberbach
authors.affiliation: Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany;
authors.forename: Axel
authors.initials: A
authors.lastname: Linke
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Leif
authors.initials: L
authors.lastname: Steil
authors.affiliation: Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany;
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schuler
authors.affiliation: Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany;
authors.forename: Volker
authors.initials: V
authors.lastname: Adams
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002256:Carbonic Anhydrases / Q000378:metabolism*; D003964:Diaphragm / Q000503:physiopathology*; D005260:Female; D051379:Mice; D018908:Muscle Weakness / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D050050:Protein Carbonylation; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D000199:Actins; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D002256:Carbonic Anhydrases
keywords: MI: protein carbonylation; chronic heart failure; skeletal muscle