Exercise-Induced Antisenescence and Autophagy Restoration Mitigate Metabolic Disorder-Induced Cardiac Disruption in Mice

Joungbo Ko, Young C. Jang, John Quindry, Rodney Guttmann, Ludmila Cosio-Lima, Scott K. Powers, Youngil Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction Metabolic disorder promotes premature senescence and poses more severe cardiac dysfunction in females than males. Although 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 was 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 (HFD/HF) diet. Methods Female C57BL/6 mice (10 wk old) were assigned to three groups (n = 11/group): normal diet group (CON), HFD/HF group, and HFD/HF diet + endurance exercise (HFD/HF + EXE) group. Upon confirmation of hyperglycemia and overweight after 12 wk of HFD/HF diet, mice assigned to HFD/HF + EXE group started treadmill running exercise (60 min·d-1, 5 d·wk-1 for 12 wk), with HFD/HF diet continued. Results EXE ameliorated HFD/HF-induced body weight gain and hyperglycemia, improved insulin signaling and glucose transporter 4 (GLUT4) 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 (tumor necrosis factor α and interleukin-1β) 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 antisenescence phenotypes, autophagy restoration, and promotion of propitiatory cell removal by apoptosis play a crucial role in cardiac protection against metabolic distress-induced cardiac disruption.

Original languageEnglish
Pages (from-to)376-388
Number of pages13
JournalMedicine and Science in Sports and Exercise
Volume55
Issue number3
DOIs
StatePublished - Mar 1 2023

Keywords

  • APOPTOSIS
  • AUTOPHAGY
  • DiABETES
  • ENDURANCE EXERCISE
  • OBESITY
  • SENESCENCE
  • Mice, Inbred C57BL
  • Metabolic Diseases
  • Male
  • Diet, High-Fat/adverse effects
  • Autophagy
  • Hyperglycemia
  • Animals
  • Female
  • Mice
  • Diabetes Mellitus, Type 2
  • Physical Conditioning, Animal

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