Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys
Niranjana Natarajan, Ana Vujic, Jishnu Das, Annie C. Wang, Krystal K. Phu, Spencer H. Kiehm, Elisabeth M. Ricci-Blair, Anthony Y. Zhu, Kelli L. Vaughan, Ricki J. Colman, Julie A. Mattison, Richard T. Lee
Niranjana Natarajan, Ana Vujic, Jishnu Das, Annie C. Wang, Krystal K. Phu, Spencer H. Kiehm, Elisabeth M. Ricci-Blair, Anthony Y. Zhu, Kelli L. Vaughan, Ricki J. Colman, Julie A. Mattison, Richard T. Lee
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Research Article Aging Cardiology

Effect of dietary fat and sucrose consumption on cardiac fibrosis in mice and rhesus monkeys

Abstract

Calorie restriction (CR) improved health span in 2 longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce cardiac fibrosis relative to controls. However, there was a 5.9-fold increase of total fibrosis in UW hearts, compared with NIA hearts. Diet composition was a prominent difference between the studies; therefore, we used the NHP diets to characterize diet-associated molecular and functional changes in the hearts of mice. Consistent with the findings from the NHP samples, mice fed a UW or a modified NIA diet with increased sucrose and fat developed greater cardiac fibrosis compared with mice fed the NIA diet, and transcriptomics analysis revealed diet-induced activation of myocardial oxidative phosphorylation and cardiac muscle contraction pathways.

Authors

Niranjana Natarajan, Ana Vujic, Jishnu Das, Annie C. Wang, Krystal K. Phu, Spencer H. Kiehm, Elisabeth M. Ricci-Blair, Anthony Y. Zhu, Kelli L. Vaughan, Ricki J. Colman, Julie A. Mattison, Richard T. Lee

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Figure 1

In NHPs, cardiac fibrosis is more abundant in UW animals compared with those from NIA.

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In NHPs, cardiac fibrosis is more abundant in UW animals compared with t...
However, no significant difference in cardiac fibrosis was observed between control and CR samples in either cohort. (A) Representative Masson’s trichrome–stained NHP LV tissues from control and CR groups of the NIA and UW studies show greater extent of cardiac fibrosis in the UW cohort. Scale bar: 50 μm. (B) Cardiac fibrosis was not significantly affected by CR in the NIA and UW cohorts. P = n.s. (nonsignificant), and ***P < 0.001 by Kruskal-Wallis test followed by pairwise Mann-Whitney U tests with appropriate Bonferroni’s corrections to adjust for multiple comparisons. In the figure panel, pairwise significance/lack of significance is indicated based on P values from Mann-Whitney U test. (C) Percentage of myocardial area occupied by fibrosis was evaluated by sex and dietary regimen. Fibrosis within each study was not significantly different between control and CR groups when matched by sex. There was greater fibrosis in UW control and CR, compared with NIA cohorts. **P < 0.01; ***P < 0.001, by Kruskal-Wallis test followed by pairwise Mann-Whitney U tests with appropriate Bonferroni’s corrections to adjust for multiple comparisons. In the figure panel, pairwise significance/lack of significance is indicated based on P values from Mann-Whitney U test. (D) Total cardiac fibrosis was significantly greater in UW LVs compared with NIA. ***P < 0.001, Mann-Whitney U test. Scatter plots to represent the data are shown with median with interquartile range. n: NIA: total n = 42, (24 control [15 male, 9 female]; 18 CR [11 male, 7 female]); UW: total n = 49 (26 control [16 male, 10 female]; 23 CR [14 male, 9 female]). (E) Heatmap of normalized expression values of specific genes in NHP heart samples from NIA and UW studies as measured from NanoString experiments. Median normalized abundances of genes assayed are shown in rows, and the columns represent each of the 4 cohorts: NIA control, UW control, NIA CR, and UW CR. Significant differences and trends among the groups are indicated by yellow boxes around pairwise comparisons; *P < 0.05 pairwise 2-tailed t test with Benjamini-Hochberg FDR correction. n = 6 for all groups.