In recent years, with the development of the west, military operations, tourism and vacation activities, people's acute exposure to high altitude has become more and more frequent. Relevant studies have shown that labor efficiency at altitudes of 3500 and 4500 m decreases by 12.61% and 18.78%, respectively, compared to plains [1]. It takes days or even weeks for the body to adapt to the altitude environment, and serious complications are likely to occur in the early days (within a few days) of acute altitude exposure [2]. Reduced fatigue and pathophysiologic changes in the body after rapid entry to the plateau affect the normal work and life of the personnel and limit the smooth implementation of plateau activities.
Acute exposure to high altitude aggravates hypoxemia, which results in insufficient oxygen supply and restricted movement; at the same time, the metabolic reflexes of the respiratory muscles regulate blood redistribution, resulting in a decrease in blood supply to the muscles [3 - 4]. The decrease of oxygen partial pressure in the nervous system, the decrease of neurotransmitter conversion and synaptic transmission, the weakening of ion channels and ion pumps, and the abnormality of neuromuscular junction conduction [5-6], all these pathophysiological changes can aggravate the fatigue of operation.
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Mitochondrial respiration produces ATP and consumes O2, which is accompanied by the production and removal of reactive oxide species (ROS). As the intensity of work increases, ROS production increases and clearance decreases, and ROS are mainly oxidized by the Na+-K+ pump, resulting in an imbalance of Na+ and K+ concentrations in and out of the skeletal muscle cell, affecting the excitability of the cell membrane, and inhibiting the release of Ca2+ from the sarcoplasmic reticulum and the sensitivity of myofibrils to Ca2+, thus leading to muscle fatigue [7]. In addition, ROS activate class IV muscle afferent nerve fibers and directly inhibit motor neurons [8].
It has been reported in the literature that an increase in ROS can lead to fatigue, and that pretreatment of isolated rat tibialis anterior muscle with superoxide dismutase (SOD) injections reduced the frequency of afferent nerve excitation, which in turn significantly ameliorated fatigue. The dysfunction of mitochondrial oxidative phosphorylation increases the production of ROS, which further oxidizes and destroys the mitochondrial membrane, electron transport system and tricarboxylic enzyme, and further inhibits mitochondrial oxidative phosphorylation, thus forming a vicious cycle [9-11]. Within 72 h after acute altitude entry, the body's antioxidant capacity was significantly weakened, oxidative stress increased significantly, and lipid peroxidation level peaked at 48 h [12]. The oxidative stress at the early stage of plateau entry aggravates the fatigue of the organism and affects its ability to act.
Coenzyme Q10 (CoQ10) is found in a wide range of tissues and organs in the human body, with high levels in central, renal and hepatic tissues where metabolism is high, and in organelles, mainly in Golgi vesicles, mitochondrial plasma membranes and lysosomes [13]. CoQ10 is a mitochondria-targeting small molecule that promotes ATP production by participating in the electron transport chain in mitochondria. At the same time, CoQ10 is an important fat-soluble antioxidant that protects cell membranes, mitochondria and other organelles (e.g., Golgi, lysosomes, endoplasmic reticulum, and peroxisomes) from free radical-induced oxidative stress.
In addition to its direct role as an antioxidant, CoQ10 is also involved in the regeneration of the antioxidants vitamin C and vitamin E. CoQ10 is approved by the Food and Drug Administration (FDA) for use as a dietary supplement, and has been well tolerated, but its effects on the ability to operate in an acute plateau and on fatigue have not been studied in depth. In this study, we evaluated the anti-fatigue effect of CoQ10 in a rat model of acute plateau exposure and explored its possible mechanisms.
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1 Materials and Methods
1.1 Animals
SPF grade male Wistar rats, body weight 200~230 g, Beijing Witong Lihua Co., Ltd, Production License No.: SCXK (Beijing) 2016-0011. The feeding environment was 40%~60% humidity, 23-27℃, 12-hour day/night cycle (light time 8:00~20:00), free intake of food and water, and the feeding process was in accordance with the guidelines of the Ethics Committee for Laboratory Animals of the Military Medical Research Institute of the Military Academy of Sciences. Ethical approval number: IACUC-DWZX-2020-778.
1.2 Drugs, Reagents and Major Instruments
CoQ10, sodium carboxymethyl cellulose (CMC-Na), and 4% tissue cell fixative, Beijing Solepol Technology Co. Malondialdehyde (MDA) kit and total superoxide dismutase (T-SOD) kit, Nanjing Jianjian Bioengineering Research Institute, Nanjing, China; TUNEL kit, Rexroth; DAB developer, Wuhan Xavier Biotechnology Co. 96-well enzyme labeling plate, Corning, USA; OmegaA15-3677 fully automated enzyme labeling instrument, BMGLABTECH, Germany; TDL-5M centrifuge, Sichuan, China; TDL-5M centrifuge, Sichuan, China; TDL-5M centrifuge, Sichuan, China; TDL-5M centrifuge, Sichuan, China. -Ltd., Guizhou Fenglei Aviation Ordnance Co., Ltd; Vit-ro-950 blood gas analyzer, Johnson & Johnson, USA; Vert.A1 optical microscope, Zeiss, Germany; rat swimming pool, manufactured by the laboratory.
1.3 Establishment and Grouping of the Rat Acute Plateau Model
Wistar rats were divided into normal pressure and normoxia (NN) group, hypobaric and hypoxia (HH) group and HH + CoQ10 group, with 12 rats in each group. The HH + CoQ10 group received CoQ10 30 mg kg-1 (prepared as a suspension with 0.5% CMC-Na) as a single daily ig-administration for 6 days, and the remaining 2 groups were given an equal volume of solvent in the same manner. After 4 d of administration, the rats in the HH and HH +CoQ10 groups were transferred to a low-pressure oxygen chamber and ascended to a simulated altitude of 6000 m at a speed of 5 m-s-1 for 2 d. The rats in the NN group were kept under NN conditions.
1.4 Swimming Exhaustion in Rats
One hour after the last dose, 6 rats in each group were randomly selected for the swimming exhaustion test. Before the experiment, the rats were weighed and a lead block weighing 8% of their body weight was attached to their tails. The rats were placed in a water tank with a depth of 30 cm and a water temperature of 27~30℃ for the exhaustion swimming test. The rats were judged to be exhausted when they were submerged underwater for ≥10 s. The time of exhaustion was recorded. The exhaustion time was recorded.
1.5 Preparation of rat blood samples, blood gas analysis and assay of serum MDA content and T-SOD activity
One hour after the last dose, the remaining 6 rats in each group were anesthetized and placed in the supine position, and blood was collected from the abdominal aorta with a heparinized 1 mL syringe. Aortic blood was partially sealed, and arterial blood pH, arterial carbon dioxide pressure (PaCO2), arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), and arterial oxygen saturation (SaO2) were analyzed by a blood gas analyzer within 10 min. arterial oxygen saturation (SaO2), and alkali residual (BE). Arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), and alkali residual (BE), arterial bicarbonate (HCO3-), serum calcium ion (Ca2+), and arterial lactate (Lac) levels were measured. A portion of aortic blood was centrifuged in a centrifuge tube at 450×g for 10 min at 4°C. The serum was extracted, and MDA and T-SOD activity were measured according to the instructions of the kit.
1.6 HE staining to observe the histopathological changes in heart, kidney, lung and brain tissues of rats
After blood sampling and execution, the apical tissues of heart, left kidney, left lung and left cerebral hemisphere of rats were fixed with 4% paraformaldehyde, dehydrated with ethanol gradient, transparent with xylene, embedded in paraffin and made into 5 μm paraffin sections. After HE staining, dehydrated and sealed, the pathological changes of heart, lung, kidney and brain tissues were observed under microscope.
1.7 TUNEL Assay for Apoptosis in Rat Heart, Liver, Kidney, Lung and Brain Tissues
Prepare heart, kidney, lung and brain tissue sections, and subject them to ethanol gradient dehydration, antigen repair and cell membrane rupture treatment, according to the instructions of the kit. After staining, sealing and microscopic observation, cells with brownish-yellow particles in the nucleus are positive cells, i.e. apoptotic cells.
1.8 Statistical Analysis
The experimental data were expressed as x±s and analyzed statistically using SPSS18.0 software. The results of HH swim exhaustion time, HCO3-, BE, Lac and Ca2+ in NN did not conform to normal distribution, and the Mann-Whitney rank sum test was used for comparison between groups. The other results were normally distributed, and t-tests with independent samples were used. p<0.05 was considered statistically significant.
2 Results
2.1 Effect of CoQ10 on the duration of swimming exhaustion in a rat model of simulated acute altitude progression
After 48 h of simulated rapid advancement to 6000 m plateau, the swimming exhaustion time of rats in the HH group was significantly shorter than that of rats in the NN group (P<0.01), and the swimming exhaustion time of rats in the HH+CoQ10 group was significantly longer than that of rats in the HH group (P<0.05) (Figure 1). This suggests that CoQ10 has a certain anti-fatigue effect.
Fig. 1 Effect of coenzyme Q10 (CoQ10) on exhaus⁃ tive swimming time in rushing-into-plateau model rats. Wistar rats were randomly divided into three Wistar rats were randomly divided into three groups: normal pressure and normoxia [NN, vehicle (0.5% CMC-Na)] group, hypo⁃ baric and hypoxia (HH, vehicle) group, and HH +CoQ10 group (CoQ10 30 mg-kg-1). All rats except those in NN group were rushed into a high altitude of 6000 m 4 d after preventive administration . Vehicle and CoQ10 were administrated for another 2 d. x± s, n=6. **P<0 .01, compared with NN group; # P<0 .05 , compared with HH group.
2.2 Effect of CoQ10 on Blood Gas Indexes of Rats in the Acute Plateau Model
As shown in Table 1, after 48 h of simulated rapid advancement to a plateau of 6000 m, arterial blood pH, PaO2, SaO2 and HCO3- levels in the HH group were significantly lower (P<0.01), and PaCO2, BE, Ca2+ and Lac levels were significantly higher (P<0.01) compared with those in the NN group. Compared with rats in the HH group, arterial blood pH was significantly increased (P<0.05), and PaCO2, Ca2+ and Lac levels were significantly decreased (P<0.05) in the HH + CoQ10 group. It was suggested that CoQ10 could improve acidosis and hyperCO2emia and reduce the serum Lac level in rats exposed to the plateau environment.
Tab. 1 Effect of CoQ10 on arterial blood gas analysis of rushing-into-plateau model rats
Parameter | NN | HH | HH+CoQ10 |
pH | 7.42±0.11 | 6.88±0.16** | 7. 10±0.15# |
PaCO2 /mmHg | 38±16 | 64±7** | 40±23# |
PaO2 /mmHg | 107±11 | 43±19** | 58±28 |
SaO2 /% | 95±3 | 23±16** | 46±28 |
BE/mmol-L-1 | -0.7±9.8 | -18.1±4.3** | -18.1±3.1 |
HCO3- /mmol-L-1 | 24.3±7.1 | 10. 1±1.9** | 11.2±1.8 |
Ca2+/mmol-L-1 | 1.29±0.18 | 1.54±0.06** | 1.33±0.21# |
Lac/mmol-L-1 | 2.8±3.5 | 12.8±2.4** | 9.5±2.0# |
See Fig. 1 for the rat treatment. PaCO2 : arterial carbon dioxide pressure; PaO2 : arterial oxygen partial pressure; SaO2 : arterial oxygen saturation; BE. alkali residual; HCO : arterial bicarbonate; Ca : serum calcium ion; Lac: alkali residual; HCO3- : arterial bicarbonate; Ca2+ : serum calcium ion; Lac: arterial lactate. 1 mmHg=0.133 kPa. x±s, n=6. **P<0.01, compared with NN group;# P<0.05, compared with HH group.
2.3 Effects of CoQ10 on the histopathological structure of heart, lung, kidney and brain tissues in rats in the acute plateau model
HE staining results (Figure 2) showed that in the NN group, the cardiomyocytes had clear boundaries, clear nuclei, and no obvious cytoplasmic degeneration and necrosis; the renal tubules and glomeruli had normal structure; the alveolar walls were thin, the alveolar septa were clear, and the vesicles were obvious; neurons in the brain tissue were of normal morphology and size, and the nuclei were large and obvious. In HH+CoQ10 group rats, myocardial, renal, lung and brain tissues showed similar pathological changes to those in HH group rats, but to a lesser extent. It is suggested that CoQ10 can improve pulmonary edema and cerebral edema, and reduce the swelling of renal tubular epithelial cells in rats simulating acute plateau environment.
2.4 Effect of CoQ10 on apoptosis in heart, lung, kidney and brain tissues of rats in the acute plateau model
TUNEL staining showed that the apoptosis rates of heart, lung and brain cells in the NN, HH and HH+CoQ10 groups (data omitted) were not significantly altered (Figure 3). The apoptosis rate of renal tubular epithelial cells in the HH group was significantly increased compared with that in the NN group (P<0.01), and the apoptosis rate of renal tubular epithelial cells in the HH+CoQ10 group was significantly decreased compared with that in the HH group (P<0.01) (Figure 4). It was suggested that CoQ10 could improve the apoptosis of renal tubular epithelial cells in rats exposed to the acute plateau environment.
2.5 Effect of CoQ10 on serum T-SOD activity and MDA content in the acute plateau model rats
Compared with rats in the NN group, serum T-SOD activity was significantly lower (P<0.01) and MDA content was significantly higher (P<0.01) in the HH group; compared with rats in the HH group, serum T-SOD activity was significantly higher (P<0.05) and MDA content was significantly lower (P<0.05) in the HH+CoQ10 group (Figure 5). It was suggested that CoQ10 could improve the level of serum oxidative stress in rats exposed to acute plateau environment.
3 Discussion
The existing simulated plateau model and the altitude of human life in high altitude areas of China is more than 4000 m. According to the literature, exposure to altitude of 5000-6000 m for 24-72 h can induce tissue pathological changes in acute plateau models [15]. According to the literature, exposure to altitude of 5000-6000 m for 24-72 h can induce histopathological changes in animals with acute plateau [15]. Therefore, in the present study, we used an altitude of 6000 m for 48 h and a low-pressure oxygen chamber to simulate the plateau environment to establish a rat model of acute plateauing, which can reach the altitude quickly and effectively reduce the experimental bias caused by the habituation of the animals and other factors during transportation to the plateau.
The results of this study showed that compared with the rats in the HH group, the preventive administration of CoQ10 significantly prolonged the time of swimming exhaustion, alleviated acidosis and high CO2emia, and significantly improved the histopathological damage of the brain, lungs and kidneys as well as the serum oxidative stress, which suggests that CoQ10 can effectively alleviate fatigue at the early stage of the plateau, improve the pathological damage of the lungs, brain, kidneys and other important organs, alleviate the oxidative damage, and maintain the health of the body. It can also reduce the oxidative damage of tissues and maintain the health of the body.
CoQ10 has been widely used as a nutritional supplement, and 300 mg-d-1 has been generally recommended for human use, and no toxic effects have been observed [16]. In the present study, we aimed to investigate the effects of CoQ10, which is commonly used in human dosage, on simulated plateau rats. 30 mg kg-1 was administered to rats in a single daily dose according to the human-rat dosage conversion (body surface area conversion method) [17], which is one of the conventional dosages of CoQ10 in CoQ10 studies [18-19].
In the present study, we found that the exercise capacity of rats decreased significantly after 48 h of exposure to simulated 6000 m plateau, and the administration of CoQ10 significantly improved the physical performance of rats. At the same time, rats in the HH group showed typical pathological changes of pulmonary and cerebral edema, such as thickening of the alveolar wall, proliferation of the alveolar epithelium, edema of cerebral neuronal cells, and nuclear consolidation, which were ameliorated by the administration of CoQ10.
It has been reported in the literature that CoQ10 can improve lipopolysaccharide-induced lung injury through its anti-inflammatory effect, and the administration of CoQ10 reduced serum C-reactive protein levels by 44.58%, alkaline phosphatase activity by 37.38%, and lactate dehydrogenase levels by 48.6%, resulting in a significant improvement in the pathologic damage of the lung tissue [20]. In another study on anesthesia and non-transplantation mild lung injury, it was also found that CoQ10 could play a role in lung protection by reducing the expression of tumor necrosis factor α [21]. These reports are consistent with the results of the present study.
Recent studies have shown that the kidney plays an important role in adaptation to the environment and plateau disease syndrome (acute high altitude sickness, high altitude cerebral edema and high altitude pulmonary edema) by regulating body fluids, electrolytes and acid-base balance, and renal injury occurs mostly in 2-4 d after acute altitude entry [12, 22-23]. In the present study, we found that the renal tubular epithelial cells in the HH group showed obvious edema and apoptosis, and the rate of apoptosis was significantly higher than that in the NN and CoQ10 groups, which indicated that CoQ10 had a certain protective effect on the early stage of renal tubular injury in the plateau-accelerated rats.
The results of this study showed that the serum MDA level was significantly increased and the T-SOD activity was significantly decreased in the HH group, while the administration of CoQ10 significantly decreased the serum MDA and increased the level of T-SOD. MDA is a peroxide formed by the attack of oxygen radicals on the polyunsaturated fatty acids in the biofilm, which triggers lipid peroxidation, and the level of MDA reflects the damage caused by oxidative stress in the organism [24]. T-SOD plays an important role in the redox balance of the organism, scavenging superoxide anion radicals (-O-2) and protecting cells from damage, and its activity can indirectly reflect the ability of the organism to scavenge oxygen radicals [24].
Goldfarb et al. [25] and Thirupathi et al. [26] found that antioxidant supplementation could reduce muscle damage, relieve fatigue, and improve work capacity. Other studies have reported that taurine supplementation can improve exercise capacity and reduce muscle damage [27-28]. However, some studies have reported that a large amount of exogenous antioxidant supplementation may interfere with the signaling pathway of the oxidative reduction response of myocytes, affecting their oxygen radical scavenging ability, and the advantages of CoQ10 as an endogenous antioxidant are more obvious [29].
In conclusion, CoQ10 can correct the acidosis and hyperCO2emia caused by pulmonary edema, improve the pathological damage of heart, lung, kidney and brain tissues, inhibit oxidative stress, and improve the anti-fatigue ability of the organism in the acute plateau environment.
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