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    Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance

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    Author
    Slater, Rebecca E
    Strom, Joshua G
    Methawasin, Mei
    Liss, Martin
    Gotthardt, Michael
    Sweitzer, Nancy
    Granzier, Henk L
    Affiliation
    Univ Arizona, Dept Cellular & Mol Med
    Univ Arizona, Coll Med, Sarver Heart Ctr
    Issue Date
    2019-01-07
    
    Metadata
    Show full item record
    Publisher
    ROCKEFELLER UNIV PRESS
    Citation
    Slater, 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.
    Journal
    JOURNAL OF GENERAL PHYSIOLOGY
    Rights
    © 2018 Slater et al.
    Collection Information
    This 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.
    Abstract
    Heart 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.
    ISSN
    1540-7748
    PubMed ID
    30567709
    DOI
    10.1085/jgp.201812259
    Version
    Final published version
    Sponsors
    National Institutes of Health [HL062881, HL118524]; Fondation Leducq [TNE-13CVD04]; European Research Council [StG282078, T32GM084905]
    Additional Links
    http://jgp.rupress.org/content/151/1/42
    ae974a485f413a2113503eed53cd6c53
    10.1085/jgp.201812259
    Scopus Count
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    UA Faculty Publications

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