The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE^–/– and Wild-Type Mice

Abstract

Background: Atherosclerosis is the leading cause of death worldwide. The disease development is by and large driven by old age and lifestyle factors, such as diet, physical activity, and smoking. In the present study, we have investigated the effect of exercise and diet on the development of atherosclerosis in young and aged mice. Objective: This study aimed at comparing multiple age-dependent factors that may influence atherosclerosis in a transgenic mouse model. Methods: Young (14 weeks) and aged (49–52 weeks) C57BL/6 wild-type (WT) and atherosclerosis-prone ApoE^–/– mice were subjected to physical endurance exercise on a treadmill, with or without a high-fat diet. Five weeks later, the frequencies of regulatory T cells (T_REGs) in lymph nodes were assessed by flow cytometry, plasmatic cytokines (interleukin [IL]-1β, IL-6, IL-10, IL-17, interferon-γ, tumor necrosis factor-α, and transforming growth factor [TGF]-β₁) levels were determined by Luminex assay. Lipids (cholesterol and triglycerides) and anti-heat shock protein 60 (HSP60) autoantibodies were measured by ELISA. Aortic lesion sizes were assessed by en face imaging. Microarray analysis and qPCR of skeletal muscle gene expression were also performed. Results: Exercise leads to a reduction of aortic lesions in young ApoE^–/– and aged WT mice independent of diet. In most groups, this reduction was followed by an increased proportion of T_REGs and TGF-β₁ levels. Moreover, gene expression analysis showed that exercise seems to affect the AMPK signaling pathway. In particular, PGC-1α₁ mRNA was induced in aged WT mice, whereas it was reduced in young ApoE^–/– mice. In addition, GSEA analysis showed a marked reduction in the insulin signaling pathway in aged ApoE^–/– mice. Conclusion: Practicing endurance exercise seems to be enough for reducing early aortic lesion formation, independent of diet. However, this was only true in mice with smaller aortic lesions, since mice with large, advanced, complicated atherosclerotic plaques did not show any reduction in lesion size with exercise training.

The Role of Intestinal Dysbacteriosis Induced Arachidonic Acid Metabolism Disorder in Inflammaging in Atherosclerosis

“…ApoE deficient (apoE -/-) mice can spontaneously develop atherosclerosis which stimulate atherosclerotic pathological processes in the arteries of humans with lesions that can be observed during the development of atherosclerosis (Nakashima et al, 1994). Furthermore, aged apoE -/mice (20 to 40 weeks of age) developed more advanced, fibrous plaques, with abundant fibrous tissue and larger necrotic cores (Jakic et al, 2019). To observe the effect of aging on more severe atherosclerosis lesions, we compared the plaque areas in young (5-week) and old (32-week) apoE -/mice with the intervention of a high fat diet for 32 weeks, another risk factor for AS, to ensure the formation of complex plaques (Yu et al, 2018).…”

Impact of aerobic exercise type on blood flow, muscle energy metabolism, and mitochondrial biogenesis in experimental lower extremity artery disease

“…We showed that forced treadmill walking, but not voluntary wheel running or forced swimming, prevented early atherosclerosis progression. A significant reduction in aortic lesion size has been recently reported in young ApoE −/− mice (without LEAD) after 5 weeks of a treadmill endurance program 39 . Our data emphasizes the clinical relevance of endurance treadmill ET for reducing cardiovascular mortality in LEAD patients as previously reported 40 .…”

Do Changes in Innate Immunity Underlie the Cardiovascular Benefits of Exercise?

“…Exercise promotes cardiovascular health and reduces atherosclerotic lesion size and vulnerability. In both ApoE knockout and LDL receptor knockouts fed a western style diet, aerobic exercise training reduced early lesion size formation and enhanced lesion regression (59, 60). Moreover, exercise training in diabetic ApoE knockout animals resulted in improved glucose tolerance, lesion size, and plaque stability.…”