Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Age-Related Cardiac Dysfunction: Hope for Better Aging?

Paola C Rosas; Chad M Warren; Heidi A Creed; Jerome P Trzeciakowski; R John Solaro; Carl W Tong

doi:10.1016/j.jacbts.2019.06.003

Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Age-Related Cardiac Dysfunction: Hope for Better Aging?

JACC Basic Transl Sci. 2019 Oct 16;4(7):817-830. doi: 10.1016/j.jacbts.2019.06.003. eCollection 2019 Nov.

Authors

Paola C Rosas¹, Chad M Warren¹, Heidi A Creed², Jerome P Trzeciakowski², R John Solaro¹, Carl W Tong^{2

3}

Affiliations

¹ Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
² Department of Medical Physiology, Texas A and M University Health Science Center, College of Medicine, College Station, Texas.
³ Catholic Health Initiatives-St. Joseph Health, Bryan, Texas.

Abstract

Cardiac myosin binding protein-C (cMyBP-C) phosphorylation prevents aging-related cardiac dysfunction. We tested this hypothesis by aging genetic mouse models of hypophosphorylated cMyBP-C, wild-type equivalent, and phosphorylated-mimetic cMyBP-C for 18 to 20 months. Phosphorylated-mimetic cMyBP-C mice exhibited better survival, better preservation of systolic and diastolic functions, and unchanging wall thickness. Wild-type equivalent mice showed decreasing cMyBP-C phosphorylation along with worsening cardiac function and hypertrophy approaching those found in hypophosphorylated cMyBP-C mice. Intact papillary muscle experiments suggested that cMyBP-C phosphorylation increased cross-bridge detachment rates as the underlying mechanism. Thus, phosphorylating cMyBP-C is a novel mechanism with potential to treat aging-related cardiac dysfunction.

Keywords: 3SA, mutated 3 serines to 3 alanines to mimic hypophosphorylated cardiac myosin binding protein-C (S273A, S282A, and S302A); 3SD, mutated 3 serines to 3 aspartic acids to mimic phosphorylated cMyBP-C (S273D, S282D, and S302D); ANOVA, analysis of variance; EF, ejection fraction; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HOP, hydroxyproline; LV, left ventricular; aging; cMyBP-C, cardiac myosin binding protein-C; cTnI, cardiac troponin I; cardiac myosin binding protein-C; dyastolic dysfunction; heart failure; phosphorylation.

Abstract

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