Heart failure is a widespread chronic condition that directly impacts nearly six million Americans, contributes to almost one in ten deaths in the United States, and drains an estimated $30 billion annually from our national economy. Current treatments can slow progression of heart failure, but do not address the underlying issues, including the problem that causes systolic heart failure, the inability of the heart to pump blood throughout the body at normal levels.
Cardiac muscle contraction – the force that enables the heart to pump blood – is generated by interactions between actin and myosin, proteins that power movement at the molecular level by converting the molecule ATP into energy. Previous research from Dr. Mike Regnier’s lab has shown that dATP (a natural variant of ATP) can be used to promote stronger heart function, but there is a pressing need for data to explain why dATP helps to increase contractile force in heart disease.
Now, a recently-published study led by Dr. Regnier, Professor of Bioengineering, faculty member at the Institute for Stem Cell and Regenerative Medicine (ISCRM), and Director of the UW Center for Translational Muscle Research, offers new insights about the nature of dATP with unprecedented precision. The results are detailed in an article, authored by graduate student Joe Powers, appearing in the latest issue of the journal PNAS.
The research team, which includes scientists from the University of Washington, the University of California San Diego, the Illinois Institute of Technology and the Argonne National Laboratory hypothesized that dATP essentially plays the role of matchmaker. “Myosin and actin are attracted to each other by electrostatic charges,” explains Regnier, referring to the electrical force that brings two oppositely-charged objects together. “Our hunch was that dATP enhances the initial attraction between these two critical muscle proteins, leading to stronger contractions.”
By developing new experimental and computational approaches, the research team was able to show how small changes in protein structure translate to improvements in performance at multiple scales – specifically, at the whole muscle, muscle cell, and the molecular levels, leading to a more holistic picture of the mechanisms behind dATP-augmented cardiac contractile force.
Regnier explains the key takeaways from the study. “A key finding was that small changes on the surface of myosin that occur when dATP is used enhance its ability to bind with actin. This suggests the structure of myosin can be optimized, opening the door to possible new therapies to improve contraction of weakened heart muscle. Thus, this report offers a novel approach and a new standard for design and characterization of future cardiac therapeutics for systolic heart failure.”
ACKNOWLEDGMENTS. This work was supported by NIH Grants R01 HL128368 and R56 AG055594 (to M.R.), NIH Grant U01 HL122199 (to M.R. and A.D.M.), NIH Grant T32-HL007312 (to J.D.P.), a Sackler Scholars Program Fellowship in Integrative Biophysics (to C.-C.Y.), NIH Grant T32-HL105373 (to K.J.M.), NIH Grant K08 HL128826 (to F.M.-H.), and NIH/NIBIB Q:21 Grant T32EB1650 (to J.D.M.). This project was supported by Grants 9 P41 GM103622 and 8 P41 GM103426 from the National Institute of General Medical Sciences of the NIH. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under Contract DE-AC02-06CH11357.