Phosphorylation of cardiac Myosin-binding protein-C is a critical mediator of diastolic function
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Background—: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for ≈50% of all cases of HF and currently has no effective treatment. Diastolic dysfunction underlies HFpEF; therefore, elucidation of the mechanisms that mediate relaxation can provide new potential targets for treatment. Cardiac myosin-binding protein-C (cMyBP-C) is a thick filament protein that modulates cross-bridge cycling rates via alterations in its phosphorylation status. Thus, we hypothesize that phosphorylated cMyBP-C accelerates the rate of cross-bridge detachment, thereby enhancing relaxation to mediate diastolic function. Methods and Results—: We compared mouse models expressing phosphorylation-deficient cMyBP-C(S273A/S282A/S302A)–cMyBP-C(t3SA), phosphomimetic cMyBP-C(S273D/S282D/S302D)–cMyBP-C(t3SD), and wild-type-control cMyBP-C(tWT) to elucidate the functional effects of cMyBP-C phosphorylation. Decreased voluntary running distances, increased lung/body weight ratios, and increased brain natriuretic peptide levels in cMyBP-C(t3SA) mice demonstrate that phosphorylation deficiency is associated with signs of HF. Echocardiography (ejection fraction and myocardial relaxation velocity) and pressure/volume measurements (−d P /d t min , pressure decay time constant τ -Glantz, and passive filling stiffness) show that cMyBP-C phosphorylation enhances myocardial relaxation in cMyBP-C(t3SD) mice, whereas deficient cMyBP-C phosphorylation causes diastolic dysfunction with HFpEF in cMyBP-C(t3SA) mice. Simultaneous force and [Ca 2+ ] i measurements on intact papillary muscles show that enhancement of relaxation in cMyBP-C(t3SD) mice and impairment of relaxation in cMyBP-C(t3SA) mice are not because of altered [Ca 2+ ] i handling, implicating that altered cross-bridge detachment rates mediate these changes in relaxation rates. Conclusions—: cMyBP-C phosphorylation enhances relaxation, whereas deficient phosphorylation causes diastolic dysfunction and phenotypes resembling HFpEF. Thus, cMyBP-C is a potential target for treatment of HFpEF.
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The excised MYBPC3 region spans 2 of 3 clustered phosphorylatable serines (S275, S284, and S304) that are key regulatory sites in MYBPC3 targeted by protein kinase A (PKA).
“Moreover, the region spans 2 of 3 clustered phosphorylatable serines (S275, S284, and S304) that are key regulatory sites in MYBPC3 targeted by protein kinase A (PKA) (Figure 5A).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Rosas et al., 2015
Phosphorylation of S275, S284, and S304 in MYBPC3 by PKA and other kinases causes the MYBPC3 N-terminal domain to dissociate from myosin heavy chain and increase cardiac crossbridge formation.
“The phosphorylation of S275, S284, and S304 in MYBPC3 by PKA and other kinases causes the MYBPC3 N-terminal domain to dissociate from myosin heavy chain and, hence, increase cardiac crossbridge formation (Rosas et al., 2015).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Rosas et al., 2015
Mutagenesis replacement of these serines with phosphonegative mimetic alanines in animal models led to hearts with abnormal relaxation velocity but not ejection fraction, suggesting the sites may function in diastolic regulation.
“Mutagenesis replacement of these serines with phosphonegative mimetic alanines in animal models led to hearts with abnormal relaxation velocity but not ejection fraction (Rosas et al., 2015), suggesting the sites may function in diastolic regulation.”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Rosas et al., 2015
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Cardiac myosin-binding protein-C is a critical mediator of diastolic function
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Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome
Lau, E., Han, Y., Williams, D. R., Thomas, C. T., Shrestha, R., Wu, J. C., & Lam, M. P. Y. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.026 · Cited by 67 · see citing works
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- Authors
- Rosas, P. C., Liu, Y., Abdalla, M. I., Thomas, C. M., Kidwell, D. T., Dusio, G. F., Mukhopadhyay, D., Kumar, R., Baker, K. M., Mitchell, B. M., Powers, P. A., Fitzsimons, D. P., Patel, B. G., Warren, C. M., Solaro, R. J., Moss, R. L., & Tong, C. W.
- Affiliations
- Texas A&M Health Science Center (US)
- ORCID
- Venue
- Circulation: Heart Failure
- Published
- 2015-05
- Volume
- 8
- Issue
- 3
- Pages
- 582-594
- ISSN
- 1941-3289 (ISSN-L)
- 1941-3297
- PMC
- PMC4447128
- OpenAlex
- W2121747051
- Cited by
- 112
- References
- 52
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 12 · 2023: 8 · 2022: 6 · 2021: 15 · 2020: 13 · 2019: 12 · 2018: 11 · 2017: 6 · 2016: 9 · 2015: 10
- FWCI
- 8.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Heart Failure (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Texas A and M University
- National Institutes of Health (5p01hl094291-05)
- National Heart, Lung, and Blood Institute (R37HL082900, K08HL114877, R37 HL82900, P01‑HL094291, P01HL062426)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- myosin binding protein C, phosphorylation, diastolic dysfunction, heart failure with preserved ejection fraction, myocardial relaxation, cross-bridge detachment, thick filaments, phosphomimetic mutant, calcium handling, papillary muscle, brain natriuretic peptide
- MeSH terms
- Myosin Binding Protein C, Animals, Blood Pressure, Carrier Proteins, Diastole, Genotype, Heart Failure, Kinetics, Mice, Transgenic, Mutation, Phenotype, Phosphorylation, Protein Processing, Post-Translational, Ventricular Function, Left, Cyclic AMP-Dependent Protein Kinases, Ventricular Dysfunction, Left
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