Author + information
- Received January 4, 2019
- Revision received January 11, 2019
- Accepted January 26, 2019
- Published online April 29, 2019.
- Evelyne M. Houang, PhDa,∗,
- Jason Bartos, MDb,∗,
- Benjamin J. Hackel, PhDc,
- Timothy P. Lodge, PhDc,d,
- Demetris Yannopoulos, MDb,
- Frank S. Bates, ScDc and
- Joseph M. Metzger, PhDa,∗ ()
- aDepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota
- bDepartment of Medicine-Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota
- cDepartment of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota
- dDepartment of Chemistry, University of Minnesota, Minneapolis, Minnesota
- ↵∗Address for correspondence:
Dr. Joseph M. Metzger, Department of Integrative Biology and Physiology, University of Minnesota Medical School, 6-125 Jackson Hall, 321 Church Street Southeast, Minneapolis, Minnesota 55455.
• In myocardial ischemia, the integrity of the cardiac sarcolemma is severely stressed in the critical earliest moments upon reperfusion. Bolstering sarcolemma integrity improves myocyte survival.
• This review focuses on cardiac sarcolemma stability and its role as a therapeutic target in ischemia-reperfusion injury.
• Synthetic block copolymers have been shown to interface with the muscle membrane to confer membrane stabilization during stress.
• Integrated multidisciplinary research teams, spanning cardiology, physiology, chemistry, and chemical engineering are essential to guide future mechanistic and translational studies of novel chemical-based membrane stabilizers for preserving viable heart muscle during ischemia-reperfusion injury in human patients.
The phospholipid bilayer membrane that surrounds each cell in the body represents the first and last line of defense for preserving overall cell viability. In several forms of cardiac and skeletal muscle disease, deficits in the integrity of the muscle membrane play a central role in disease pathogenesis. In Duchenne muscular dystrophy, an inherited and uniformly fatal disease of progressive muscle deterioration, muscle membrane instability is the primary cause of disease, including significant heart disease, for which there is no cure or highly effective treatment. Further, in multiple clinical forms of myocardial ischemia-reperfusion injury, the cardiac sarcolemma is damaged and this plays a key role in disease etiology. In this review, cardiac muscle membrane stability is addressed, with a focus on synthetic block copolymers as a unique chemical-based approach to stabilize damaged muscle membranes. Recent advances using clinically relevant small and large animal models of heart disease are discussed. In addition, mechanistic insights into the copolymer-muscle membrane interface, featuring atomistic, molecular, and physiological structure-function approaches are highlighted. Collectively, muscle membrane instability contributes significantly to morbidity and mortality in prominent acquired and inherited heart diseases. In this context, chemical-based muscle membrane stabilizers provide a novel therapeutic approach for a myriad of heart diseases wherein the integrity of the cardiac muscle membrane is at risk.
↵∗ Drs. Houang and Bartos contributed equally to this work and are joint first authors.
Drs. Metzger and Yannopoulos have received grants from the National Institutes of Health. Dr. Metzger is on the scientific advisory board of and holds zero value equity shares in Phrixus Pharmaceuticals Inc., a company developing novel therapeutics for heart failure and DMD, and this is actively managed by the UMN Office of Institutional Compliance. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and U.S. Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received January 4, 2019.
- Revision received January 11, 2019.
- Accepted January 26, 2019.
- 2019 The Authors
- Central Illustration
- Overview: Cardiac Muscle Membrane Integrity and Heart Performance
- The Cardiac Membrane as a Direct Therapeutic Target in Myocardial I/R
- Myocardial I/R Injury Clinical Features
- Block Copolymers: First-in-Class Synthetic Muscle Membrane Stabilizers
- Copolymer-Based Membrane Stabilizers in Myocardial I/R Injury
- The Copolymer-Membrane Interface: Toward the Mechanism of Muscle Membrane Stabilization
- Summary and Future Opportunities