Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose
Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong
Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong
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Research Article Cardiology Cell biology

Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose

Abstract

Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes–induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.

Authors

Jing Li, Bradley Richmond, Ahmad A. Cluntun, Ryan Bia, Maureen A. Walsh, Kikuyo Shaw, J. David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M. Shaw, TingTing Hong

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Figure 3

Exogenous cBIN1 normalizes GLUT4 expression at t-tubules.

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Exogenous cBIN1 normalizes GLUT4 expression at t-tubules. (A and B) Repr...
(A and B) Representative GLUT4 and IRAP confocal images in posttreatment isolated cardiomyocytes with corresponding fluorescence intensity profiles (A), and quantification of GLUT4 and IRAP peak power density (B) at t-tubules (n = 42–58 cells from 3 hearts). Scale bar: 10 μm. Data are presented as mean ± SEM. Kruskal-Wallis test followed by Dunn’s test was used for comparison between selected pairs. *, *** indicates P < 0.05, 0.001, respectively, for comparison versus db/m + GFP; ††† indicates P < 0.001 for comparison between db/db + GFP and db/db + cBIN1. (C and D) Intracellular distribution of GLUT4 and IRAP (peak power density analysis, n = 34–61 cells from 3 hearts) (C) and glucose uptake (D) following insulin (0 and 10 nM) stimulation in cardiomyocytes isolated from each group (n = 10–12 repeats from 4 animals per group). Metformin (Met; 20 μM) was included as a positive control treatment. Two-way ANOVA followed by Tukey’s (3 or more treatment groups) or Bonferroni’s test (2 insulin doses) was used for multiple comparison among groups. **, *** indicates P < 0.01, 0.001, respectively, for comparison versus db/m + GFP within the same insulin dose groups, and †, ††, ††† indicates P < 0.05, 0.01, 0.001, respectively, for comparison versus db/db + GFP within the same insulin dose groups. #, ##, ### indicates P < 0.05, 0.01, 0.001, respectively, for comparison of 10 nM insulin versus 0 insulin baseline within each therapeutic group.