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DCRL RESEARCH: Muscular changes in animal models of heart failure with preserved ejection fraction: what comes closest to the patient?

Keita Goto1, Antje Schauer1, Antje Augstein1, Mei Methawasin2, Henk Granzier2, Martin Halle3,4,
Emeline M Van Craenenbroeck5, Natale Rolim6, Stephan Gielen7, Burkert Pieske8, Ephraim B. Winzer1,
Axel Linke1,9 and Volker Adams1,9*
1Laboratory for Experimental and Molecular Cardiology, Department of Internal Medicine and Cardiology, TU Dresden, Heart Center Dresden University Hospital,
Fetscherstrasse 76, Dresden, 01307, Germany; 2Department of Cellular and Molecular Medicine, University of Arizona, Tucson, USA; 3Prevention and Sports Medicine,
Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; 4DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich,
Germany; 5Research group Cardiovascular Diseases, GENCOR Department, Antwerp University Hospital, Edegem, Belgium; 6Department of Circulation and Medical Imaging,
Faculty of Medicine, NTNU, K.G. Jebsen Center of Exercise in Medicine, Trondheim, Norway; 7Department of Cardiology, Angiology and Intensive Care, Klinikum Lippe,
Detmold, Germany; 8Department of Internal Medicine and Cardiology Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Berlin, Germany; 9Dresden
Cardiovascular Research Institute and Core Laboratories GmbH, Dresden, Germany
Abstract
Aims Heart failure with preserved ejection fraction (HFpEF) is associated with reduced exercise capacity elicited by skeletal
muscle (SM) alterations. Up to now, no clear medical treatment advice for HFpEF is available. Identification of the ideal animal
model mimicking the human condition is a critical step in developing and testing treatment strategies. Several HFpEF animals
have been described, but the most suitable in terms of comparability with SM alterations in HFpEF patients is unclear. The aim
of the present study was to investigate molecular changes in SM of three different animal models and to compare them with
alterations of muscle biopsies obtained from human HFpEF patients.
Methods and results Skeletal muscle tissue was obtained from HFpEF and control patients and from three different animal
models including the respective controls—ZSF1 rat, Dahl salt-sensitive rat, and transverse aortic constriction
surgery/deoxycorticosterone mouse. The development of HFpEF was verified by echocardiography. Protein expression and enzyme
activity of selected markers were assessed in SM tissue homogenates. Protein expression between SM tissue obtained
from HFpEF patients and the ZSF1 rats revealed similarities for protein markers involved in muscle atrophy (MuRF1 expression,
protein ubiquitinylation, and LC3) and mitochondrial metabolism (succinate dehydrogenase and malate dehydrogenase
activity, porin expression). The other two animal models exhibited far less similarities to the human samples.
Conclusions None of the three tested animal models mimics the condition in HFpEF patients completely, but among the
animal models tested, the ZSF1 rat (ZSF1-lean vs. ZSF1-obese) shows the highest overlap to the human condition. Therefore,
when studying therapeutic interventions to treat HFpEF and especially alterations in the SM, we suggest that the ZSF1 rat is a
suitable model.