Abstract
Introduction:
Metabolic disorder promotes premature senescence and poses more severe cardiac dysfunction in females than males. While endurance exercise (EXE) has been known to confer cardioprotection against metabolic diseases, whether EXE-induced cardioprotection is associated with mitigating senescence in females remains unknown. Thus, the aim of the present study is to examine metabolic disorder-induced cardiac anomalies (cellular senescence, metabolic signaling, and autophagy) using a mouse model of obese/type 2 diabetes induced by a high-fat/high-fructose diet.
Methods:
Female C57BL/6 mice (10 wks. old) were assigned to three groups (n = 11/group): normal diet group (CON), high-fat/high-fructose (HFD/HF) group, and high-fat/high-fructose diet + endurance exercise (HFD/HF + EXE) group. Upon confirmation of hyperglycemia and overweight after 12 weeks of HFD/HF diet, mice assigned to HFD/HF + EXE group started treadmill running exercise (60 min/day, five days/week for 12 weeks), with HFD/HF diet continued.
Results:
EXE ameliorated HFD/HF-induced body weight gain and hyperglycemia, improved insulin signaling and glucose transporter 4 (GLUT 4) levels, and counteracted cardiac disruption. EXE reversed HFD/HF-induced myocyte premature senescence (e.g., prevention of p53, p21, p16, and lipofuscin accumulation), resulting in suppression of a senescence-associated secretory phenotype such as inflammation (TNF-α and IL1β) and oxidative stress (protein carbonylation). Moreover, EXE restored HFD/HF-induced autophagy flux deficiency, evidenced by increased LC3-II concomitant with p62 reduction and restoration of lysosome function-related proteins (LAMP2, CATHEPSIN L, TFEB, and SIRT1). More importantly, EXE retrieved HFD/HF-induced apoptosis arrest (e.g., increased cleaved CASPASE3, PARP, and TUNEL positive cells).
Conclusions:
Our study demonstrated that EXE-induced anti-senescence phenotypes, autophagy restoration, and promotion of propitiatory cell removal by apoptosis play a crucial role in cardiac protection against metabolic distress-induced cardiac disruption.
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