title: Cardiac myosin-binding protein-C phosphorylation and cardiac function.
abstract: The role of cardiac myosin binding protein-C (cMyBP-C) phosphorylation in cardiac physiology or pathophysiology is unclear. To investigate the status of cMyBP-C phosphorylation in vivo, we determined its phosphorylation state in stressed and unstressed mouse hearts. cMyBP-C phosphorylation is significantly decreased during the development of heart failure or pathologic hypertrophy. We then generated transgenic (TG) mice in which the phosphorylation sites of cMyBP-C were changed to nonphosphorylatable alanines (MyBP-C(AllP-)). A TG line showing &40% replacement with MyBP-C(AllP-) showed no changes in morbidity or mortality but displayed depressed cardiac contractility, altered sarcomeric structure and upregulation of transcripts associated with a hypertrophic response. To explore the effect of complete replacement of endogenous cMyBP-C with MyBP-C(AllP-), the mice were bred into the MyBP-C(t/t) background, in which less than 10% of normal levels of a truncated MyBP-C are present. Although MyBP-C(AllP-) was incorporated into the sarcomere and expressed at normal levels, the mutant protein could not rescue the MyBP-C(t/t) phenotype. The mice developed significant cardiac hypertrophy with myofibrillar disarray and fibrosis, similar to what was observed in the MyBP-C(t/t) animals. In contrast, when the MyBP-C(t/t) mice were bred to a TG line expressing normal MyBP-C (MyBP-CWT), the MyBP-C(t/t) phenotype was rescued. These data suggest that cMyBP-C phosphorylation is essential for normal cardiac function.
authors.affiliation: Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH, USA.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
authors.forename: James
authors.initials: J
authors.lastname: Gulick
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Martin
authors.forename: Harvey S
authors.initials: HS
authors.lastname: Hahn
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Raisa
authors.initials: R
authors.lastname: Klevitsky
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism; D002352:Carrier Proteins; D004452:Echocardiography; D005355:Fibrosis; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D010766:Phosphorylation; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D008840:Microfilament Proteins; D000099163:Myosin Binding Protein C