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

Paola C Rosas1, Chad M Warren1, Heidi A Creed2

  • 1Department of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.

JACC. Basic to Translational Science
|January 31, 2020
PubMed

Insights

Phosphorylating cardiac myosin binding protein-C (cMyBP-C) prevents age-related heart dysfunction. This study shows phosphorylated-mimetic cMyBP-C mice maintained better heart function and survival, suggesting a therapeutic target.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Aging Research

Background:

  • Aging leads to cardiac dysfunction, a significant health concern.
  • Cardiac myosin binding protein-C (cMyBP-C) is crucial for heart muscle contraction.
  • Phosphorylation of cMyBP-C is a potential regulator of cardiac function during aging.

Purpose of the Study:

  • To investigate whether cMyBP-C phosphorylation prevents aging-related cardiac dysfunction.
  • To determine the functional consequences of altered cMyBP-C phosphorylation in aging mouse models.

Main Methods:

  • Aging of genetic mouse models with hypophosphorylated, wild-type equivalent, and phosphorylated-mimetic cMyBP-C for 18-20 months.
  • Assessment of cardiac function, including systolic and diastolic parameters, and cardiac hypertrophy.
  • Intact papillary muscle experiments to elucidate the underlying molecular mechanisms.

Main Results:

  • Mice with phosphorylated-mimetic cMyBP-C showed improved survival, preserved systolic and diastolic functions, and stable wall thickness.
  • Wild-type equivalent mice exhibited decreased cMyBP-C phosphorylation with worsening cardiac function and hypertrophy.
  • Phosphorylation of cMyBP-C was linked to increased cross-bridge detachment rates.

Conclusions:

  • cMyBP-C phosphorylation is a key mechanism that prevents aging-related cardiac dysfunction.
  • Targeting cMyBP-C phosphorylation represents a novel therapeutic strategy for age-related heart disease.
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 varianceEF, ejection fractionHF, heart failureHFpEF, heart failure with preserved ejection fractionHOP, hydroxyprolineLV, left ventricularagingcMyBP-C, cardiac myosin binding protein-CcTnI, cardiac troponin Icardiac myosin binding protein-Cdyastolic dysfunctionheart failurephosphorylation

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