title: Essential light chain S195 phosphorylation is required for cardiac adaptation under physical stress.
abstract: Regulatory proteins of the sarcomere are pivotal for normal heart function and when affected by mutations are frequently causing cardiomyopathy. The exact function of these regulatory proteins and how mutations in these translate into distinct cardiomyopathy phenotypes remains poorly understood. Mutations in the essential myosin light chain (ELC) are linked to human cardiomyopathy characterized by a marked variability in disease phenotypes and high incidences of sudden death. Here we studied the role of the highly conserved S195 phosphorylation site of ELC using heterozygous adult zebrafish lazy susan (laz(m647)) in regulating contractile function in normal physiology and disease.
  
  
  
  Echocardiography revealed signs of systolic dysfunction in otherwise phenotypically unremarkable heterozygote mutants. However, after physical stress, heart function of laz heterozygous zebrafish severely deteriorated causing heart failure and sudden death. Mechanistically, we show that upon physical stress, ELCs become phosphorylated and lack of S195 dominant-negatively impairs ELC phosphorylation. In vitro motility analysis with native myosin from adult heterozygous hearts demonstrates that S195 loss, specifically following physical stress, results in altered acto-myosin sliding velocities and myosin binding cooperativity, causing reduced force generation and organ dysfunction.
  
  
  
  Using adult heterozygous zebrafish, we show that ELC S195 phosphorylation is pivotal for adaptation of cardiac function to augmented physical stress and we provide novel mechanistic insights into the pathogenesis of ELC-linked cardiomyopathy.
authors.affiliation: Medical Biophysics Unit, Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Lisa-Mareike
authors.initials: LM
authors.lastname: Scheid
authors.affiliation: Medical Biophysics Unit, Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Matias
authors.initials: M
authors.lastname: Mosqueira
authors.affiliation: Department of Medicine III, Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Selina
authors.initials: S
authors.lastname: Hein
authors.affiliation: Department of Medicine III, Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Kossack
authors.affiliation: Department of Medicine III, Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Lonny
authors.initials: L
authors.lastname: Juergensen
authors.affiliation: Department of Medicine III, Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Department of Medicine III, Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Medical Biophysics Unit, Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Rainer H A
authors.initials: RH
authors.lastname: Fink
authors.affiliation: Department of Medicine III, Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Medicine III, Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany david.hassel@med.uni-heidelberg.de.
authors.forename: David
authors.initials: D
authors.lastname: Hassel
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D030801:Animals, Genetically Modified; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006579:Heterozygote; D053580:Muscle Strength; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D013312:Stress, Physiological; D013997:Time Factors; D016276:Ventricular Function; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C532158:Cmlc1 protein, zebrafish; D018994:Myosin Light Chains; D029961:Zebrafish Proteins
keywords: Animal models of human disease; Functional genomics; Genetics of cardiovascular disease; Myocardial cardiomyopathy disease