title: A post-MI power struggle: adaptations in cardiac power occur at the sarcomere level alongside MyBP-C and RLC phosphorylation.
abstract: Myocardial remodeling in response to chronic myocardial infarction (CMI) progresses through two phases, hypertrophic "compensation" and congestive "decompensation." Nothing is known about the ability of uninfarcted myocardium to produce force, velocity, and power during these clinical phases, even though adaptation in these regions likely drives progression of compensation. We hypothesized that enhanced cross-bridge-level contractility underlies mechanical compensation and is controlled in part by changes in the phosphorylation states of myosin regulatory proteins. We induced CMI in rats by left anterior descending coronary artery ligation. We then measured mechanical performance in permeabilized ventricular trabecula taken distant from the infarct zone and assayed myosin regulatory protein phosphorylation in each individual trabecula. During full activation, the compensated myocardium produced twice as much power and 31% greater isometric force compared with noninfarcted controls. Isometric force during submaximal activations was raised >2.4-fold, while power was 2-fold greater. Electron and confocal microscopy demonstrated that these mechanical changes were not a result of increased density of contractile protein and therefore not an effect of tissue hypertrophy. Hence, sarcomere-level contractile adaptations are key determinants of enhanced trabecular mechanics and of the overall cardiac compensatory response. Phosphorylation of myosin regulatory light chain (RLC) increased and remained elevated post-MI, while phosphorylation of myosin binding protein-C (MyBP-C) was initially depressed but then increased as the hearts became decompensated. These sensitivities to CMI are in accordance with phosphorylation-dependent regulatory roles for RLC and MyBP-C in crossbridge function and with compensatory adaptation in force and power that we observed in post-CMI trabeculae.
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Laboratory of Molecular Physiology, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland; christopher_toepfer@HMS.harvard.edu.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Toepfer
authors.affiliation: Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Markus B
authors.initials: MB
authors.lastname: Sikkel
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Laboratoire Physico-Chimie, UMR168, Institute Curie, Paris, France;
authors.forename: Valentina
authors.initials: V
authors.lastname: Caorsi
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Anupama
authors.initials: A
authors.lastname: Vydyanath
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Iratxe
authors.initials: I
authors.lastname: Torre
authors.affiliation: Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: O'Neal
authors.initials: O
authors.lastname: Copeland
authors.affiliation: Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Nationa Institute of Health Research Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom;
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.affiliation: Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Steven B
authors.initials: SB
authors.lastname: Marston
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Luther
authors.affiliation: Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Macleod
authors.affiliation: Royal Veterinary College London, Structure & Motion Laboratory, North Mymms, United Kingdom; and.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: West
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ferenczi
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003331:Coronary Vessels / Q000601:surgery; D008026:Ligation; D008297:Male; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D018994:Myosin Light Chains / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D018994:Myosin Light Chains; D000099163:Myosin Binding Protein C
keywords: contractile apparatus; contractile function; infarction; myosin binding protein-C; regulatory light chain