The effects of exercise training on cardiac matrix metalloproteinases activity and cardiac function in mice with diabetic cardiomyopathy

Abstract

Aim: To evaluate the effects of exercise training (ET) on cardiac extracellular matrix (ECM) proteins homeostasis and cardiac dysfunction in mice with diabetic cardiomyopathy.

Methods: Thirty-six male C57BL/6 mice were randomized into 3 groups for 8 weeks (12mice/group): Diabetic control-DC: Diabetes was induced by single streptozotocin injection (200 mg/kg i.p.); Diabetic exercise-DE: Diabetic mice underwent ET program on motorized-treadmill (6-times/week, 60min/session); Non-diabetic control-NDC: Vehicle-treated, sedentary, non-diabetic mice served as controls. Before euthanasia, all groups underwent transthoracic echocardiography (TTE). Post-mortem, left-ventricle (LV) samples were histologically analysed for ECM proteins (collagen, elastin), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs).

Results: DC group showed significantly higher cardiac contents of collagen and MMP-9 and lower elastic concentration than NDC (p < 0.001). The implementation of ET completely outweighed those diabetes-induced changes (DE vs NDC, p > 0.05). TIMP-1 levels significantly increased across all groups (DC: 18.98 ± 3.47%, DE: 24.24 ± 2.36%, NDC: 46.36 ± 5.91%; p < 0.05), while MMP-9/TIMP-1 ratio followed a reverse pattern. ET tended to increase MMP-2 concentrations versus DC (p = 0.055), but did not achieve non-diabetic levels (p < 0.05). TIMP-2 cardiac concentrations remained unaltered throughout the study (p > 0.05). Importantly, ET ameliorated both LV end-systolic internal diameter (LVESD) (p < 0.001) and the percentage of LV fractional shortening (FS%) (p = 0.006) compared to DC. Despite that favorable effect, the cardiac function level of DE group remained worse than NDC group (%FS: p = 0.002; LVESD: p < 0.001).

Conclusion: Systemic ET may favorably change ECM proteins, MMP-9 and TIMP-1 cardiac concentrations in mice with diabetic cardiomyopathy. Those results were associated with partial improvement of echocardiography-assessed cardiac function, indicating a therapeutic effect of ET in diabetic cardiomyopathy.

Keywords: Diabetes; Diabetic cardiomyopathy; Exercise training; Matrix metalloproteinases; Tissue inhibitor of MMPs.