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dc.contributor.authorSlater, Rebecca E
dc.contributor.authorStrom, Joshua G
dc.contributor.authorMethawasin, Mei
dc.contributor.authorLiss, Martin
dc.contributor.authorGotthardt, Michael
dc.contributor.authorSweitzer, Nancy
dc.contributor.authorGranzier, Henk L
dc.date.accessioned2019-06-05T22:59:01Z
dc.date.available2019-06-05T22:59:01Z
dc.date.issued2019-01-07
dc.identifier.citationSlater, R. E., Strom, J. G., Methawasin, M., Liss, M., Gotthardt, M., Sweitzer, N., & Granzier, H. L. (2019). Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance. The Journal of general physiology, 151(1), 42-52.en_US
dc.identifier.issn1540-7748
dc.identifier.pmid30567709
dc.identifier.doi10.1085/jgp.201812259
dc.identifier.urihttp://hdl.handle.net/10150/632510
dc.description.abstractHeart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery with deoxycorticosterone acetate (DOCA) supplementation to obtain a mouse model with increased diastolic stiffness and exercise intolerance. Echocardiography and pressure-volume analysis reveal that providing metformin to TAC/DOCA mice improves diastolic function in the left ventricular (LV) chamber. Muscle mechanics show that metformin lowers passive stiffness of the LV wall muscle. Concomitant with this improvement in diastolic function, metformin-treated TAC/DOCA mice also demonstrate preserved exercise capacity. No metformin effects are seen in sham operated mice. Extraction experiments on skinned ventricular muscle strips show that the metformin-induced reduction of passive stiffness in TAC/DOCA mice is due to an increase in titin compliance. Using phospho-site-specific antibodies, we assay the phosphorylation of titin's PEVK and N2B spring elements. Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to tower titin's stiffness. Consistent with this result, experiments with a mouse model deficient in the N2B element reveal that the beneficial effect of metformin on LV chamber and muscle stiffness requires the presence of the N2B element. We conclude that metformin offers therapeutic benefit during HFpEF by lowering titin-based passive stiffness.en_US
dc.description.sponsorshipNational Institutes of Health [HL062881, HL118524]; Fondation Leducq [TNE-13CVD04]; European Research Council [StG282078, T32GM084905]en_US
dc.language.isoenen_US
dc.publisherROCKEFELLER UNIV PRESSen_US
dc.relation.urlhttp://jgp.rupress.org/content/151/1/42en_US
dc.rights© 2018 Slater et al.en_US
dc.titleMetformin improves diastolic function in an HFpEF-like mouse model by increasing titin complianceen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Cellular & Mol Meden_US
dc.contributor.departmentUniv Arizona, Coll Med, Sarver Heart Ctren_US
dc.identifier.journalJOURNAL OF GENERAL PHYSIOLOGYen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleThe Journal of general physiology
refterms.dateFOA2019-06-05T22:59:01Z


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