Myocardial glycogen depletion leads to improved left ventricular remodeling in a mouse MI model

Abstract

High glycogen (GLN) content is generally considered deleterious in prolonged ischemia, however, the exact role of GLN during permanent myocardial infarction (MI) and left ventricular (LV) remodeling post-MI, remains poorly understood. This study aimed to investigate whether myocardial GLN depletion can attenuate adverse LV remodeling post-MI. We used a transgenic knock-in (KI) mouse, in which the allosteric pathway of GLN synthesis is inhibited in muscle, leading to dramatically suppressed myocardial GLN levels. WT and KI male mice (10–12 weeks old) were subjected to MI by left anterior descending (LAD) coronary artery permanent ligation. Heart function was measured by 2D-echo (Vevo 2100, Visualsonics). Mice were sacrificed 56 days post-MI and hearts were collected to measure myocardial GLN content and perform IHC and mRNA studies. Basal GLN content was dramatically depressed in KI hearts. We demonstrated a robustly reduced LV dilatation in KI mice 56 days post-MI, as evidenced by lower end-diastolic volume (WT: 167.69 ± 13.42 vs KI: 138.00 ± 4.62 μl; P < 0.05) and end-systolic volume (WT: 147.62 ± 14.58 vs KI: 123.15 ± 4.05 μl; P < 0.05). Moreover, KI mice exhibited attenuated global LV fibrosis (WT: 61.69 ± 11.10 vs KI: 37.42 ± 6.90%; P < 0.05) and a significant decrease in border zone fibrosis (WT: 58.59 ± 12.11 vs KI: 30.33 ± 4.94%; P < 0.05). Surprisingly, KI MI mice demonstrated a dramatic decrease in myocardial rupture incidence (WT: 40.00 vs KI: 6.25%) and improved survival 56 days post-MI (WT: 42.86% vs KI: 60%). GLN depletion in KI hearts attenuates post-MI adverse LV remodeling and improves survival compared to WT. There is a strong correlation between the reduction of cardiac remodeling and a drastic effect on fibrosis deposition, especially in the border zone. Further studies are required, in order to shed light onto the association between low GLN content, cardioprotection and fibrosis.