| Autor: |
Ochala J; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Lewis CTA; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Beck T; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Iwamoto H; SPring-8, Japan Synchrotron Radiation Research Institute, Hyogo, Japan., Hessel AL; Institute of Physiology II, University of Muenster, Muenster, Germany.; Accelerated Muscle Biotechnologies, Boston, Massachusetts, United States., Campbell KS; Department of Physiology, University of Kentucky, Lexington, Kentucky, United States.; Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, United States., Pyle WG; IMPART Investigator Team, Dalhousie Medicine, Saint John, New Brunswick, Canada.; Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada. |
| Abstrakt: |
Dilated cardiomyopathy (DCM) is a naturally occurring heart failure condition in humans and dogs, notably characterized by a reduced contractility and ejection fraction. As the identification of its underlying cellular and molecular mechanisms remain incomplete, the aim of the present study was to assess whether the molecular motor myosin and its known relaxed conformational states are altered in DCM. For that, we dissected and skinned thin cardiac strips from left ventricle obtained from six DCM Doberman Pinschers and six nonfailing (NF) controls. We then used a combination of Mant-ATP chase experiments and X-ray diffraction to assess both energetic and structural changes of myosin. Using the Mant-ATP chase protocol, we observed that in DCM dogs, the amount of myosin molecules in the ATP-conserving conformational state, also known as superrelaxed (SRX), is significantly increased when compared with NF dogs. This alteration can be rescued by applying EMD-57033, a small molecule activating myosin. Conversely, with X-ray diffraction, we found that in DCM dogs, there is a higher proportion of myosin heads in the vicinity of actin when compared with NF dogs (1,0 to 1,1 intensity ratio). Hence, we observed an uncoupling between energetic (Mant-ATP chase) and structural (X-ray diffraction) data. Taken together, these results may indicate that in the heart of Doberman Pinschers with DCM, myosin molecules are potentially stuck in a nonsequestered but ATP-conserving SRX state, that can be counterbalanced by EMD-57033 demonstrating the potential for a myosin-centered pharmacological treatment of DCM. NEW & NOTEWORTHY The key finding of the present study is that, in left ventricles of dogs with a naturally occurring dilated cardiomyopathy, relaxed myosin molecules favor a nonsequestered superrelaxed state potentially impairing sarcomeric contractility. This alteration is rescuable by applying a small molecule activating myosin known as EMD-57033. |
