{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:25:02Z","timestamp":1785803102473,"version":"3.56.0"},"reference-count":22,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Commission, Framework Programme 7","award":["EU 602405-2"],"award-info":[{"award-number":["EU 602405-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) shows diverse disease patterns, with various combinations of comorbidities and symptoms. A common hallmark is exercise intolerance, caused by alterations in the peripheral skeletal muscle (SKM) including a recently indicated titin hyperphosphorylation. Our aim is to compare a metabolic syndrome- (ZSF-1 rats) and a hypertension-driven (Dahl salt-sensitive (DSS) rats) HFpEF rat-model in relation to SKM function and titin phosphorylation. Obese ZSF-1 and high-salt fed DSS rats (HFpEF) were compared to lean ZSF-1 and low-salt fed rats (con). HFpEF was confirmed by echocardiography and invasive haemodynamic measurements. SKM atrophy, in vitro force measurements, titin- and contractile protein expression were evaluated. Obese ZSF-1 HFpEF rats showed muscle atrophy, reduced muscle force and increased titin phosphorylation compared to controls, which was not detected in hypertensive DSS rats. Fiber type specific troponins, myostatin and four and a half LIM domain 1 were differently regulated between the two models. Altogether, our results show that both animal models of HFpEF exhibit different SKM phenotypes, probably based on the divergent disease etiologies, which may help to define the most suitable animal model for HFpEF to test potential treatment regimens.<\/jats:p>","DOI":"10.3390\/ijms26136196","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Skeletal Muscle Alterations in Different Phenotypes of Heart Failure with Preserved Ejection Fraction"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8110-1943","authenticated-orcid":false,"given":"Beatrice","family":"Vahle","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, University Clinic, Department of Internal Medicine, Heart Center, University of Technology Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy","family":"Kl\u00e4dtke","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, University Clinic, Department of Internal Medicine, Heart Center, University of Technology Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Schauer","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, University Clinic, Department of Internal Medicine, Heart Center, University of Technology Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1740-2474","authenticated-orcid":false,"given":"T. Scott","family":"Bowen","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-3587","authenticated-orcid":false,"given":"Ulrik","family":"Wisl\u00f8ff","sequence":"additional","affiliation":[{"name":"Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, 7006 Trondheim, Norway"},{"name":"Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Linke","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, University Clinic, Department of Internal Medicine, Heart Center, University of Technology Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7955-7324","authenticated-orcid":false,"given":"Volker","family":"Adams","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, University Clinic, Department of Internal Medicine, Heart Center, University of Technology Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1093\/eurheartj\/ehz641","article-title":"How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)","volume":"40","author":"Pieske","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/ejhf.1621","article-title":"Phenomapping of patients with heart failure with preserved ejection fraction using machine learning-based unsupervised cluster analysis","volume":"22","author":"Segar","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1093\/cvr\/cvab328","article-title":"Titin (TTN): From molecule to modifications, mechanics, and medical significance","volume":"118","author":"Loescher","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1016\/j.jacc.2019.01.072","article-title":"Exercise Intolerance in Patients With Heart Failure: JACC State-of-the-Art Review","volume":"73","author":"Arena","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Vahle, B., Heilmann, L., Schauer, A., Augstein, A., Jarabo, M.-E.P., Barthel, P., Mangner, N., Labeit, S., Bowen, T.S., and Linke, A. (2024). Modulation of Titin and Contraction-Regulating Proteins in a Rat Model of Heart Failure with Preserved Ejection Fraction: Limb vs. Diaphragmatic Muscle. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126618"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/ehf2.13142","article-title":"Muscular changes in animal models of heart failure with preserved ejection fraction: What comes closest to the patient?","volume":"8","author":"Goto","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"120998","DOI":"10.1016\/j.lfs.2022.120998","article-title":"Acetylation and phosphorylation changes to cardiac proteins in experimental HFpEF due to metabolic risk reveal targets for treatment","volume":"309","author":"Koser","year":"2022","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/387083a0","article-title":"Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member","volume":"387","author":"McPherron","year":"1997","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7479","DOI":"10.1073\/pnas.0811129106","article-title":"Muscle hypertrophy driven by myostatin blockade does not require stem\/precursor-cell activity","volume":"106","author":"Amthor","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.fob.2015.08.011","article-title":"FHL1 activates myostatin signalling in skeletal muscle and promotes atrophy","volume":"5","author":"Lee","year":"2015","journal-title":"FEBS Open Bio"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.ajhg.2009.07.015","article-title":"Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy","volume":"85","author":"Gueneau","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rasmussen, M., and Jin, J.-P. (2021). Troponin Variants as Markers of Skeletal Muscle Health and Diseases. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.747214"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1097\/HCO.0000000000000824","article-title":"Skeletal muscle (dys)function in heart failure with preserved ejection fraction","volume":"36","author":"Saw","year":"2021","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/ejhf.239","article-title":"Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle","volume":"17","author":"Bowen","year":"2015","journal-title":"Eur. J. Heart Fail."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Stolina, M., Luo, X., Dwyer, D., Han, C.-Y., Chen, R., Zhang, Y., Xiong, Y., Chen, Y., Yin, J., and Shkumatov, A. (2020). The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15. PLoS ONE, 15.","DOI":"10.1101\/2020.03.20.000307"},{"key":"ref_16","unstructured":"Watson, R.R., and Dokken, B. (2014). Chapter 14\u2014Animal Models of Diabetic Cardiomyopathy. Glucose Intake and Utilization in Pre-Diabetes and Diabetes: Implications for Cardiovascular Disease, Elsevier. [1st ed.]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1161\/01.HYP.0000022880.45113.C9","article-title":"High-salt diet enhances insulin signaling and induces insulin resistance in Dahl salt-sensitive rats","volume":"40","author":"Ogihara","year":"2002","journal-title":"Hypertension"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nogueira-Ferreira, R., Santos, I., Ferreira, R., Fontoura, D., Sousa-Mendes, C., Falc\u00e3o-Pires, I., Louren\u00e7o, A.P., Leite-Moreira, A., Duarte, I.F., and Moreira-Gon\u00e7alves, D. (2023). Exercise training impacts skeletal muscle remodelling induced by metabolic syndrome in ZSF1 rats through metabolism regulation. Biochim. Biophys. Acta Mol. Basis Dis., 1869.","DOI":"10.1016\/j.bbadis.2023.166709"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Winzer, E.B., Schauer, A., Langner, E., Augstein, A., Goto, K., M\u00e4nnel, A., Barthel, P., Jannasch, A., Labeit, S., and Mangner, N. (2022). Empagliflozin Preserves Skeletal Muscle Function in a HFpEF Rat Model. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231910989"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.ahj.2014.07.008","article-title":"Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population","volume":"168","author":"Cheng","year":"2014","journal-title":"Am. Heart J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.jacc.2007.04.064","article-title":"Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: A report from the OPTIMIZE-HF Registry","volume":"50","author":"Fonarow","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.mex.2017.09.007","article-title":"Detection and quantification of the giant protein titin by SDS-agarose gel electrophoresis","volume":"4","author":"Zhu","year":"2017","journal-title":"MethodsX"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6196\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:59:57Z","timestamp":1760032797000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,27]]},"references-count":22,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136196"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136196","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,27]]}}}