Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure models
Abstract Cardiac myosin binding protein-C (cMyBP-C) is an important regulator of sarcomeric function. Reduced phosphorylation of cMyBP-C has been linked to compromised contractility in heart failure patients. Here, we used previously published cMyBP-C peptides 302A and 302S, surrogates of the regula...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-08169-1 |
| _version_ | 1818320930561064960 |
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| author | Luqia Hou Mohit Kumar Priti Anand Yinhong Chen Nesrine El-Bizri Chad J. Pickens W. Michael Seganish Sakthivel Sadayappan Gayathri Swaminath |
| author_facet | Luqia Hou Mohit Kumar Priti Anand Yinhong Chen Nesrine El-Bizri Chad J. Pickens W. Michael Seganish Sakthivel Sadayappan Gayathri Swaminath |
| author_sort | Luqia Hou |
| collection | DOAJ |
| description | Abstract Cardiac myosin binding protein-C (cMyBP-C) is an important regulator of sarcomeric function. Reduced phosphorylation of cMyBP-C has been linked to compromised contractility in heart failure patients. Here, we used previously published cMyBP-C peptides 302A and 302S, surrogates of the regulatory phosphorylation site serine 302, as a tool to determine the effects of modulating the dephosphorylation state of cMyBP-C on cardiac contraction and relaxation in experimental heart failure (HF) models in vitro. Both peptides increased the contractility of papillary muscle fibers isolated from a mouse model expressing cMyBP-C phospho-ablation (cMyBP-CAAA) constitutively. Peptide 302A, in particular, could also improve the force redevelopment rate (k tr) in papillary muscle fibers from cMyBP-CAAA (nonphosphorylated alanines) mice. Consistent with the above findings, both peptides increased ATPase rates in myofibrils isolated from rats with myocardial infarction (MI), but not from sham rats. Furthermore, in the cMyBP-CAAA mouse model, both peptides improved ATPase hydrolysis rates. These changes were not observed in non-transgenic (NTG) mice or sham rats, indicating the specific effects of these peptides in regulating the dephosphorylation state of cMyBP-C under the pathological conditions of HF. Taken together, these studies demonstrate that modulation of cMyBP-C dephosphorylation state can be a therapeutic approach to improve myosin function, sarcomere contractility and relaxation after an adverse cardiac event. Therefore, targeting cMyBP-C could potentially improve overall cardiac performance as a complement to standard-care drugs in HF patients. |
| first_indexed | 2024-12-13T10:32:50Z |
| format | Article |
| id | doaj.art-b15ebb87cdaf439295dcec183101f5d9 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T10:32:50Z |
| publishDate | 2022-03-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-b15ebb87cdaf439295dcec183101f5d92022-12-21T23:50:47ZengNature PortfolioScientific Reports2045-23222022-03-0112111410.1038/s41598-022-08169-1Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure modelsLuqia Hou0Mohit Kumar1Priti Anand2Yinhong Chen3Nesrine El-Bizri4Chad J. Pickens5W. Michael Seganish6Sakthivel Sadayappan7Gayathri Swaminath8Cardiometabolic Department, Merck & Co., Inc.Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of CincinnatiCardiometabolic Department, Merck & Co., Inc.Cardiometabolic Department, Merck & Co., Inc.Cardiometabolic Department, Merck & Co., Inc.Analytical R&D, Merck & Co., Inc.Discovery Chemistry, Merck & Co., Inc.Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of CincinnatiCardiometabolic Department, Merck & Co., Inc.Abstract Cardiac myosin binding protein-C (cMyBP-C) is an important regulator of sarcomeric function. Reduced phosphorylation of cMyBP-C has been linked to compromised contractility in heart failure patients. Here, we used previously published cMyBP-C peptides 302A and 302S, surrogates of the regulatory phosphorylation site serine 302, as a tool to determine the effects of modulating the dephosphorylation state of cMyBP-C on cardiac contraction and relaxation in experimental heart failure (HF) models in vitro. Both peptides increased the contractility of papillary muscle fibers isolated from a mouse model expressing cMyBP-C phospho-ablation (cMyBP-CAAA) constitutively. Peptide 302A, in particular, could also improve the force redevelopment rate (k tr) in papillary muscle fibers from cMyBP-CAAA (nonphosphorylated alanines) mice. Consistent with the above findings, both peptides increased ATPase rates in myofibrils isolated from rats with myocardial infarction (MI), but not from sham rats. Furthermore, in the cMyBP-CAAA mouse model, both peptides improved ATPase hydrolysis rates. These changes were not observed in non-transgenic (NTG) mice or sham rats, indicating the specific effects of these peptides in regulating the dephosphorylation state of cMyBP-C under the pathological conditions of HF. Taken together, these studies demonstrate that modulation of cMyBP-C dephosphorylation state can be a therapeutic approach to improve myosin function, sarcomere contractility and relaxation after an adverse cardiac event. Therefore, targeting cMyBP-C could potentially improve overall cardiac performance as a complement to standard-care drugs in HF patients.https://doi.org/10.1038/s41598-022-08169-1 |
| spellingShingle | Luqia Hou Mohit Kumar Priti Anand Yinhong Chen Nesrine El-Bizri Chad J. Pickens W. Michael Seganish Sakthivel Sadayappan Gayathri Swaminath Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure models Scientific Reports |
| title | Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure models |
| title_full | Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure models |
| title_fullStr | Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure models |
| title_full_unstemmed | Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure models |
| title_short | Modulation of myosin by cardiac myosin binding protein-C peptides improves cardiac contractility in ex-vivo experimental heart failure models |
| title_sort | modulation of myosin by cardiac myosin binding protein c peptides improves cardiac contractility in ex vivo experimental heart failure models |
| url | https://doi.org/10.1038/s41598-022-08169-1 |
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