Cardiac myosin-binding protein-C phosphorylation and cardiac function.
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.
Sadayappan
Sakthivel
S
Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH, USA.
Gulick
James
J
Osinska
Hanna
H
Martin
Lisa A
LA
Hahn
Harvey S
HS
Dorn
Gerald W
GW
Klevitsky
Raisa
R
Seidman
Christine E
CE
Seidman
Jonathan G
JG
Robbins
Jeffrey
J
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
D002352:Carrier Proteins; D008840:Microfilament Proteins; D000099163:Myosin Binding Protein C