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April 1, 2026Open Access

High-Intensity Interval Training Outperforms Moderate-Intensity Exercise in Hyperlipidemic ApoE⁻/⁻ Mice: A Molecular and Histological Comparison

Key Points

This study aims to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on myocardial stress in hyperlipidemic ApoE⁻/⁻ mice.
Forty male ApoE⁻/⁻ mice aged 8 weeks were divided into four groups: control, high-fat diet (HFD), HFD+MICT, and HFD+HIIT.
Training sessions lasted for 12 weeks with specific intensities for MICT and HIIT.
Analyzed serum lipid levels and myocardial tissue changes using staining and protein expression techniques.
HIIT significantly reduced total cholesterol and triglyceride levels compared to MICT (p < 0.05).
HIIT lowered the levels of inflammatory markers and improved antioxidant signaling.
Histological analysis showed reduced fibrosis and inflammation in the HIIT group.

Abstract

Background: Hyperlipidemia is highly prevalent worldwide and can affect cardiac pathophysiology. This study aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the molecular mechanisms of myocardial stress and pathological remodeling in non-obese apolipoprotein E knockout (ApoE⁻/⁻) mice with hypercholesterolemia. Methods: Thirty-five 8-week-old male ApoE⁻/⁻ mice were randomly assigned to four groups as follows: control (normal diet); HFD (high-fat diet); HFD+MICT (60% maximal running speed); and HFD+HIIT (85% maximal running speed). After a 12-week intervention, serum levels of blood lipids and B-type natriuretic peptide (BNP) as well as pathological changes in the myocardial tissue (hematoxylin and eosin staining and Masson’s trichrome staining) were detected. Protein expression analyses of lipid metabolism markers (CD36, CD68 (Cluster of Differentiation 36/68), lectin-type oxidized low-density lipoprotein receptor 1 and peroxisome proliferator-activated receptor-gamma), antioxidant regulators (sirtuin 1/3 SIRT1/3, nuclear factor erythroid 2-related factor 2 NRF2, and superoxide dismutase 2 SOD2), inflammatory cytokines (interleukin IL-6 and IL-18), and fibrosis-related proteins (transforming growth factor-beta 1 TGF-β1, collagen I/III) was performed using immunohistochemistry and western blotting. Results: The HFD condition increased serum total cholesterol (TC) and triglyceride (TG) levels, but did not increase body weight, consistent with a lean hyperlipidemia model. Compared with the MICT condition, the HIIT condition demonstrated superior efficacy in reducing HFD-induced TC, TG and BNP levels (p < 0.05). Histologically, HIIT reduced myocardial fibrosis and inflammation. HIIT downregulated lipid transporters CD36/CD68, upregulate the antioxidant SIRT1/3-NRF2-SOD2 axis, inhibit pro-inflammatory factors IL-1β, IL-6, and IL-18, and reduce the deposition of fibrotic TGF-β1 and collagen I and III (p < 0.05). Conclusion: In a non-obese, hypercholesterolemic ApoE⁻/⁻ model, HIIT elicited more favorable molecular signatures than MICT for ameliorating myocardial stress and pathological remodeling in terms of lipid deposition, oxidative stress, inflammation and fibrosis pathways.

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