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

Rebecca E. Slater, Joshua G. Strom, Mei Methawasin, Martin Liss, Michael Gotthardt, Nancy K Sweitzer, Hendrikus "Henk" Granzier

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 lower 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.

Original languageEnglish (US)
Pages (from-to)42-52
Number of pages11
JournalThe Journal of general physiology
Volume151
Issue number1
DOIs
StatePublished - Jan 7 2019

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Connectin
Metformin
Compliance
Heart Failure
Desoxycorticosterone
Constriction
Acetates
Muscles
Phosphorylation
Phospho-Specific Antibodies
Exercise
Mechanics
Left Ventricular Function
Echocardiography
Therapeutics

ASJC Scopus subject areas

  • Physiology

Cite this

Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance. / Slater, Rebecca E.; Strom, Joshua G.; Methawasin, Mei; Liss, Martin; Gotthardt, Michael; Sweitzer, Nancy K; Granzier, Hendrikus "Henk".

In: The Journal of general physiology, Vol. 151, No. 1, 07.01.2019, p. 42-52.

Research output: Contribution to journalArticle

Slater, Rebecca E. ; Strom, Joshua G. ; Methawasin, Mei ; Liss, Martin ; Gotthardt, Michael ; Sweitzer, Nancy K ; Granzier, Hendrikus "Henk". / Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance. In: The Journal of general physiology. 2019 ; Vol. 151, No. 1. pp. 42-52.
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