Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance
Author
Slater, Rebecca EStrom, Joshua G
Methawasin, Mei
Liss, Martin
Gotthardt, Michael
Sweitzer, Nancy
Granzier, Henk L
Affiliation
Univ Arizona, Dept Cellular & Mol MedUniv Arizona, Coll Med, Sarver Heart Ctr
Issue Date
2019-01-07
Metadata
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ROCKEFELLER UNIV PRESSCitation
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 PHYSIOLOGYRights
© 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
1540-7748PubMed ID
30567709Version
Final published versionSponsors
National Institutes of Health [HL062881, HL118524]; Fondation Leducq [TNE-13CVD04]; European Research Council [StG282078, T32GM084905]Additional Links
http://jgp.rupress.org/content/151/1/42ae974a485f413a2113503eed53cd6c53
10.1085/jgp.201812259