Cardiac myosin-binding protein-C is a critical mediator of diastolic function.
Diastolic dysfunction prominently contributes to heart failure with preserved ejection fraction (HFpEF). Owing partly to inadequate understanding, HFpEF does not have any effective treatments. Cardiac myosin-binding protein-C (cMyBP-C), a component of the thick filament of heart muscle that can modulate cross-bridge attachment/detachment cycling process by its phosphorylation status, appears to be involved in the diastolic dysfunction associated with HFpEF. In patients, cMyBP-C mutations are associated with diastolic dysfunction even in the absence of hypertrophy. cMyBP-C deletion mouse models recapitulate diastolic dysfunction despite in vitro evidence of uninhibited cross-bridge cycling. Reduced phosphorylation of cMyBP-C is also associated with diastolic dysfunction in patients. Mouse models of reduced cMyBP-C phosphorylation exhibit diastolic dysfunction while cMyBP-C phosphorylation mimetic mouse models show enhanced diastolic function. Thus, cMyBP-C phosphorylation mediates diastolic function. Experimental results of both cMyBP-C deletion and reduced cMyBP-C phosphorylation causing diastolic dysfunction suggest that cMyBP-C phosphorylation level modulates cross-bridge detachment rate in relation to ongoing attachment rate to mediate relaxation. Consequently, alteration in cMyBP-C regulation of cross-bridge detachment is a key mechanism that causes diastolic dysfunction. Regardless of the exact molecular mechanism, ample clinical and experimental data show that cMyBP-C is a critical mediator of diastolic function. Furthermore, targeting cMyBP-C phosphorylation holds potential as a future treatment for diastolic dysfunction.
Department of Medical Physiology, Texas A&M Health Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX, 76504, USA, CTong@medicine.tamhsc.edu.
Carl W
CW
Tong
Nandini A
NA
Nair
Karen M
KM
Doersch
Yang
Y
Liu
Paola C
PC
Rosas
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003971:Diastole; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D000099163:Myosin Binding Protein C