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 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 (ktr) 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.

• Authors: Luqia Hou, Mohit Kumar, Priti Anand, Yinhong Chen, Nesrine El-Bizri, Chad J Pickens, W Michael Seganish, Sakthivel Sadayappan, Gayathri Swaminath
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 4337 (03 14 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35288601 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Carrier Proteins
• Cytoskeletal Proteins
• Peptides
• Cardiac Myosins
• Myosins

Topics

• Animals
• Cardiac Myosins (metabolism)
• Carrier Proteins (metabolism)
• Cytoskeletal Proteins (metabolism)
• Heart Failure
• Humans
• Mice
• Myocardial Contraction (physiology)
• Myocardium (metabolism)
• Myosins (metabolism)
• Peptides (metabolism)
• Phosphorylation (physiology)
• Rats