The effect of resistance and endurance training with ursolic acid on atrophy‐related biomarkers in muscle tissue of diabetic male rats induced by streptozotocin and ahigh‐fatdiet

Abstract

In this study, the effect of resistance and endurance training with/without ursolic acid supplementation was evaluated to identify atrophy‐related biomarkers in elderly rats induced by diabetes and a high‐fat diet (HFD) based on in silico analysis algorithms and pharmaceutical methods. The visualizer software found differential gene expression levels in skeletal muscle atrophy via computed hub gene network parameters. Also, the impact of ursolic acid, as a potent inducer of the Trp53 protein in ameliorating decreased muscle mass, was analyzed in diabetic rats. Fifty‐six‐old male Wistar rats were randomly assigned into seven groups, including healthy control (Control), diabetic control (DM), Ursolic acid supplementation (UA), resistance training (RT), endurance training (ET), resistance training+ Ursolic acid supplementation (RT + U), and endurance training in combination with Ursolic acid supplementation (ET + U). Exercise intervention included 8 weeks of resistance or endurance training programs. Biomedical informatic outputs determined the P53 signaling pathway as a remarkable causative factor in the pathomechanism of atrophy. In addition, the results demonstrated that exercise and supplementation of UA impeded the interactions among p53/ATF4/p21. Moreover, ET and ursolic acid had a synergetic effect on the signaling pathway of p53/ATF4/p21 and probably could inhibit the aging process and modulate the p53/ATF4/p21 molecular pathway. The interaction between UA and endurance exercise significantly modified the activity of the p53/ATF4/p21 signaling pathway. Based on in silico studies, the p53/ATF4/p21 pathway plays an essential role in aging, and the inhibition of this pathway would be beneficial in decelerating the aging process. Practical applications Ursolic acid (UA) is a natural pentacyclic triterpenoid carboxylic acid found in apples (a major compound of apple wax) and other fruits; it is known to improve skeletal muscle function and reduce the muscular atrophy pathways. We indicated that p53/ATF4/p21 signaling is an essential factor in aging, and the suppression of this pathway could be beneficial in the deceleration of the aging process. Therefore, this work would shed light on understanding the effect of exercise and nutrition interventions on preventing atrophy markers of skeletal muscle in diabetic rats. Further studies are needed to seek the precise mechanism of the synergism between UA and exercise in ameliorating atrophy markers.

The Role of p53 in Skeletal Muscle Adaptation During Exercise: A Literature Review

“…In a study done by Zolfaghari et al (2022) analyzing treadmill running on diabetic Wistar rats, p53 content was found to be lower following 8 weeks of endurance training compared to the control [15]. However, within the same study, resistance training through weighted climbing did not have any observed effects on p53 levels, suggesting training modality specificity in relation to p53 protein content.…”

“…Exercise has been extensively studied to both combat muscle atrophy and promote hypertrophy, particularly through resistance training. As well, previous research has already established a possible relationship between p53 and sarcopenia [15]. Thus, there is a natural role p53 can play when analyzing its activity during exercise-induced hypertrophy.…”

“…Firstly, the momentary increase in p53 that slowly decreased postexercise, seen by Chen et al (2002), was caused by a single session of tetanic contractions [16]. This differed from the study by Zolfaghari et al (2022) which involved 8 weeks of adaptation and 72 hours of recovery before the muscle biopsy [15]. As such, it is possible that with a longer timeframe for adaptation, Chen et al (2002) would have also lacked any observable changes in p53 post-resistance training.…”

Identification of the Exercise and Time Effects on Human Skeletal Muscle through Bioinformatics Methods

“…Antitumor drugs have a great contribution to muscle wasting by directly acting on muscle cells and through their systemic side effects. Zolfaghari, et al found that endurance exercise significantly modified the activity of the p53/ATF4/p21 signaling pathway [30].…”

“…Antitumor drugs have a great contribution to muscle wasting by directly acting on muscle cells and through their systemic side effects. Zolfaghari, et al found that endurance exercise significantly modified the activity of the p53/ATF4/p21 signaling pathway [ 30 ]. The results of Ashutosh, et al showed that LRRC8 complex regulates insulin-PI3K-AKT-mTOR signal in skeletal muscle, which affects the differentiation of skeletal muscle in vitro and the size of the skeletal myofiber [ 31 ].…”