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A trend in large yellow croaker (Larimichthys crocea) aquaculture is to establish production sites suitable for extreme weather conditions. However, continuous and strong currents can harm fish welfare. To determine a suitable site location, the swimming ability of large yellow croakers must be assessed. This study aims to provide novel insights into the physiological characteristics of large yellow croaker swimming and a reference for fishing and cage site selection. Currently, research on large yellow croakers has focused on behavior analysis. Herein, we investigate the effects of swimming on large yellow croakers' metabolites by examining the preferred speed of the group and the sustained swimming ability of single-tailed fish. We evaluated factors that influence the large yellow croaker's swimming fatigue by quantifying the metabolite contents and constructing a sustained swimming model. The results showed that large yellow croaker populations tend to grow in low-velocity environments, similar to their traditional habitat. The samples were taken at different swimming times at a flow velocity of 0.35 m/s. According to the results of the metabolite content analysis, blood glucose levels are closely associated with the swimming ability in large yellow croakers. The content of liver glycogen, which regulates blood glucose concentration, decreased in a certain linear relationship. The sustained swimming model of the large yellow croaker was constructed according to the changes in liver glycogen content. Based on our findings, we recommend the following: (1) for large yellow croakers with a size of approximately 13.5 cm (approximately 1 year old), the water velocity inside the cage should not exceed 2.6 BL/s; (2) the concentration of liver glycogen limits the sustained swimming ability of the large yellow croaker, providing a reference for studying the swimming ability of other fish. [ABSTRACT FROM AUTHOR]

Background: Fatigability in community-dwelling older adults is highly prevalent and disabling, but lacks a treatment. Greater nigrostriatal dopaminergic signaling can ameliorate performance fatigability in healthy young adults, but its role in community-dwelling older adults is not known. We hypothesized that higher nigrostriatal dopaminergic integrity would be associated with lower performance fatigability, independent of cardiopulmonary and musculoskeletal energetics and other health conditions., Methods: In 125 older adults participating in the Study of Muscle, Mobility and Aging, performance fatigability was measured as performance deterioration during a fast 400 m walk (% slowing down from the 2nd to the 9th lap). Nigrostriatal DA integrity was measured using (+)-[11C] dihydrotetrabenazine (DTBZ) PET imaging. The binding signal was obtained separately for the subregions regulating sensorimotor (posterior putamen), reward (ventral striatum), and executive control processes (dorsal striatum). Multivariable linear regression models of performance fatigability (dependent variable) estimated the coefficients of dopamine integrity in striatal subregions, adjusted for demographics, comorbidities, and cognition. Models were further adjusted for skeletal muscle energetics (via biopsy) and cardiopulmonary fitness (via cardiopulmonary exercise testing)., Results: Higher [11C]-DTBZ binding in the posterior putamen was significantly associated with lower performance fatigability (demographic-adjusted standardized β = -1.08, 95% CI: -1.96, -0.20); results remained independent of adjustment for other covariates, including cardiopulmonary and musculoskeletal energetics. Associations with other striatal subregions were not significant., Discussion: Dopaminergic integrity in the sensorimotor striatum may influence performance fatigability in older adults without clinically overt diseases, independent of other aging systems., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This systematic review synthesizes evidence on biomarker responses to physiological loads in professional male team sport athletes, providing insights into induced fatigue states. Structured searches across major databases yielded 28 studies examining various biomarkers in elite team sport players. Studies evaluated muscle damage markers, anabolic/catabolic hormones reflecting metabolic strain, inflammatory markers indicating immune activity and tissue damage, immunological markers tied to infection risk, and oxidative stress markers showing redox imbalances from excessive physiological load. Responses were examined in official matches and training across competitive seasons. The evidence shows that professional team sports induce significant alterations in all studied biomarkers, reflecting measurable physiological strain, muscle damage, oxidative stress, inflammation, and immunosuppression during intensive exercise. These effects tend to be larger and more prolonged after official matches compared to training. Reported recovery time courses range from 24-h to several days post-exercise. Monitoring biomarkers enables quantifying cumulative fatigue and physiological adaptations to training/competition loads, helping to optimize performance while mitigating injury and overtraining. Key biomarkers include creatine kinase, testosterone, cortisol, testosterone/cortisol ratio, salivary immunoglobulin-A, and markers of inflammation and oxidative stress. Further research should extend biomarker monitoring to cover psychological stress and affective states alongside physiological metrics for deeper insight into athlete wellness and readiness.

With the declining birth rates and aging societies in developed countries, the average age of the working population is increasing. Older people tend to get tired more easily, so prevention of fatigue is important to improve the quality of life for older workers. This study aimed to assess the mechanism of fatigue in older people, especially focused on relation between dysfunction of erythrocyte and fatigue. Total power (TP), which is the value of autonomic nerve activity, was measured as a value of fatigue and significantly decreased in workers with aging. As properties of senescent erythrocytes, the erythrocyte sedimentation rate and damaged erythrocytes population increased with aging and correlated with TP. These results suggested that the accumulation of damaged erythrocytes contributes to fatigue. Recent studies revealed that senescence-associated secretory phenotype (SASP), a phenomenon in which senescent cells secrete a variety of cytokines, affected hematopoiesis in bone marrow. We analyzed the effects of SASP factors on erythropoiesis and found that Interleukin -1α (IL-1α) suppressed erythrocyte differentiation of hematopoietic stem cells in vitro. We also showed that IL-1α levels in human blood and saliva increase with aging, suggesting the possibility that IL-1α level in saliva can be used to predict the decline in hematopoietic function., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: In patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), momentary cortisol concentrations in blood, urine, and saliva are lower compared to healthy controls. Long-term cortisol concentration can be assessed through hair, but it is unclear whether these concentrations are also lower. Additionally, it is unknown if lower cortisol extends to other patients suffering from persistent fatigue and how hair cortisol concentration (HCC) relates to fatigue levels. Therefore, this study examines HCC in fatigued patients with ME/CFS, Q fever Fatigue Syndrome (QFS), Post-COVID-19 condition (PCC), and Juvenile Idiopathic Arthritis (JIA)., Methods: Adolescent and young adult patients with ME/CFS (n=12), QFS (n=20), PCC (n=8), JIA (n=19), and controls (n=57) were included. Patients participated in a randomized cross-over trial (RCT) targeting fatigue through lifestyle and dietary self-management strategies. HCC was measured pre-post RCT in patients and once in controls, quantified using a LC-MS/MS-based method. Fatigue severity was measured with the Checklist Individual Strength-8. HCC was compared between groups with ANOVAs. Relations between HCC, fatigue severity, and other variables were investigated using linear regression analyses., Results: The ME/CFS (p=.009) and QFS (p=.047) groups had lower HCC compared to controls. Overall, HCC was negatively associated with the presence of symptoms related to chronic fatigue syndromes (e.g., sleeping issues, often feeling tired, trouble thinking clearly; β=-0.018, p=.035), except in the QFS group (β=.063, p<.001). Baseline HCC did not predict fatigue improvement during the RCT (p=.449), and HCC increased during the trial (M dif =.076, p=.021) regardless of clinically relevant fatigue improvement (p=.658)., Conclusion: Lower cortisol concentration can also be observed in the long-term. Lower HCC is not limited to ME/CFS, as it was also observed in QFS. The role of cortisol may differ between these diagnoses and appears to be unrelated to fatigue levels., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

γ-aminobutyric acid (GABA) and rare ginsenosides are good antioxidant and anti-fatigue active components that can be enriched via probiotic fermentation. In this study, ginseng and germinated brown rice were used as raw materials to produce six fermented purees using fermentation and non-fermentation technology. We tested the chemical composition of the purees and found that the content of GABA and rare ginsenoside (Rh 4 , Rg 3 , and CK) in the puree made of ginseng and germinated brown rice (FGB) increased significantly after fermentation. The antioxidant activity of the six purees was determined using cell-free experiments, and it was found that FGB had better ferric-ion-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging rates, exhibiting better antioxidant effects. We then evaluated the antioxidant effect of FGB in HepG 2 cells induced by H 2 O 2 and found that FGB can reduce the generation of reactive oxygen species (ROS) in HepG 2 cells and increase the membrane potential level, thereby improving oxidative damage in these cells. In vivo experiments also showed that FGB has good antioxidant and anti-fatigue activities, which can prolong the exhaustive swimming time of mice and reduce the accumulation of metabolites, and is accompanied by a corresponding increase in liver glycogen and muscle glycogen levels as well as superoxide dismutase and lactate dehydrogenase activities. Finally, we believe that the substances with good antioxidant and anti-fatigue activity found in FGB are derived from co-fermented enriched GABA and rare ginsenosides.

Background: Constant availability, overtime and feeling overwhelmed by work can impact employees' wellbeing and their biological stress responses. Especially working parents often struggle to balance the demands of their work and family life and were found to be distracted from their work due to family responsibilities. The Family-to-Work Conflict (FWC) indicates the extent to which participating in work is made difficult by family demands. Recent studies have found associations between FWC and biological outcomes such as the Cortisol Awakening Response (CAR), a measure of an individual's Hypothalamic-Pituitary-Adrenal (HPA)-axis activity. This diary study investigates the effect of parental work demands on next day's cortisol response as well as the moderating role of FWC and the mediating role of fatigue., Methods: Over the course of five consecutive days (from Monday to Friday), 168 observations were made on a total of 42 parents. Participants had at least one child and worked a minimum of 20 hours per week. Salivary cortisol samples were obtained immediately, 15 and 30 minutes after awakening each day. Work demands, FWC and fatigue were assessed using standardized questionnaires. Within-person effects were examined using multilevel modeling and mediation analyses., Results: Our results indicate that there are no main effects of work demands on next day's cortisol response. The multilevel analysis revealed that FWC predicts lower wakening cortisol levels and confirmed FWC as an increasing moderator between work demands and next day's HPA-axis activity. Further, work overload was found to increase fatigue, which in turn leads to higher CAR on the following day. This indicates that fatigue mediates the relationship between work demands and CAR. Our findings add to a growing body of research demonstrating further predictors for HPA-axis activity and emphasise the importance of considering family related demands when investigating biological outcomes for working parents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Moringa oleifera Lam. leaves contain various nutrients and bioactive compounds. The present study aimed to assess the anti-fatigue capacity of a flavonoids concentrate purified from M. oleifera Lam. leaves. The total flavonoids in the purified extract were analyzed by ultra-performance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC-MS/MS). The mice were supplemented with purified M. oleifera Lam. leaf flavonoid-rich extract (MLFE) for 14 days. The weight-loaded forced swimming test was used for evaluating exercise endurance. The 90-min non-weight-bearing swimming test was carried out to assess biochemical biomarkers correlated to fatigue and energy metabolism. UPLC-MS/MS analysis identified 83 flavonoids from MLFE. MLFE significantly increased the swimming time by 60%. Serum lactate (9.9 ± 0.9 vs. 8.9 ± 0.7), blood urea nitrogen (BUN) (8.8 ± 0.8 vs. 7.2 ± 0.5), and nonesterified fatty acid (NEFA) (2.4 ± 0.2 vs. 1.7 ± 0.3) were significantly elevated; phosphoenolpyruvate carboxykinase (PEPCK) , glucokinase (GCK) , and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression were significantly downregulated; and heme oxygenase 1 mRNA expression was significantly upregulated in muscle after swimming. MLFE supplement significantly decreased serum lactate (8.0 ± 1.0 vs. 9.9 ± 0.9), BUN (8.6 ± 0.4 vs. 8.9 ± 0.8), and NEFA (2.3 ± 0.4 vs. 2.4 ± 0.2) and increased the protein and mRNA expression of GCK , PEPCK , and Nrf2 . The enhancement of glucose metabolism and antioxidant function by MLFE contributes partly to its anti-fatigue action.

Dysregulation of monoaminergic networks might have a role in the pathogenesis of fatigue in multiple sclerosis (MS). We investigated longitudinal changes of resting state (RS) functional connectivity (FC) in monoaminergic networks and their association with the development of fatigue in MS. Eighty-nine MS patients and 49 age- and sex-matched healthy controls (HC) underwent neurological, fatigue, and RS functional MRI assessment at baseline and after a median follow-up of 1.3 years (interquartile range = 1.01-2.01 years). Monoaminergic-related RS FC was estimated with an independent component analysis constrained to PET atlases for dopamine (DA), noradrenaline (NA), and serotonin (5-HT) transporters. At baseline, 24 (27%) MS patients were fatigued (F) and 65 were not fatigued (NF). Of these, 22 (34%) developed fatigue (DEV-FAT) at follow-up and 43 remained not fatigued (NO-FAT). At baseline, F-MS patients showed increased monoaminergic-related RS FC in the caudate nucleus vs NF-MS and in the hippocampal, postcentral, temporal, and occipital cortices vs NF-MS and HC. Moreover, F-MS patients exhibited decreased RS FC in the frontal cortex vs NF-MS and HC, and in the thalamus vs NF-MS. During the follow-up, no RS FC changes were observed in HC. NO-FAT patients showed limited DA-related RS FC modifications, whereas DEV-FAT MS patients showed increased DA-related RS FC in the left hippocampus, significant at time-by-group interaction analysis. In the NA-related network, NO-FAT patients showed decreased RS FC over time in the left superior frontal gyrus. This region showed increased RS FC in both DEV-FAT and F-MS patients; this divergent behavior was significant at time-by-group interaction analysis. Finally, DEV-FAT MS patients presented increased 5-HT-related RS FC in the angular and middle occipital gyri, while this latter region showed decreased 5-HT-related RS FC during the follow-up in F-MS patients. In MS patients, distinct patterns of alterations were observed in monoaminergic networks based on their fatigue status. Fatigue was closely linked to specific changes in the basal ganglia and hippocampal, superior frontal, and middle occipital cortices., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Exhaustion disorder (ED) is a stress-related disorder characterized by physical and mental symptoms of exhaustion. Recent data suggest that pathophysiological processes in the central nervous system are involved in the biological mechanisms underlying ED. The aims of this study were to investigate if plasma levels of neuro-related proteins differ between patients with ED and healthy controls, and, if so, to investigate if these differences persist over time. Using the Olink Neuro Exploratory panel, we quantified the plasma levels of 92 neuro-related proteins in 163 ED patients at the time of diagnosis (baseline), 149 patients at long-term follow-up (7-12 years later, median follow-up time 9 years and 5 months), and 100 healthy controls. We found that the plasma levels of 40 proteins were significantly higher in the ED group at baseline compared with the control group. Out of these, the plasma levels of 36 proteins were significantly lower in the ED group at follow-up compared with the same group at baseline and the plasma levels of four proteins did not significantly differ between the groups. At follow-up, the plasma levels of two proteins were significantly lower in the ED group compared with the control group. These data support the hypothesis that pathophysiological processes in the central nervous system are involved in the biological mechanisms underlying ED., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study compared brain glucose metabolism using FDG-PET in the caudate nucleus, putamen, globus pallidus, thalamus, and dorsolateral prefrontal cortex (DLPFC) among patients with Long COVID, patients with fatigue, people with multiple sclerosis (PwMS) patients with fatigue, and COVID recovered controls. PwMS exhibited greater hypometabolism compared to long COVID patients with fatigue and the COVID recovered control group in all studied brain areas except the globus pallidus (effect size range 0.7-1.5). The results showed no significant differences in glucose metabolism between patients with Long COVID and the COVID recovered control group in these regions. These findings suggest that long COVID fatigue may involve non-CNS systems, neurotransmitter imbalances, or psychological factors not captured by FDG-PET, while MS-related fatigue is associated with more severe frontal-striatal circuit dysfunction due to demyelination and neurodegeneration. Symmetrical standardized uptake values (SUVs) between hemispheres in all groups imply that fatigue in these conditions may be related to global or network-level alterations rather than hemisphere-specific changes. Future studies should employ fine-grained analysis methods, explore other brain regions, and control for confounding factors to better understand the pathophysiology of fatigue in MS and long COVID. Longitudinal studies tracking brain glucose metabolism in patients with Long COVID could provide insights into the evolution of metabolic patterns as the condition progresses., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A trend in large yellow croaker (Larimichthys crocea) aquaculture is to establish production sites suitable for extreme weather conditions. However, continuous and strong currents can harm fish welfare. To determine a suitable site location, the swimming ability of large yellow croakers must be assessed. This study aims to provide novel insights into the physiological characteristics of large yellow croaker swimming and a reference for fishing and cage site selection. Currently, research on large yellow croakers has focused on behavior analysis. Herein, we investigate the effects of swimming on large yellow croakers’ metabolites by examining the preferred speed of the group and the sustained swimming ability of single-tailed fish. We evaluated factors that influence the large yellow croaker’s swimming fatigue by quantifying the metabolite contents and constructing a sustained swimming model. The results showed that large yellow croaker populations tend to grow in low-velocity environments, similar to their traditional habitat. The samples were taken at different swimming times at a flow velocity of 0.35 m/s. According to the results of the metabolite content analysis, blood glucose levels are closely associated with the swimming ability in large yellow croakers. The content of liver glycogen, which regulates blood glucose concentration, decreased in a certain linear relationship. The sustained swimming model of the large yellow croaker was constructed according to the changes in liver glycogen content. Based on our findings, we recommend the following: (1) for large yellow croakers with a size of approximately 13.5 cm (approximately 1 year old), the water velocity inside the cage should not exceed 2.6 BL/s; (2) the concentration of liver glycogen limits the sustained swimming ability of the large yellow croaker, providing a reference for studying the swimming ability of other fish.

Objective: It is to investigate the effects of β-asarone on learning and memory, hippocampal morphology, synaptophysin (SYP) and postsynaptic density 95(PSD95) protein expression, N-methyl-D-aspartic acid receptor 2B (NR2B)- Ca 2+ /calmodulin (CaM)-dependent protein kinase II (CaMKII) - Extracellular signal-regulated kinase (ERK) / Cyclic-AMP response element binding protein (CREB) signal in hippocampus of rats with exhaustive exercise-induced fatigue., Methods: Fifty Sprague-Dawley male rats were randomly divided into five groups: normal group, exercise group, exercise and β-asarone (2.5, 10, 40 mg/kg)-treated groups. The learning and memory in rats were tested by Morris water maze experiment. We measured the hippocampal morphology by Nissl staining. The levels of SYP, PSD95, NR2B, CaMKII, ERK1/2, CREB, p-NR2B, p-CaMKII, p-ERK1/2 and p-CREB expression were measured by western blot analysis., Results: The results demonstrated that β-asarone (10, 40 mg/kg) treatment significantly decreased the latency to find the platform, increased the time spent in the target quadrant and the number of crossing the platform of rats with exhaustive exercise-induced fatigue. β-asarone (10, 40 mg/kg) treatment increased the cell density in the hippocampus CA1 region, significantly up-regulated NR2B-CaMKII-ERK/CREB signal and improved the protein expression levels of SYP and PSD95 in hippocampus of rats with exhaustive exercise-induced fatigue., Conclusions: It suggests that β-asarone could improve learning and memory of rats with exhaustive exercise-induced fatigue. The mechanism might be related to β-asarone protecting the morphology of hippocampus, increasing the protein expression levels of SYP and PSD95 and up-regulating NR2B-CaMKII-ERK/CREB signal in hippocampus of rats with exhaustive exercise-induced fatigue., Competing Interests: Declaration of Competing Interest There are no conflicts to declare., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Persisting neurological symptoms after COVID-19 affect up to 10% of patients and can manifest in fatigue and cognitive complaints. Based on recent evidence, we evaluated whether cerebral hemodynamic changes contribute to post-COVID syndrome (PCS)., Methods: Using resting-state functional magnetic resonance imaging, we investigated brain perfusion and oxygen level estimates in 47 patients (44.4 ± 11.6 years; F:M = 38:9) and 47 individually matched healthy control participants. Group differences were calculated using two-sample t-tests. Multivariable linear regression was used for associations of each regional perfusion and oxygen level measure with cognition and sleepiness measures. Exploratory hazard ratios were calculated for each brain metric with clinical measures., Results: Patients presented with high levels of fatigue (79%) and daytime sleepiness (45%). We found widespread decreased brain oxygen levels, most evident in the white matter (false discovery rate adjusted-p-value (p- FDR ) = 0.038) and cortical grey matter (p- FDR  = 0.015). Brain perfusion did not differ between patients and healthy participants. However, delayed patient caudate nucleus perfusion was associated with better executive function (p- FDR  = 0.008). Delayed perfusion in the cortical grey matter and hippocampus were associated with a reduced risk of daytime sleepiness (hazard ratio (HR) = 0.07, p = 0.037 and HR = 0.06, p = 0.034). Decreased putamen oxygen levels were associated with a reduced risk of poor cognitive outcome (HR = 0.22, p = 0.019). Meanwhile, lower thalamic oxygen levels were associated with a higher risk of cognitive fatigue (HR = 6.29, p = 0.017)., Interpretation: Our findings of lower regional brain blood oxygen levels suggest increased cerebral metabolism in PCS, which potentially holds a compensatory function. These hemodynamic changes were related to symptom severity, possibly representing metabolic adaptations., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Previous studies investigating sinusoidal exercise were not devoted to an analysis of its energetics and of the effects of fatigue. We aimed to determine the contribution of aerobic and anaerobic lactic metabolism to the energy balance and investigate the fatigue effects on the cardiorespiratory and metabolic responses to sinusoidal protocols, across and below critical power (CP)., Methods: Eight males (26.6 ± 6.2 years; 75.6 ± 8.7 kg; maximum oxygen uptake 52.8 ± 7.9 ml·min -1 ·kg -1 ; CP 218 ± 13 W) underwent exhausting sinusoidal cycloergometric exercises, with sinusoid midpoint (MP) at CP (CP ex ) and 50 W below CP (CP-50 ex ). Sinusoid amplitude (AMP) and period were 50 W and 4 min, respectively. MP, AMP, and time-delay (t D ) between mechanical and metabolic signals of expiratory ventilation ( V ˙ E ), oxygen uptake ( V ˙ O 2 ), and heart rate ( f H ) were assessed sinusoid-by-sinusoid. Blood lactate ([La - ]) and rate of perceived exertion (RPE) were determined at each sinusoid., Results: V ˙ O 2 AMP was 304 ± 11 and 488 ± 36 ml·min -1 in CP ex and CP-50 ex , respectively. Asymmetries between rising and declining sinusoid phases occurred in CP ex (36.1 ± 7.7 vs. 41.4 ± 9.7 s for V ˙ O 2 t D up and t D down , respectively; P < 0.01), with unchanged t D s. V ˙ O 2 MP and RPE increased progressively during CP ex . [La - ] increased by 2.1 mM in CP ex but remained stable during CP-50 ex . Anaerobic contribution was larger in CP ex than CP-50 ex ., Conclusion: The lower aerobic component during CP ex than CP-50 ex associated with lactate accumulation explained lower V ˙ O 2 AMP in CP ex . The asymmetries in CP ex suggest progressive decline of muscle phosphocreatine concentration, leading to fatigue, as witnessed by RPE., (© 2024. The Author(s).)

Performance fatigability is typically experienced as insufficient energy to complete daily physical tasks, particularly with advancing age, often progressing toward dependency. Thus, understanding the etiology of performance fatigability, especially cellular-level biological mechanisms, may help to delay the onset of mobility disability. We hypothesized that skeletal muscle energetics may be important contributors to performance fatigability. Participants in the Study of Muscle, Mobility and Aging completed a usual-paced 400-m walk wearing a wrist-worn ActiGraph GT9X to derive the Pittsburgh Performance Fatigability Index (PPFI, higher scores = more severe fatigability) that quantifies percent decline in individual cadence-versus-time trajectory from their maximal cadence. Complex I&II-supported maximal oxidative phosphorylation (max OXPHOS) and complex I&II-supported electron transfer system (max ETS) were quantified ex vivo using high-resolution respirometry in permeabilized fiber bundles from vastus lateralis muscle biopsies. Maximal adenosine triphosphate production (ATP max ) was assessed in vivo by 31 P magnetic resonance spectroscopy. We conducted tobit regressions to examine associations of max OXPHOS, max ETS, and ATP max with PPFI, adjusting for technician/site, demographic characteristics, and total activity count over 7-day free-living among older adults (N = 795, 70-94 years, 58% women) with complete PPFI scores and ≥1 energetics measure. Median PPFI score was 1.4% [25th-75th percentile: 0%-2.9%]. After full adjustment, each 1 standard deviation lower max OXPHOS, max ETS, and ATP max were associated with 0.55 (95% CI: 0.26-0.84), 0.39 (95% CI: 0.09-0.70), and 0.54 (95% CI: 0.27-0.81) higher PPFI score, respectively. Our findings suggested that therapeutics targeting muscle energetics may potentially mitigate fatigability and lessen susceptibility to disability among older adults., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Cancer-related fatigue (CRF) significantly impacts the quality of life of cancer patients. This study investigates the therapeutic potential of Shenqi Fuzheng injection (SFI) in managing CRF, focusing on its mechanistic action in skeletal muscle. We utilized a CRF mouse model to examine the effects of SFI on physical endurance, monitoring activity levels, swimming times and rest periods. Proteomic analysis of the gastrocnemius muscle was performed using isobaric tags and liquid chromatography-tandem mass spectrometry to map the muscle proteome changes post-SFI treatment. Mitochondrial function in skeletal muscle was assessed via ATP bioluminescence assay. Furthermore, the regulatory role of the hypoxia inducible factor 1 subunit alpha (HIF-1α) signalling pathway in mediating SFI's effects was explored through western blotting. In CRF-induced C2C12 myoblasts, we evaluated cell viability (CCK-8 assay), apoptosis (flow cytometry) and mitophagy (electron microscopy). The study also employed pulldown, luciferase and chromatin immunoprecipitation assays to elucidate the molecular mechanisms underlying SFI's action, particularly focusing on the transcriptional regulation of PINK1 through HIF-1α binding at the PINK1 promoter region. Our findings reveal that SFI enhances physical mobility, reduces fatigue symptoms and exerts protective effects on skeletal muscles by mitigating mitochondrial damage and augmenting antioxidative responses. SFI promotes cell viability and induces mitophagy while decreasing apoptosis, primarily through the modulation of HIF-1α, PINK1 and p62 proteins. These results underscore SFI's efficacy in enhancing mitochondrial autophagy, thereby offering a promising approach for ameliorating CRF. The study not only provides insight into SFI's potential therapeutic mechanisms but also establishes a foundation for further exploration of SFI interventions in CRF management., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Emerging research links the endocannabinoid system to gut microbiota, influencing nociception, mood, and immunity, yet the molecular interactions remain unclear. This study focused on the effects of probiotics on ECS markers-cannabinoid receptor type 2 (CB2) and fatty acid amide hydrolase (FAAH)-in dancers, a group selected due to their high exposure to physical and psychological stress. In a double-blind, placebo-controlled trial (ClinicalTrials.gov NCT05567653), 15 dancers were assigned to receive either a 12-week regimen of Lactobacillus helveticus Rosell-52 and Bifidobacterium longum Rosell-17 or a placebo (PLA: n = 10, PRO: n = 5). There were no significant changes in CB2 (probiotic: 0.55 to 0.29 ng/mL; placebo: 0.86 to 0.72 ng/mL) or FAAH levels (probiotic: 5.93 to 6.02 ng/mL; placebo: 6.46 to 6.94 ng/mL; p > 0.05). A trend toward improved sleep quality was observed in the probiotic group, while the placebo group showed a decline (PRO: from 1.4 to 1.0; PLA: from 0.8 to 1.2; p = 0.07841). No other differences were noted in assessed outcomes (pain and fatigue). Probiotic supplementation showed no significant impact on CB2 or FAAH levels, pain, or fatigue but suggested potential benefits for sleep quality, suggesting an area for further research.

Avoiding fatigue is a long-standing challenge in both healthy and diseased individuals. Establishing objective standard markers of fatigue is essential to evaluate conditions in spatiotemporally different locations and individuals and identify agents to fight against fatigue. Herein, we introduced a novel method for evaluating fatigue using nervous system markers (including dopamine, adrenaline, and noradrenaline), various cytokine levels (such as interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-10, IL-2, IL-5 and IL-17A), and oxidative stress markers (such as diacron-reactive oxygen metabolites [d-ROMs] and biological antioxidant potential [BAP]) in a rat fatigue model. Using this method, the anti-fatigue effects of methyl dihydrojasmonate (MDJ) and linalool, the fragrance/flavor compounds used in various products, were assessed. Our method evaluated the anti-fatigue effects of the aforementioned compounds based on the changes in levels of the nerves system markers, cytokines, and oxidative stress markers. MDJ exerted more potent anti-fatigue effects than linalool. In conclusion, the reported method could serve as a useful tool for fatigue studies and these compounds may act as effective therapeutic agents for abrogating fatigue symptoms., (© 2024. The Author(s).)

Camellia seed oil (CO) has high nutritional value and multiple bioactivities. However, the specific anti-fatigue characteristics and the implied mechanism of CO have not yet been fully elucidated. Throughout this investigation, male C57BL/6J mice, aged 8 weeks, underwent exhaustive exercise with or without CO pretreatment (2, 4, and 6 mL/kg BW) for 28 days. CO could extend the rota-rod and running time, reduce blood urea nitrogen levels and serum lactic acid, and increase muscle and hepatic glycogen, adenosine triphosphate, and anti-oxidative indicators. Additionally, CO could upregulate the mRNA and Nrf2 protein expression levels, as well as enhance the levels of its downstream antioxidant enzymes and induce the myofiber-type transformation from fast to slow and attenuate the gut mechanical barrier. Moreover, CO could ameliorate gut dysbiosis by reducing Firmicutes to Bacteroidetes ratio at the phylum level, increasing the percentage of Alistipes, Alloprevotella, Lactobacillus, and Muribaculaceae, and decreasing the proportion of Dubosiella at the genus level. In addition, specific bacterial taxa, which were altered by CO, showed a significant correlation with partial fatigue-related parameters. These findings suggest that CO may alleviate fatigue by regulating antioxidant capacity, muscle fiber transformation, gut mechanical barrier, and gut microbial composition in mice. PRACTICAL APPLICATION: Our study revealed that camellia seed oil (CO) could ameliorate exercise-induced fatigue in mice by modulating antioxidant capacity, muscle fiber, and gut microbial composition in mice. Our results promote the application of CO as an anti-fatigue functional food that targets oxidative stress, myofiber-type transformation, and microbial community., (© 2024 Institute of Food Technologists.)

Lactobacillus curvatus HY7602 fermented antler (FA) ameliorates sarcopenia and improves exercise performance by increasing muscle mass, muscle fiber regeneration, and mitochondrial biogenesis; however, its anti-fatigue and antioxidant effects have not been studied. Therefore, this study aimed to investigate the anti-fatigue and antioxidant effects and mechanisms of FA. C2C12 and HepG2 cells were stimulated with 1 mM of hydrogen peroxide (H 2 O 2 ) to induce oxidative stress, followed by treatment with FA. Additionally, 44-week-old C57BL/6J mice were orally administered FA for 4 weeks. FA treatment (5-100 μg/mL) significantly attenuated H 2 O 2 -induced cytotoxicity and reactive oxygen species (ROS) production in both cell lines in a dose-dependent manner. In vivo experiments showed that FA treatment significantly increased the mobility time of mice in the forced swimming test and significantly downregulated the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatine kinase (CK), and lactate. Notably, FA treatment significantly upregulated the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione/oxidized glutathione ratio (GSH/GSSG) and increased the mRNA expression of antioxidant genes ( SOD1 , SOD2 , CAT , GPx1 , GPx2 , and GSR ) in the liver. Conclusively, FA is a potentially useful functional food ingredient for improving fatigue through its antioxidant effects.

Fatigue is a serious disturbance to human health, especially in people who have a severe disease such as cancer, or have been infected with COVID-19. Our research objective is to evaluate the anti-fatigue effect and mechanism of icariin through a mouse experimental model. Mice were treated with icariin for 30 days and anti-fatigue effects were evaluated by the weight-bearing swimming test, serum urea nitrogen test, lactic acid accumulation and clearance test in blood and the amount of liver glycogen. The protein expression levels of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1-α) in the skeletal muscle of mice in each group were measured by western blotting. Results showed that icariin prolonged the weight-bearing swimming time of animals, reduced the serum urea nitrogen level after exercise, decreased the blood lactic acid concentration after exercise and increased the liver glycogen content observably. Compared to that in the control group, icariin upregulated AMPK and PGC1-α expression in skeletal muscle. Icariin can improve fatigue resistance in mice and its mechanism may be through improving the AMPK/PGC-1α pathway in skeletal muscle to enhance energy synthesis, decreasing the accumulation of metabolites and slowing glycogen consumption and decomposition.

During submaximal exercise, there is a heterogeneous recruitment of skeletal muscle fibers, with an ensuing heterogeneous depletion of muscle glycogen both within and between fiber types. Here, we show that the mean (95% CI) mitochondrial volume as a percentage of fiber volume of non-glycogen-depleted fibers was 2 (-10:6), 5 (-21:11), and 12 (-21:-2)% lower than all the sampled fibers after continuing exercise for 1, 2 h, and until task failure, respectively. Therefore, a glycogen-dependent fatigue of individual fibers during submaximal exercise may reduce the muscular oxidative power. These findings suggest a relationship between glycogen and mitochondrial content in individual muscle fibers, which is important for understanding fatigue during prolonged exercise., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Importance: While the understanding of inflammation in the pathogenesis of many neurological diseases is now accepted, this special commentary addresses the need to study chronic inflammation in the propagation of cognitive Fog, Asthenia, and Depression Related to Inflammation which we name Brain FADE syndrome. Patients with Brain FADE syndrome fall in the void between neurology and psychiatry because the depression, fatigue, and fog seen in these patients are not idiopathic, but instead due to organic, inflammation involved in neurological disease initiation., Observations: A review of randomized clinical trials in stroke, multiple sclerosis, Parkinson's disease, COVID, traumatic brain injury, and Alzheimer's disease reveal a paucity of studies with any component of Brain FADE syndrome as a primary endpoint. Furthermore, despite the relatively well-accepted notion that inflammation is a critical driving factor in these disease pathologies, none have connected chronic inflammation to depression, fatigue, or fog despite over half of the patients suffering from them., Conclusions and Relevance: Brain FADE Syndrome is important and prevalent in the neurological diseases we examined. Classical "psychiatric medications" are insufficient to address Brain FADE Syndrome and a novel approach that utilizes sequential targeting of innate and adaptive immune responses should be studied., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hanafy and Jovin.)

Purpose: Diabetes is a metabolic disorder characterized by chronic hyperglycemia due to insulin deficiency and/or loss of its action. Diabetic myopathy causes functional limitations in diabetic patients. The beneficial effects of high-intensity interval training (HIIT) are widely reported. We have hypothesized that HIIT application would prevent the development of diabetic myopathy., Methods: Male, Wistar albino rats (10 W) were randomly divided into four groups (1)Control(C), (2)Diabetes(DM), (3)Training(HIIT), and (4)Diabetes + Training(DM + HIIT). Streptozotocin(60 mg/kg) was injected for the induction of diabetes. The maximum exercise capacity(MEC) of animals was determined by an incremental load test. HIIT protocol (4 min 85-95 % MEC, 2 min 40-50 % MEC, 6 cycles, 5 days/week) was applied for 8 weeks. In the end, functional parameters, atrophy, and resistance to fatigue in soleus and EDL muscles were evaluated. IL-6, FNDC5, and myonectin levels were measured in EDL, soleus, and serum., Results: We observed atrophy, fatigue sensitivity, and proinflammatory alterations (IL-6 increase) in the EDL samples due to diabetic myopathy which were not observed in the soleus samples. HIIT application prevented the aforementioned detrimental alterations. Both force-frequency response and parallelly the twitch amplitude increased significantly in the DM + HIIT group. Half relaxation time (DT 50 ) increased in both exercising and sedentary diabetics. FNDC5 was significantly higher in the exercising animals in soleus samples. Myonectin was significantly higher in the soleus muscle only in the DM + HIIT group., Conclusion: Current findings show that diabetic myopathy develops earlier in glycolytic-fast-twitch fibers(EDL) than in oxidative-slow-twitch fibers(soleus). Furthermore, HIIT application prevents atrophy in skeletal muscle, increases resistance to fatigue, and has an anti-inflammatory effect., New Findings: The current study analyzes the myokine profile and skeletal muscle function under the effect of diabetes HIIT-type exercise. We also measured maximal exercise capacity and tailored the exercise program individually according to the result. Diabetic myopathy is an important complication of diabetes yet still, it is not understood completely. Our results show that HIIT-type training would be beneficial in diabetic myopathy but further investigation is needed to understand the whole molecular mechanism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Fatigue is a serious health problem, and long-term fatigue can lead to mental illnesses and accelerated aging. Oxidative stress, which causes excessive production of reactive oxygen species, is generally thought to increase during exercise and is an indicator of fatigue. Peptides obtained by enzymatic decomposition of mackerel (EMP) contain selenoneine, a strong antioxidant. Although antioxidants increase endurance, the effects of EMP on physical fatigue are unknown. The present study aimed to clarify this aspect. We investigated the effects of EMP on changes in locomotor activity, expression levels of silent mating type information regulation 2 homolog peroxisome 1 (SIRT1), proliferator-activated receptor-γ coactivator-1α (PGC1α), and antioxidative-related proteins including superoxide dismutase 1 (SOD1), SOD2, glutathione peroxidase 1, and catalase in the soleus muscle following EMP treatment before and/or after forced walking. Treatment with EMP before and after forced walking, and not only at one or another time point, improved the subsequent decrease in the locomotor activity and enhanced the levels of SIRT1, PGC1α, SOD1, and catalase expression in the soleus muscle of mice. Moreover, EX-527, a SIRT1 inhibitor, abolished these effects of EMP. Thus, we suggest that EMP combats fatigue by modulating the SIRT1/PGC1α/SOD1-catalase pathway., Competing Interests: Declaration of competing interest Satoshi Matsumoto is employee of LS Corporation Co. Ltd., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Under high-altitude hypoxia environment, the body is more prone to fatigue, which occurs in both peripheral muscles and the central nervous system (CNS). The key factor determining the latter is the imbalance of brain energy metabolism, which makes it difficult to maintain the central nervous system to send peripheral nerve impulse continuously. During strenuous exercise, lactate released from astrocytes is taken up by neurons stored for energy to maintain synaptic transmission, a process mediated by monocarboxylate transporters (MCTs) in CNS. The present study investigated the correlation among the adaptability to exercise-induced fatigue, brain lactate metabolism and neuronal hypoxia injury under high-altitude hypoxia environment. Rats were subjected to exhaustive incremental load treadmill exercise under either normal pressure and normoxic conditions or simulated high-altitude low pressure and hypoxic conditions, with subsequent evaluation of the average exhaustive time as well as the expression of monocarboxylate transporters 2 (MCT2), MCT4, the average neuronal density in the cerebral motor cortex, and the lactate content in rat brain. At the early stage of simulated high-altitude environment, the average exhaustive time and neuronal density of rats decreased rapidly, then gradually recovered to some extent with the extension of altitude acclimatization time. The expression of MCT2, MCT4 and the lactate content in rat brain also increased gradually with the extension of altitude acclimatization time. After the application of lactate transport inhibitor, the recovery of exercise capacity of rats after altitude acclimatization was quickly blocked, and the neuronal injury in the cerebral motor cortex of rats was also significantly aggravated. These findings demonstrate that MCT-dependent mechanism is involved in the adaptability of the body to central fatigue, and provide a potential basis for medical intervention for exercise-induced fatigue under high-altitude hypoxia environment., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

For the past 200 years, lactate has been regarded as a metabolic waste end product that causes fatigue during exercise. However, lactate production is closely correlated with energy metabolism. The lactate dehydrogenase-catalyzed reaction uses protons to produce lactate, which delays ongoing metabolic acidosis. Of note, lactate production differs depending on exercise intensity and is not limited to muscles. Importantly, controlling physiological effect of lactate may be a solution to alleviating some chronic diseases. Released through exercise, lactate is an important biomarker for fat oxidation in skeletal muscles. During recovery after sustained strenuous exercise, most of the lactate accumulated during exercise is removed by direct oxidation. However, as the muscle respiration rate decreases, lactate becomes a desirable substrate for hepatic glucose synthesis. Furthermore, improvement in brain function by lactate, particularly, through the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, is being increasingly studied. In addition, it is possible to improve stress-related symptoms, such as depression, by regulating the function of hippocampal mitochondria, and with an increasingly aging society, lactate is being investigated as a preventive agent for brain diseases such as Alzheimer's disease. Therefore, the perception that lactate is equivalent to fatigue should no longer exist. This review focuses on the new perception of lactate and how lactate acts extensively in the skeletal muscles, heart, brain, kidney, and liver. Additionally, lactate is now used to confirm exercise performance and should be further studied to assess its impact on exercise training., (Copyright © 2022 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

The body is more prone to fatigue in a high-altitude hypoxic environment, in which fatigue occurs in both peripheral muscles and the central nervous system (CNS). The key factor determining the latter is the imbalance in brain energy metabolism. During strenuous exercise, lactate released from astrocytes is taken up by neurons via monocarboxylate transporters (MCTs) as a substrate for energy metabolism. The present study investigated the correlations among the adaptability to exercise-induced fatigue, brain lactate metabolism and neuronal hypoxia injury in a high-altitude hypoxic environment. Rats were subjected to exhaustive incremental load treadmill exercise under either normal pressure and normoxic conditions or simulated high-altitude, low-pressure and hypoxic conditions, with subsequent evaluation of the average exhaustive time as well as the expression of MCT2 and MCT4 in the cerebral motor cortex, the average neuronal density in the hippocampus, and the brain lactate content. The results illustrate that the average exhaustive time, neuronal density, MCT expression and brain lactate content were positively correlated with the altitude acclimatization time. These findings demonstrate that an MCT-dependent mechanism is involved in the adaptability of the body to central fatigue and provide a potential basis for medical intervention for exercise-induced fatigue in a high-altitude hypoxic environment., (© 2023. The Author(s).)

Objective: Near-Infrared Spectroscopy (NIRS) analysis techniques can often be complex to perform and interpret resulting in a barrier for wide-spread clinical use. The traditional Point-by-Point analysis methodology and our Post-Exertion Rate of Reperfusion method were examined during the recovery phases following repeated bouts of physical exertion to determine the physiological processes and information captured by each methodology under normal exertion conditions (FiO 2 : 0.210) and when in hypoxic conditions (FiO 2 : 0.129)., Methods: To achieve this, a total of n = 15 participants performed 3 sets of leg extensions to failure at 70 % their maximal effort. A 1-min rest was performed following each set where the Point-by-Point analysis means were calculated at every 6-s time to recovery for a total of 10 mean values. The Post-Exertion Rate of Reperfusion examined the linear slopes for the entire 60-s. The near-infrared spectroscopy device was placed over the vastus lateralis and measure for muscle tissue oxygen saturation, oxygenated hemoglobin, deoxygenated hemoglobin, and total hemoglobin were obtained for both the Point-by-Point and Post-Exertion Rate of Reperfusion analysis., Results: Post-Exertion Rate of Reperfusion slopes were significantly different between normoxia and hypoxia for muscle tissue oxygen saturation (Normoxia: 0.151-0.171; Hypoxia: 0.068-0.116), oxygenated hemoglobin (Normoxia: 0.127 - 0.134; Hypoxia: 0.045 - 0.076), deoxygenated hemoglobin (Normoxia: -0.142 to -0.152; Hypoxia: -0.054 to -0.100), and total hemoglobin (Normoxia: -0.011 to 0.0250; Hypoxia: -0.009 to 0.024). Point-by-Point analysis identified significant differences between muscle tissue oxygen saturation and oxygenated hemoglobin, but not deoxygenated hemoglobin and total hemoglobin., Conclusion: Point-by-Point analysis and Post-Exertion Rate of Reperfusion can each provide distinctly unique information during exertional recovery. Point-by-Point analysis was ideal for detecting the onset of change in muscle oxygen status. Post-Exertion Rate of Reperfusion identified overall rates of change and was shown to be more sensitive at identifying changes in overall recovery of skeletal tissue reperfusion rates. Point-by-Point analysis and Post-Exertion Rate of Reperfusions may be utilized individually or separately to improve the interpretability of skeletal NIRS metrics within research or clinical settings., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The metabolic and mechanical stresses associated with muscle-fatiguing exercise result in perturbations to bodily tissues that lead to exercise-induced muscle damage (EIMD), a state of fatigue involving oxidative stress and inflammation that is accompanied by muscle weakness, pain and a reduced ability to perform subsequent training sessions or competitions. This review collates evidence from previous research on a wide range of nutritional compounds that have the potential to speed up post-exercise recovery. We show that of the numerous compounds investigated thus far, only two-tart cherry and omega-3 fatty acids-are supported by substantial research evidence. Further studies are required to clarify the potential effects of other compounds presented here, many of which have been used since ancient times to treat conditions associated with inflammation and disease.

Objective: Patients with SLE frequently have debilitating fatigue and reduced physical activity. Intermuscular adipose tissue (IMAT) accumulation is associated with reduced physical exercise capacity. We hypothesised that IMAT is increased in patients with SLE and associated with increased fatigue, reduced physical activity and increased inflammation., Methods: In a cross-sectional study, 23 patients with SLE and 28 control participants were evaluated. IMAT was measured in the calf muscles using sequential T 1 -weighted MRI. Patient-reported physical activity and fatigue were measured and a multiplex proteomic assay was used to measure markers and mediators of inflammation., Results: IMAT accumulation (percentage of IMAT area to muscle area) was significantly higher in SLE versus control participants (7.92%, 4.51%-13.39% vs 2.65%, 1.15%-4.61%, median, IQR, p<0.001) and remained significant after adjustment for age, sex, race and body mass index (p<0.001). In patients with SLE, IMAT accumulation did not differ significantly among corticosteroid users and non-users (p=0.48). In the study cohort (patients and controls), IMAT was positively correlated with self-reported fatigue score (rho=0.52, p<0.001) and inversely correlated with self-reported walking distance (rho=-0.60, p<0.001). Several markers of inflammation were associated with IMAT accumulation in patients with SLE, and gene ontology analysis showed significant enrichment for pathways associated with macrophage migration and activation in relation to IMAT., Conclusion: Patients with SLE have greater IMAT accumulation than controls in the calf muscles. Increased IMAT is associated with greater fatigue and lower physical activity. Future studies should evaluate the effectiveness of interventions that improve muscle quality to alleviate fatigue in patients with SLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Brassica rapa L., an edible, feeding and medicinal plant cultivated on the Tibetan plateau with altitudes above 3800 m, has several pharmacological effects. However, its therapeutic effects against memory impairment and central fatigue have yet to be conclusively established. In this study, the Y-maze and Morris water maze tasks revealed that Brassica rapa L. aqueous extract (BE) significantly ameliorated cognitive deficits of sleep deprivation (SD)-treated mice. Moreover, BE treatment partially alleviated SD-induced reductions in the levels of peripheral energy metabolism, and significantly decreased inflammatory factor levels in serum and hippocampus. In addition, BE treatment significantly relieved central fatigue and stabilized the excitability as well as activities of neurons by regulating the levels of hypothalamus tryptophan metabolites and striatum neurotransmitters. The neuroprotective effects of BE were also confirmed using glutamate-treated HT22 cells, whereby BE pretreatment significantly attenuated intracellular ROS production and mitochondrial depolarization via adenosine 5'-monophosphate activated protein kinase/peroxisome proliferators-activated receptors (AMPK/PPAR-γ) signaling pathways. Thus, BE might probably prevent SD-induced learning and memory deficits by inhibiting neuroinflammation and restoring mitochondrial energy metabolism in the hippocampus. These findings imply that BE is a potential complementary therapy for those suffering from deficient sleep or neurometabolic disorders, although this needs verification by prospective clinical studies.

Chronotype is frequently assessed in human observational studies using various morningness-eveningness questionnaires. An alternative single-item chronotype question has been proposed for its reduced administration time and its accessibility to all types of populations. We investigated whether this single-item chronotype is associated with dim light melatonin onset, the "gold standard" for estimating the endogenous circadian phase. We used data from a randomised trial in 166 (non-)Hodgkin lymphoma survivors with cancer-related fatigue. All participants completed a questionnaire, including a single-item chronotype question. A subsample of 47 participants also provided saliva samples before sleep onset for melatonin measurement. Using multiple linear regression, we examined whether chronotype based on a single question was associated with dim light melatonin onset. The subsample of 47 participants had a mean age of 44.6 years. The mean (SD) dim light melatonin onset was at 8:42 (1:19) p.m. and the most common chronotype was more evening than morning person (29.2%). A gradual increase in dim light melatonin onset with later chronotype (i.e. evening preference) was observed, with a mean ranging from 7:45 p.m. in definite morning persons to 9:16 p.m. in definite evening persons. Our study shows that single-item chronotype is associated with dim light melatonin onset as a marker of the endogenous circadian phase of fatigued lymphoma survivors. This type of chronotype assessment can therefore be a useful alternative for more extensive morningness-eveningness questionnaires., (© 2022 European Sleep Research Society.)

In recent years, the accumulation of phosphate ions and the increase in acidity have been described as crucial metabolic fatigue-leading factors that disturb muscle fiber contractions. This fact is especially important in the context of mitochondrial dysfunctions in which excessive fatigue is one of the possible symptoms. However, little is known about the precise fatigue-inducing thresholds of work intensity in mitochondrial dysfunctions of various types and at various stages of their severity. Possible interactions of additional factors such as disturbances in electrolyte concentrations (i.e. magnesium ions) were also not precisely defined. One of the best-suited tools for this kind of problem is systems biology, which enables modeling of metabolic pathways. In this research, a computer model of working skeletal muscle was adapted. The relationship between the decrease in oxidative phosphorylation and the workload shows a linear dependence for dysfunctions that evenly disturb the activity of each element of the pathway (which is equivalent to the decrease in mitochondrial mass). In case of dysfunctions that disrupt only one element of the pathway, the relationship between fatigue threshold and exercise intensity is exponential, but with higher threshold deficiency values. Muscle phosphate levels were the most vulnerable to disruptions of complex III and ATP synthase. Surprisingly, disruptions of the ATP/ADP exchanger emerged as equally disruptive and capable of significantly increasing phosphate concentrations also in the rest state, whereas the impact of the impairment of the phosphate transporter was negligible. Perturbations in magnesium concentration also did not show a significant effect in any of these models.

The mammalian neuromuscular junction (NMJ) comprises a presynaptic terminal, a postsynaptic receptor region on the muscle fiber (endplate), and the perisynaptic (terminal) Schwann cell. As with any synapse, the purpose of the NMJ is to transmit signals from the nervous system to muscle fibers. This neural control of muscle fibers is organized as motor units, which display distinct structural and functional phenotypes including differences in pre- and postsynaptic elements of NMJs. Motor units vary considerably in the frequency of their activation (both motor neuron discharge rate and duration/duty cycle), force generation, and susceptibility to fatigue. For earlier and more frequently recruited motor units, the structure and function of the activated NMJs must have high fidelity to ensure consistent activation and continued contractile response to sustain vital motor behaviors (e.g., breathing and postural balance). Similarly, for higher force less frequent behaviors (e.g., coughing and jumping), the structure and function of recruited NMJs must ensure short-term reliable activation but not activation sustained for a prolonged period in which fatigue may occur. The NMJ is highly plastic, changing structurally and functionally throughout the life span from embryonic development to old age. The NMJ also changes under pathological conditions including acute and chronic disease. Such neuroplasticity often varies across motor unit types. © 2022 American Physiological Society. Compr Physiol 12:1-36, 2022., (Copyright © 2022 American Physiological Society. All rights reserved.)

Rapid oscillations in cytosolic calcium (Ca 2+ ) coordinate muscle contraction, relaxation, and physical movement. Intriguingly, dietary nitrate decreases ATP cost of contraction, increases force production, and increases cytosolic Ca 2+ , which would seemingly necessitate a greater demand for sarcoplasmic reticulum Ca 2+ ATPase (SERCA) to sequester Ca 2+ within the sarcoplasmic reticulum (SR) during relaxation. As SERCA is highly regulated, we aimed to determine the effect of 7-day nitrate supplementation (1 mM via drinking water) on SERCA enzymatic properties and the functional interaction between SERCA and mitochondrial oxidative phosphorylation. In soleus, we report that dietary nitrate increased force production across all stimulation frequencies tested, and throughout a 25 min fatigue protocol. Mice supplemented with nitrate also displayed an ∼25% increase in submaximal SERCA activity and SERCA efficiency ( P = 0.053) in the soleus. To examine a possible link between ATP consumption and production, we established a methodology coupling SERCA and mitochondria in permeabilized muscle fibers. The premise of this experiment is that the addition of Ca 2+ in the presence of ATP generates ADP from SERCA to support mitochondrial respiration. Similar to submaximal SERCA activity, mitochondrial respiration supported by SERCA-derived ADP was increased by ∼20% following nitrate in red gastrocnemius. This effect was fully attenuated by the SERCA inhibitor cyclopiazonic acid and was not attributed to differences in mitochondrial oxidative capacity, ADP sensitivity, protein content, or reactive oxygen species emission. Overall, these findings suggest that improvements in submaximal SERCA kinetics may contribute to the effects of nitrate on force production during fatigue. NEW & NOTEWORTHY We show that nitrate supplementation increased force production during fatigue and increased submaximal SERCA activity. This was also evident regarding the high-energy phosphate transfer from SERCA to mitochondria, as nitrate increased mitochondrial respiration supported by SERCA-derived ADP. Surprisingly, these observations were only apparent in muscle primarily expressing type I (soleus) but not type II fibers (EDL). These findings suggest that alterations in SERCA properties are a possible mechanism in which nitrate increases force during fatiguing contractions.

Purpose: The aim of the present investigation was to determine whether a 1-h floatation-restricted environmental stimulation therapy (floatation-REST) session could augment recovery from high-intensity resistance exercise (6 × 10 back squats, 2-min rest) known to induce significant metabolic, adrenergic, and mechanical stress., Methods: Eleven healthy resistance-trained males (age, 22.5 ± 2.3 yr; height, 176.4 ± 6.0 cm; weight, 85.7 ± 6.2 kg; back squat one-repetition maximum, 153.1 ± 20.1 kg; strength-to-weight ratio, 1.8 ± 0.2) completed the within-subject, crossover controlled study design. Participants completed two exercise testing blocks separated by a 2-wk washout. In one block, the high-intensity resistance exercise protocol was followed by a 1-h floatation-REST session, whereas recovery in the alternate block consisted of a passive sensory-stimulating control. Markers of metabolic stress, neuroendocrine signaling, structural damage, inflammation, and perceptions of soreness, mood state, and fatigue were assessed over a 48-h recovery window., Results: Floatation-REST significantly attenuated muscle soreness across recovery ( P = 0.035) with greatest treatment difference immediately after the intervention ( P = 0.002, effect size (ES) = 1.3). Significant differences in norepinephrine ( P = 0.028, ES = 0.81) and testosterone ( P = 0.028, ES = 0.81) immediately after treatment revealed the modification of neuroendocrine signaling pathways, which were accompanied by greater improvements in mood disturbance ( P = 0.029, ES = 0.81) and fatigue ( P = 0.001, ES = 1.04)., Conclusions: Because no adverse effects and significant and meaningful benefits were observed, floatation-REST may prove a valuable intervention for managing soreness and enhancing performance readiness after exercise., (Copyright © 2022 by the American College of Sports Medicine.)

Preimplantation embryos often consist of a combination of euploid and aneuploid cells, suggesting that safeguards preventing the generation and propagation of aneuploid cells in somatic cells might be deficient in embryos. In somatic cells, a mitotic timer mechanism has been described, in which even a small increase in the duration of M phase can cause a cell cycle arrest in the subsequent interphase, preventing further propagation of cells that have undergone a potentially hazardously long M phase. Here, we report that cell divisions in the mouse embryo and embryonic development continue even after a mitotic prolongation of several hours. However, similar M-phase extensions caused cohesion fatigue, resulting in prematurely separated sister chromatids and the production of micronuclei. Only extreme prolongation of M phase caused a subsequent interphase arrest, through a mechanism involving DNA damage. Our data suggest that the simultaneous absence of a robust mitotic timer and susceptibility of the embryo to cohesion fatigue could contribute to chromosome instability in mammalian embryos. This article has an associated 'The people behind the papers' interview., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Cryotherapy is one of the most common treatments for trauma or fatigue in the field of sports medicine. However, the molecular biological effects of acute cold exposure on skeletal muscle remain unclear. Therefore, we used zebrafish, which have recently been utilized as an animal model for skeletal muscle, to comprehensively investigate and selectively clarify the time-course changes induced by cryotherapy. Zebrafish were exposed intermittently to cold stimulation three times for 15 min each. Thereafter, skeletal muscle samples were collected after 15 min and 1, 2, 4, and 6 h. mRNA sequencing revealed the involvement of trim63a, fbxo32, fbxo30a, and klhl38b in "protein ubiquitination" from the top 10 most upregulated genes. Subsequently, we examined the time-course changes of the four genes by quantitative PCR, and their expression peaked 2 h after cryotherapy and returned to baseline after 6 h. Moreover, the proteins encoded by trim63a and fbxo32 (muscle-specific RING finger protein 1 [MuRF1] and muscle atrophy F-box, respectively), which are known to be major genes encoding E3 ubiquitin ligases, were examined by western blotting, and MuRF1 expression displayed similar temporal changes as trim63a expression. These findings suggest that acute cold exposure transiently upregulates E3 ubiquitin ligases, especially MuRF1; thus, cryotherapy may contribute to the treatment of trauma or fatigue by promoting protein processing., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Corn peptides (CPs) are rich in branched-chain amino acids such as leucine and have a variety of biological activities such as antioxidant and improved lipid distribution. In this article, we prepared CPs by enzymatic digestion of corn proteins and evaluated their anti-fatigue activity., Results: We evaluated the anti-fatigue effect of CPs through an exhaustive swimming experiment. The results showed that CPs were able to significantly reduce the rate of body weight gain and prolong the duration of exhaustive swimming. Besides, CPs reduced blood urea nitrogen (BUN) levels after exercise, while they significantly increased muscle glycogen and liver glycogen stores. They reduced muscle cell damage from exercise. In addition, CPs were effective in increasing AMPK, PGC-1α and PI3K protein expression levels and promoting Akt phosphorylation. Correlation analysis showed that CPs increased the abundance of probiotics such as Lactobacillus and Akkermansia in the gut microflora., Conclusion: CPs, which enhanced exercise performance in mice and could modulate gut microbial composition, had significant anti-fatigue activity. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Purpose of Review: This review combines existing mechano-energetic principles to provide a refreshing perspective in heart failure (HF) and examine if the phenomenon of myocardial fatigue can be rigorously tested in vitro with current technological advances as a bridge between pre-clinical science and clinical practice., Recent Findings: As a testament to the changing paradigm of HF pathophysiology, there has been a shift of focus from structural to functional causes, as reflected in its modern universal definition and redefined classification. Bolstered by recent landmark trials of sodium-glucose cotransport-2 inhibitors across the HF spectrum, there is a rekindled interest to revisit the basic physiological tenets of energetic efficiency, metabolic flexibility, and mechanical load on myocardial performance. Indeed, these principles are well established in the study of skeletal muscle fatigue. Since both striated muscles share similar sarcomeric building blocks, is it possible that myocardial fatigue can occur in the face of sustained adverse supra-physiological load as a functional cause of HF? Myocardial fatigue is a mechano-energetic concept that offers a novel functional mechanism in HF. It is supported by current studies on exercise-induced cardiac fatigue and reverse translational science such as from recent landmark trials on sodium glucose co-transporter 2 inhibitors in HF. We propose a novel framework of myocardial fatigue, injury, and damage that aligns with the contemporary notion of HF as a continuous spectrum, helps determine the chance and trajectory of myocardial recovery, and aims to unify the plethora of cellular and molecular mechanisms in HF., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For migratory fish, passing through the cold, fast flowing water of a dam causes stress, leading to disease and even death. To determine the immune response to cold stress in a dam-lake after swimming fatigue in Chinese sucker (Myxocyprinus asiaticus), the spleen mRNA expression profiles in response to cold stress (CS) after fatigue stress (FS) were compared with that of the control (SS). We identified 40,952 differentially expressed genes (DEGs) in the spleen for at least one comparison among 211,397 unigenes. We identified 11,869 DEGs (4,968 upregulated and 6,901 downregulated), 17,803 DEGs (10,610 upregulated and 7,193 downregulated), and 30,579 DEGs (20,652 upregulated and 9,927 downregulated) in the SS vs. FS, SS vs. CS, and FS vs. CS comparisons, respectively. Enrichment analysis indicated the involvement of the immune system and infectious diseases, including the toll-like receptor pathway, the complement and coagulation cascade, and the natural killer cell-mediated cytotoxicity pathway. There were 2,991 DEGs (271 upregulated and 2,720 downregulated), and 2,878 DEGs (873 upregulated and 2,005 downregulated) associated with these pathways in the SS vs. FS and SS vs. CS comparisons, respectively. In the cold stress after fatigue group, the expression levels of heat shock protein (HSP) 70 and HSP90 genes were significantly upregulated; however, more immune response genes showed significantly downregulated expression in SS vs. CS compared with that in SS vs. FS, including those encoding tumor necrosis factor, C-C motif chemokines (3, 8, and 13), complement components (C3, C4, C6, and C7), immunoglobulin, and cathepsins. Overall, cold stress combined with swimming fatigue from passing the dam resulted in the downregulation of many immune genes, suggesting that the Chinese sucker might have experienced serious immune suppression., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The 24 h responses to professional female netball-specific training were examined. British Superleague players (n = 14) undertook a 90-min on-court training session incorporating key movement, technical, and scenario-specific match-play drills. Perceptual (mood, fatigue, soreness), neuromuscular (countermovement jump peak power output [PPO], PPO relative to mass [PPOrel], jump height [JH]), endocrine (salivary cortisol [C], testosterone [T] concentrations) and biochemical (creatine kinase concentrations [CK]) markers were assessed at baseline (immediately before; Pre), and immediately, two and 24 hours after (+0h, +2h, +24h) training. Session (sRPE) and differential (dRPE) ratings of perceived exertion were recorded at +0h. Identification of clear between time-point differences were based on the 95% confidence interval (CI) for mean differences relative to baseline values not overlapping. At +0h, C (raw unit mean difference from baseline; 95% CI: 0.16; 0.06 to 0.25 μg·dl-1), T (32; 20 to 45 pg⋅ml-1), CK (39; 28 to 50 u·L-1), PPOrel (2.4; 0.9 to 3.9 W·kg-1) and PPO (169; 52 to 286 W) increased. At +2h, fatigue (15; 7 to 24 AU), CK (49; 38 to 60 u·L-1), and soreness (14; 3 to 25 AU) increased, while T (-24; -37 to -11 pg⋅ml-1) and mood (-20; -27 to -12 AU) reduced. At +24h, CK increased (25; 13 to 36 u·L-1) whereas PPOrel (-1.6; -3.2 to -0.1 W·kg-1) and JH (-0.02; -0.03 to -0.08 m) reduced. Responses were variable specific, and recovery of all variables did not occur within 24h. The residual effects of the prior stimulus should be accounted for in the planning of training for professional female netball players., Competing Interests: The authors have declared that no competing interests exist.

We aimed to investigate whether changes in prefrontal cortex (PFC) oxyhemoglobin (O 2 Hb) and deoxyhemoglobin (HHb) associates with inspiratory muscle effort during inspiratory threshold loading (ITL) in healthy participants. Participants performed an incremental ITL. Breathing pattern, partial pressure of end-tidal CO 2 (P ET CO 2 ), mouth pressure and O 2 Hb and HHb over the right dorsolateral PFC, sternocleidomastoid (SCM), and diaphragm/intercostals (Dia/IC) were monitored. Fourteen healthy participants (8 men; 29 ± 5 years) completed testing. Dyspnea was higher post- than pre-ITL (5 ± 1 vs. 0 ± 1, respectively; P<0.05). PFC O 2 Hb increased (P < 0.001) and HHb decreased (P = 0.001) at low loads but remained stable with increasing ITL intensities. PFC total hemoglobin increased at task failure compared to rest. SCM HHb increased throughout increasing intensities. SCM and Dia/IC total hemoglobin increased in the at task failure compared to rest. P ET CO 2 did not change (P = 0.528). PFC is activated early during the ITL but does not show central fatigue at task failure despite greater dyspnea and an imbalance of SCM oxygen demand and delivery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]., Main Methods: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S)., Key Findings: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair., Significance: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI)., Methods: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin., Key Findings: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces., Significance: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Postoperative fatigue (POF) is the most common and long-lasting complication after surgery, which brings heavy burden to individuals and society. Recently, hastening postoperative recovery receives increasing attention, but unfortunately, the mechanisms underlying POF remain unclear. Propofol is a wildly used general anesthetic in clinic, and inspired by the rapid antidepressant effects induced by ketamine at non-anesthetic dose, the present study was undertaken to investigate the anti-fatigue effects and underlying mechanisms of propofol at a non-anesthetic dose in 70% hepatectomy induced POF model in rats. We first showed here that single administration of propofol at 0.1 mg/kg ameliorated acute POF in hepatectomy induced POF rats. Based on metabonomics analysis, we hypothesized that propofol exerted anti-fatigue activity in POF rats by facilitating free fatty acid (FFA) oxidation and gluconeogenesis. We further confirmed that propofol restored the deficit in FFA oxidation and gluconeogenesis in POF rats, as evidenced by the elevated FFA utilization, acetyl coenzyme A content, pyruvic acid content, phosphoenolpyruvic acid content, hepatic glucose output and glycogen storage. Moreover, propofol stimulated glucagon secretion and up-regulated expression of cAMP-response element binding protein (CREB), phosphorylated CREB, peroxlsome prolifeator-activated receptor-γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinade1 and carnitine palmitoltransferase 1A. In summary, our study suggests for the first time that propofol ameliorates acute POF by promoting glucagon-regulated gluconeogenesis via CREB/PGC-1α signaling and accelerating FFA beta-oxidation., Competing Interests: Declaration of competing interest The author have declared that no competing interest exists., (Copyright © 2021 Elsevier Inc. All rights reserved.)