Effects of intermittent ladder-climbing exercise training on mitochondrial biogenesis and endoplasmic reticulum stress of the cardiac muscle in obese middle-aged rats

Abstract

The aim of this study is to investigate the effects of intermittent ladder-climbing exercise training on mitochondrial biogenesis and ER stress of the cardiac muscle in high fat diet-induced obese middle-aged rats. We induced obesity over 6 weeks of period in 40 male Sprague-Dawley rats around 50 weeks old, and were randomly divided into four experimental groups: chow, HFD, exercise+HFD, and exercise+chow. The exercising groups underwent high-intensity intermittent training using a ladder-climbing and weight exercise 3 days/week for a total of 8 weeks. High-fat diet and concurrent exercise resulted in no significant reduction in body weight but caused a significant reduction in visceral fat weight (p<0.05). Expression of PPARδ increased in the exercise groups and was significantly increased in the high-fat diet+exercise group (p<0.05). Among the ER stress-related proteins, the expression levels of p-PERK and CHOP, related to cardiac muscle damage, were significantly higher in the cardiac muscle of the high-fat diet group (p<0.05), and were significantly reduced by intermittent ladder-climbing exercise training (p<0.05). Specifically, this reduction was greater when the rats underwent exercise after switching back to the chow diet with a reduced caloric intake. Collectively, these results suggest that the combination of intermittent ladder-climbing exercise training and a reduced caloric intake can decrease the levels of ER stress-related proteins that contribute to cardiac muscle damage in obesity and aging. However, additional validation is required to understand the effects of these changes on mitochondrial biogenesis during exercise.

Comparison of endoplasmic reticulum stress and mitochondrial biogenesis responses after 12 weeks of treadmill running and ladder climbing exercises in the cardiac muscle of middle-aged obese rats

“…In the current work, PGC-1α levels were found to be significantly increased in both the RE and AE groups, as were levels of markers of mitochondrial biogenesis. Activation of mitochondrial biogenesis in the myocardium due to resistance training has also been confirmed in one of our previous studies ( 12 ), and long, low-intensity resistance training resulting in fatigue is thought to promote mitochondrial biogenesis ( 37 ). Moreover, the present investigation confirmed that RE and AE are similar in terms of the relationship between mitochondrial biogenesis and ER stress, a finding that is supported by a previous study, in which changes in PERK were shown to influence the mitochondria-associated ER membrane ( 20 ).…”

“…Nonetheless, in the RE group, phosphorylation of PERK also decreased significantly and CHOP expression was reduced. Furthermore, our previous work has shown that 8 weeks of resistance training decreases PERK phosphorylation and CHOP levels in the myocardium ( 12 ); thus, such exercise does appear to affect these factors. It seems likely that AE was particularly effective because the significant decreases in body weight and intraperitoneal fat observed in rats of this group led to a decrease in the degree of obesity, and obesity is known to be responsible for ER stress ( 30 ).…”

“…During ER stress, the unfolded protein response (UPR) activates the following protective mechanisms: prevention of protein translation, decreased introduction of new proteins, enhancement of the protein folding ability of the ER, removal of misfolded proteins, and apoptosis to eliminate damaged cells ( 19 ). Chronic ER stress causes oxidative stress and inflammatory responses ( 20 ), and obesity is known to increase ER stress in metabolically active tissues ( 12 ). The activity of PERK, phospho-inositol-requiring enzyme 1α (phospho-IRE1α), and c-Jun N-terminal kinase (JNK) in the fat and liver tissues of mice kept on a high-fat diet has been found to be significantly higher than that in lean animals ( 21 ).…”

“…PERK is a key ER stress sensor and molecular mediator of the ER-mitochondria contact sites and is required to regulate inter-organellar cross-talk in ROS-induced cell death, a role not shared with other ER stress sensors, like IRE1. Therefore, PERK and pro-apoptotic C/EBP homologous protein (CHOP), a downstream of PERK, are key factors for understanding an association between ER stress and mitochondria malfunction caused by obesity ( 12 ). However, compared to knowledge of ER stress in other tissues ( 13 ), our understanding of this process in cardiac muscle is highly limited, and no clear correlation with mitochondria has yet been identified ( 14 ).…”

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

“…Besides CR, also exercise training is an effective non-pharmacological approach to improve heart function in cardiac ageing and disease [6]. In an aged rat model, a combination of intermittent ladder-climbing exercise training and a reduced caloric intake were found to decrease the levels of ER stress-related proteins, including phosphorylated PERK and CHOP, proteins that contribute to cardiac muscle damage in ageing [94]. Moreover, high-intensity training can improve cardiac function and reduce cardiac infarction by decreasing the expression of GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, ATF6, XBP1, CHOP, and cleaved caspase-3 in an intermittent I/R rat model [95,96].…”