Chronic Restraint Stress-Induced Muscle Atrophy Leads to Fatigue in Mice by Inhibiting the AMPK Signaling Pathway

Abstract

Currently, an increasing number of people are suffering from fatigue due to the state of their lifestyles, such as sedentary work in a relatively small space, irregular sleep patterns, or the lack of movement and exercise. The present study was designed to simulate the occurrence of fatigue in the above populations through a chronic restraint stress (CRS) model, and to reveal its dynamic processes and potential underlying molecular mechanisms. ICR mice were subjected to 8 h of restraint stress each day for 5, 10, or 15 days. It was found that the weight-loaded swimming performance, grip strength, and locomotor activity of the mice all decreased under CRS treatment, and that up to 15 days of CRS induced notable fatigue. Gastrocnemius muscle atrophy and some abnormal biochemical parameters related to fatigue under CRS were observed. Furthermore, transcriptome data showed that the changes in muscle cell metabolism and mitochondrial dysfunction were associated with the AMPK signaling pathway in CRS-treated mice. Western blotting analysis of the AMPK/PGC-1α signaling pathway revealed that CRS could decrease mitochondrial biogenesis and reduce the numbers of type I skeletal muscle fibers in the gastrocnemius of mice. CRS could also block the protective mitophagic flux to inhibit the abnormal clearance of damaged mitochondria. Our study suggests a critical link between muscle atrophy and CRS-induced fatigue in mice, suggesting that the pharmacological promotion of muscle and mitochondrial function can be used as a treatment for stress-induced fatigue.

Nelumbinis Stamen Ameliorates Chronic Restraint Stress-Induced Muscle Dysfunction and Fatigue in Mice by Decreasing Serum Corticosterone Levels and Activating Sestrin2

“…Consistent with the findings of previous studies, 17,26 we found that body weight, lean body mass, and fat mass were reduced following CRS induction. Although NS did not restore body weight, it increased fat catabolism and attenuated skeletal muscle loss.…”

“…Other studies as well as our previous studies have reported mitochondrial dysfunction in muscle disorders. 17,29 NS treatment protected mitochondria not only from CRS but also from the effects of corticosterone injection. Mitochondrial homeostasis is determined by a dynamic balance between biogenesis and the removal of damaged mitochondria via autophagy.…”

“…Our previous study explored the dynamic process of CRS-induced fatigue in mice and demonstrated its association with gastrocnemius mitochondrial dysfunction. 17 The antifatigue effect of NS treatment in the CRS-induced mice was observed as increased grip strength and exhaustive swimming endurance capacity in behavioral experiments. In the present study, our purpose is to determine the antifatigue effect of NS whole extract and elucidate the underlying mechanisms.…”

“…The exhaustive swimming test (EST) and grip strength test (GST) were conducted as described . Briefly, for the EST, the mice were loaded with lead at 8% body weight on their tail and individually placed in a swimming box (diameter, 20 cm) containing water at a temperature of 25 ± 1 °C and depth of 25 cm.…”

“…The exhaustive swimming test (EST) and grip strength test (GST) were conducted as described. 17 Briefly, for the EST, the mice were loaded with lead at 8% body weight on their tail and individually placed in a swimming box (diameter, 20 cm) containing water at a temperature of 25 ± 1 °C and depth of 25 cm. Swimming behavior was recorded from the beginning of swimming to exhaustion, and the first successive sinking time and time to exhaustion were calculated.…”