High-Intensity Interval Training Attenuates Cardiac P53–p21 Stress Signaling in a Mouse Model of Type 2 Diabetes

Abstract

Background: Type 2 diabetes mellitus (T2D) is associated with chronic hyperglycemia-induced disruption of myocardial redox balance and activation of stress-responsive signaling pathways that contribute to cardiac dysfunction. Among these pathways, the p53–p21 axis plays a key role in regulating cell-cycle arrest and apoptosis in metabolically stressed cardiomyocytes. Although high-intensity interval training (HIIT) has been shown to improve metabolic and cardiovascular outcomes, its effects on myocardial p53 and p21 expression in diabetes remain poorly characterized. Objectives: This study aimed to investigate the effects of an 8-week HIIT protocol on cardiac p53 and p21 protein expression in a murine model of T2D. Methods: A total of 40 adult male NMRI mice were randomly assigned to four groups (n = 10 per group): nondiabetic sedentary, nondiabetic trained, diabetic sedentary, and diabetic trained. Type 2 diabetes was induced using a high-fat diet combined with a low-dose streptozotocin injection. Exercise-trained animals performed treadmill-based interval running 5 days per week for 8 weeks, with work intervals at 85 - 90% of maximal running speed (Vmax) interspersed with active recovery at 50 - 60% of Vmax. Myocardial p53 and p21 protein expression levels were assessed using Western blot analysis. Results: Diabetic sedentary mice showed significantly increased p53 and p21 protein expression compared with nondiabetic controls. Eight weeks of HIIT significantly reduced the elevated expression of these stress-related proteins in diabetic trained animals. In contrast, no significant differences were observed between nondiabetic trained mice and their sedentary counterparts. Conclusions: High-intensity interval training attenuated myocardial p53 and p21 protein expression in a murine model of type 2 diabetes. These findings indicate that HIIT modulates the cardiac p53–p21 stress-responsive signaling axis under diabetic conditions. However, because this study assessed molecular protein expression without directly evaluating cardiac function or apoptosis, further studies are needed to determine whether these molecular changes translate into functional cardiac benefits.