Author + information
- Received March 30, 2019
- Revision received June 14, 2019
- Accepted June 19, 2019
- Published online November 25, 2019.
- Paola C. Rosas, MD, PhD, BSPharma,∗ (, )
- Chad M. Warren, MSa,
- Heidi A. Creed, BSb,
- Jerome P. Trzeciakowski, PhDb,
- R. John Solaro, PhDa and
- Carl W. Tong, MD, PhDb,c,∗∗ ()
- aDepartment of Physiology and Biophysics, Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
- bDepartment of Medical Physiology, Texas A and M University Health Science Center, College of Medicine, College Station, Texas
- cCatholic Health Initiatives-St. Joseph Health, Bryan, Texas
- ↵∗Address for correspondence:
Dr. Paola C. Rosas, Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 South Wolcott Avenue, Chicago, Illinois 60612.
- ↵∗∗Dr. Carl W. Tong, Department of Medical Physiology, Texas A&M University, 8447 Riverside Parkway, RM 2346 MREB-2, Bryan, Texas 77807.
• With aging, phosphorylated-mimetic cMyBP-C mice exhibited better survival, better preservation of systolic and diastolic functions, and unchanging wall thickness compared with control mice.
• Aged wild-type equivalent mice exhibited decreasing cMyBP-C phosphorylation (S273 and S282) along with worsening cardiac function and hypertrophy similarly to what was observed in hypophosphorylated cMyBP-C mice.
• Intact papillary muscle experiments suggest that cMyBP-C phosphorylation increased cross-bridge detachment rates as the underlying mechanism.
• Phosphorylating cMyBP-C is therefore a novel mechanism that can prevent aging-related development of cardiac dysfunction.
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.
This work was supported by the American Heart Association (16POST29990013 to Dr. Rosas) and the National Heart, Lung, and Blood Institute of the National Institutes of Health (K08HL114877, R03HL140266, and R01HL145534 to Dr. Tong, and R01HL128468 and P01HL624026 to Dr. Solaro). Dr. Solaro is a consultant for Cytokinetics, Inc. and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received March 30, 2019.
- Revision received June 14, 2019.
- Accepted June 19, 2019.
- 2019 The Authors