α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. α-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3), one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the β adrenergic receptor (ADRB2) as a downstream target for PHD3. We found AKG inhibited PHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise-generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.-Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., Shu, G. α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway.
10.1096/fj.201700670R
Inflammation-induced activation of the indoleamine 2,3-dioxygenase pathway: Relevance to cancer-related fatigue.
Kim Sangmi,Miller Brian J,Stefanek Michael E,Miller Andrew H
Cancer
Cancer-related fatigue (CRF) is a common complication of cancer and its treatment that can significantly impair quality of life. Although the specific mechanisms remain poorly understood, inflammation is now considered to be a distinct component of CRF in addition to effects of depression, anxiety, insomnia, and other factors. One key biological pathway that may link inflammation and CRF is indoleamine 2,3-dioxygenase (IDO). Induced by inflammatory stimuli, IDO catabolizes tryptophan to kynurenine (KYN), which is subsequently converted into neuroactive metabolites. Here we summarize current knowledge concerning the relevance of the IDO pathway to CRF, including activation of the IDO pathway in cancer patients and, as a consequence, accumulation of neurotoxic KYN metabolites and depletion of serotonin in the brain. Because IDO inhibitors are already being evaluated as therapeutic agents in cancer, the elucidation of the relationship between IDO activation and CRF in cancer patients may lead to novel diagnostic and clinical approaches to managing CRF and its debilitating consequences.
10.1002/cncr.29302
Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren's syndrome.
Bårdsen Kjetil,Brede Cato,Kvivik Ingeborg,Kvaløy Jan Terje,Jonsdottir Kristin,Tjensvoll Anne Bolette,Ruoff Peter,Omdal Roald
Journal of neuroinflammation
BACKGROUND:Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren's syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 β-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. METHODS:Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). RESULTS:Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1β activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1β-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. CONCLUSIONS:The main findings of this study indicate a functional network in which several IL-1β-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.
10.1186/s12974-019-1502-8
TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis.
Zong Mei,Bruton Joseph D,Grundtman Cecilia,Yang Huan,Li Jian Hua,Alexanderson Helene,Palmblad Karin,Andersson Ulf,Harris Helena E,Lundberg Ingrid E,Westerblad Håkan
Annals of the rheumatic diseases
OBJECTIVES:Polymyositis and dermatomyositis are characterised by muscle weakness and fatigue even in patients with normal muscle histology via unresolved pathogenic mechanisms. In this study, we investigated the mechanisms by which high mobility group box protein 1 (HMGB1) acts to accelerate muscle fatigue development. METHODS:Intact single fibres were dissociated from flexor digitorum brevis (FDB) of wild type, receptor for advanced glycation endproduct (RAGE) knockout and toll like receptor 4 (TLR4) knockout mice and cultured in the absence or presence of recombinant HMGB1. A decrease in sarcoplasmic reticulum Ca(2+) release during a series of 300 tetanic contractions, which reflects the development of muscle fatigue, was determined by measuring myoplasmic free tetanic Ca(2+). TLR4 and major histocompatibility complex (MHC)-class I expression in mouse FDB fibres were investigated by immunofluorescence and confocal microscopy. Immunohistochemistry was used to investigate TLR4, MHC-class I and myosin heavy chain expression in muscle fibres of patients. RESULTS:Our results demonstrate that TLR4 is expressed in human and mouse skeletal muscle fibres, and coexpressed with MHC-class I in muscle fibres of patients with myositis. Furthermore, we show that HMGB1 acts via TLR4 but not RAGE to accelerate muscle fatigue and to induce MHC-class I expression in vitro. In order to bind and signal via TLR4, HMGB1 must have a reduced cysteine 106 and a disulphide linkage between cysteine 23 and 45. CONCLUSIONS:The HMGB1-TLR4 pathway may play an important role in causing muscle fatigue in patients with polymyositis or dermatomyositis and thus is a potential novel target for future therapy.
10.1136/annrheumdis-2012-202207
Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression.
Maes Michael,Twisk Frank N M,Ringel Karl
Psychotherapy and psychosomatics
BACKGROUND:Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell-mediated immune (CMI) responses between depression and ME/CFS. METHODS:We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients. RESULTS:Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio-somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-α were significantly greater in depression than in ME/CFS. CONCLUSIONS:Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared 'pathway phenotype', i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks.
10.1159/000336803
ORM Promotes Skeletal Muscle Glycogen Accumulation via CCR5-Activated AMPK Pathway in Mice.
Qin Zhen,Wan Jing-Jing,Sun Yang,Wang Peng-Yuan,Su Ding-Feng,Lei Hong,Liu Xia
Frontiers in pharmacology
We found previously that acute phase protein orosomucoid reacts to fatigue and activates C-C chemokine receptor type 5 to increase muscle glycogen storage and enhance muscle endurance (Lei et al., 2016). To explore the underlying molecular mechanisms, we investigated the role of AMP-activated protein kinase, a critical fuel sensor in skeletal muscle, in C-C chemokine receptor type 5-mediated orosomucoid action. It was found orosomucoid increased skeletal muscle AMP-activated protein kinase activation in a time- and dose- dependent manner, which was largely prevented by pharmacological blocking or knockout of C-C chemokine receptor type 5. Administration of orosomucoid also significantly increased the de-phosphorylation and activity of muscle glycogen synthase, the rate-limiting enzyme for glycogen synthesis. The effect was largely absent in mice deficient in C-C chemokine receptor type 5(-/-) or AMP-activated protein kinase α2(-/-), the predominant isoform in skeletal muscle. Moreover, deletion of AMP-activated protein kinase α2 abolished the effect of orosomucoid on fatigue and muscle glycogen. These findings indicate that orosomucoid may promote glycogen storage and enhance muscle function through C-C chemokine receptor type 5-mdiated activation of AMP-activated protein kinase, which in turn activates glycogen synthase and increases muscle glycogen.
10.3389/fphar.2016.00302
An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways.
Maes Michael
Progress in neuro-psychopharmacology & biological psychiatry
There is a significant 'comorbidity' between depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Depressive symptoms frequently occur during the course of ME/CFS. Fatigue and somatic symptoms (F&S), like pain, muscle tension, and a flu-like malaise, are key components of depression. At the same time, depression and ME/CFS show major clinical differences, which allow to discriminate them with a 100% accuracy. This paper aims to review the shared pathways that underpin both disorders and the pathways that discriminate them. Numerous studies have shown that depression and ME/CFS are characterized by shared aberrations in inflammatory, oxidative and nitrosative (IO&NS) pathways, like systemic inflammation and its long-term sequels, including O&NS-induced damage to fatty acids, proteins and DNA; dysfunctional mitochondria; lowered antioxidant levels, like zinc and coenzyme Q10; autoimmune responses to neoepitopes formed by O&NS; lowered omega-3 polyunsaturated fatty acid levels; and increased translocation of gram-negative bacteria. Some IO&NS-related pathways, like the induction of indoleamine 2-3-dioxygenase, neurodegeneration and decreased neurogenesis, are more specific to depression, whereas other pathways, like the 2'-5' oligoadenylate synthetase/RNase L pathway, are specific to ME/CFS. Most current animal models of depression, e.g. those induced by cytokines, are not reminiscent of human depression but reflect a mixture of depressive and F&S symptoms. The latter symptoms, sometimes called sickness behavior, differ from depression and ME/CFS because the former is a (sub)acute response to infection-induced pro-inflammatory cytokines that aims to enhance recovery, whereas the latter are characterized by long-term sequels in multiple IO&NS pathways. Depression and ME/CFS are not 'comorbid' disorders, but should be regarded as 'co-associated disorders' that are clinical manifestations of shared pathways.
10.1016/j.pnpbp.2010.06.023
Ursolic acid induces mitochondrial biogenesis through the activation of AMPK and PGC-1 in C2C12 myotubes: a possible mechanism underlying its beneficial effect on exercise endurance.
Food & function
Mitochondrial biogenesis, which involves an increase in mitochondrial number and the overall capacity of oxidative phosphorylation, is a critical determinant of skeletal muscle function. Recent findings have shown that some natural products can enhance mitochondrial adaptation to aerobic exercise, which in turn improves exercise performance, presumably by delaying muscle fatigue. Ursolic acid (UA), a natural triterpene, is commonly found in various vegetables and fruits. In the current study, UA was shown to increase mitochondrial mass and ATP generation capacity, with a concomitant production of a low level of mitochondrial reactive oxygen species (ROS) in C2C12 myotubes. Mitochondrial ROS, in turn, activated the redox sensitive adenosine monophosphate-dependent protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator-1(PGC-1) pathway. The activation of AMPK/PGC-1 further increased the expression of cytochrome c oxidase (COX) and uncoupling protein 3. Animal studies showed that UA can also dose-dependently increase the endurance exercise capacity in mice, as assessed by a weight-loaded swimming test and a hanging wire test. Our findings suggest that UA may induce mitochondrial biogenesis through the activation of AMPK and PGC-1 pathways in skeletal muscle, thereby offering a promising prospect for its use to enhance exercise endurance and alleviating fatigue in humans.
10.1039/c7fo00127d
Antifatigue Activity of Liquid Cultured Tricholoma matsutake Mycelium Partially via Regulation of Antioxidant Pathway in Mouse.
Li Quan,Wang Yanzhen,Cai Guangsheng,Kong Fange,Wang Xiaohan,Liu Yang,Yang Chuanbin,Wang Di,Teng Lirong
BioMed research international
Tricholoma matsutake has been popular as food and biopharmaceutical materials in Asian countries for its various pharmacological activities. The present study aims to analyze the antifatigue effects on enhancing exercise performance of Tricholoma matsutake fruit body (ABM) and liquid cultured mycelia (TM) in mouse model. Two-week Tricholoma matsutake treatment significantly enhances the exercise performance in weight-loaded swimming, rotating rod, and forced running test. In TM- and ABM-treated mice, some factors were observed at 60 min after swimming compared with nontreated mice, such as the increased levels of adenosine triphosphate (ATP), antioxidative enzymes, and glycogen and the reduced levels of malondialdehyde and reactive oxygen species in muscle, liver, and/or serum. Further data obtained from western blot show that CM and ABM have strongly enhanced the activation of 5'-AMP-activated protein kinase (AMPK), and the expressions of peroxisome proliferator have activated receptor γ coactivator-1α (PGC-1α) and phosphofructokinase-1 (PFK-1) in liver. Our data suggest that both Tricholoma matsutake fruit body and liquid cultured mycelia possess antifatigue effects related to AMPK-linked antioxidative pathway. The information uncovered in our study may serve as a valuable resource for further identification and provide experimental evidence for clinical trials of Tricholoma matsutake as an effective agent against fatigue related diseases.
10.1155/2015/562345
Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome.
Sweetman Eiren,Ryan Margaret,Edgar Christina,MacKay Angus,Vallings Rosamund,Tate Warren
International journal of immunopathology and pharmacology
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood disease affecting 0.2%-2% of the global population. To gain insight into the pathophysiology of ME/CFS in New Zealand, we examined the transcriptomes of peripheral blood mononuclear cells by RNA-seq analysis in a small well-characterized patient group (10 patients), with age/gender-matched healthy controls (10 control subjects). Twenty-seven gene transcripts were increased 1.5- to sixfold and six decreased three- to sixfold in the patient group ( P < 0.01). The top enhanced gene transcripts, IL8, NFΚBIA and TNFAIP3, are functionally related to inflammation, and significant changes were validated for IL8 and NFΚBIA by quantitative polymerase chain reaction (qPCR). Functional network analysis of the altered gene transcripts ( P < 0.01) detected interactions between the products related to inflammation, circadian clock function, metabolic dysregulation, cellular stress responses and mitochondrial function. Ingenuity pathway analysis ( P < 0.05) provided further insights into the dysfunctional physiology, highlighting stress and inflammation pathways. This analysis provides novel insights into the molecular changes in ME/CFS and contributes to the understanding of the pathophysiological mechanisms of the disease.
10.1177/2058738418820402
Decrease of hepatic delta-aminolevulinate dehydratase activity in an animal model of fatigue.
Tahara Tsuyoshi,Tanaka Masaaki,Nozaki Satoshi,Jin Guanghua,Onoe Hirotaka,Watanabe Yasuyoshi
Biochemical and biophysical research communications
Fatigue can be defined physiologically as inability to maintain the expected power output. At present, no standard of fatigue are yet available. In order to find biomarkers of fatigue, we investigated the level of delta-aminolevulinic acid (ALA), the first intermediate metabolite in the heme biosynthetic pathway, in the plasma and urine of an animal model of fatigue. To prepare fatigued animals, we kept rats for 5 days in a cage filled with water to a height of 1.5 cm. As a result, the plasma and urinary ALA levels were increased in the fatigued animals as compared with those in the control animals. One day after the rats had been returned to their normal cages, these increased levels were restored to the control ones. We also examined the activity of the enzyme ALA dehydratase (ALAD), which is the second enzyme in the heme biosynthetic pathway, and ALAD gene expression during the fatigue and its recovery sessions. The ALAD activity, as well as its gene expression, in the liver of the fatigued animals was decreased as compared with those of the control animals. Both activity and gene expression of ALAD were recovered to their respective control levels after the rats had been allowed to rest in their normal cages for 1 day. Furthermore, the activity of ALA synthase (ALAS), the rate-limiting enzyme in the heme biosynthesis, in the liver was increased after the fatigue session for 5 days. Although this level of increase in the plasma concentration of ALA may not induce fatigue, increase in plasma and urinary ALA levels can be biomarkers of fatigue.
10.1016/j.bbrc.2006.12.139
SR Ca leak in skeletal muscle fibers acts as an intracellular signal to increase fatigue resistance.
Ivarsson Niklas,Mattsson C Mikael,Cheng Arthur J,Bruton Joseph D,Ekblom Björn,Lanner Johanna T,Westerblad Håkan
The Journal of general physiology
Effective practices to improve skeletal muscle fatigue resistance are crucial for athletes as well as patients with dysfunctional muscles. To this end, it is important to identify the cellular signaling pathway that triggers mitochondrial biogenesis and thereby increases oxidative capacity and fatigue resistance in skeletal muscle fibers. Here, we test the hypothesis that the stress induced in skeletal muscle fibers by endurance exercise causes a reduction in the association of FK506-binding protein 12 (FKBP12) with ryanodine receptor 1 (RYR1). This will result in a mild Ca leak from the sarcoplasmic reticulum (SR), which could trigger mitochondrial biogenesis and improved fatigue resistance. After giving mice access to an in-cage running wheel for three weeks, we observed decreased FKBP12 association to RYR1, increased baseline [Ca], and signaling associated with greater mitochondrial biogenesis in muscle, including PGC1α1. After six weeks of voluntary running, FKBP12 association is normalized, baseline [Ca] returned to values below that of nonrunning controls, and signaling for increased mitochondrial biogenesis was no longer present. The adaptations toward improved endurance exercise performance that were observed with training could be mimicked by pharmacological agents that destabilize RYR1 and thereby induce a modest Ca leak. We conclude that a mild RYR1 SR Ca leak is a key trigger for the signaling pathway that increases muscle fatigue resistance.
10.1085/jgp.201812152
Fatigue-induced Orosomucoid 1 Acts on C-C Chemokine Receptor Type 5 to Enhance Muscle Endurance.
Lei Hong,Sun Yang,Luo Zhumin,Yourek Gregory,Gui Huan,Yang Yili,Su Ding-Feng,Liu Xia
Scientific reports
Understanding and managing fatigue is a significant challenge in clinic and society. In attempting to explore how the body responds to and regulates fatigue, we found in rodent fatigue models that orosomucoid 1 (ORM1) was significantly increased in multiple tissues, including blood and muscle. Interestingly, administration of exogenous ORM1 increased muscle glycogen and enhanced muscle endurance, whereas ORM1 deficiency resulted in a significant decrease of muscle endurance both in vivo and in vitro, which could largely be restored by exogenous ORM1. Further studies demonstrated that ORM1 can bind to C-C chemokine receptor type 5 (CCR5) on muscle cells and deletion of the receptor abolished the effect of ORM1. Thus, fatigue upregulates the level of ORM1, which in turn functions as an anti-fatigue protein to enhance muscle endurance via the CCR5 pathway. Modulation of the level of ORM1 and CCR5 signaling could be a novel strategy for the management of fatigue.
10.1038/srep18839
[The effects of salidroside on the apoptosis pathway of myocardial cells in acute exhausted rats].
Qie Tao,Xu Peng,Zhang Bing-Xin,Cao Xue-Bin
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology
OBJECTIVE:To investigate whether salidroside (Sal) plays a part in protecting myocardial cell through reducing the myocardial ischemia and the apoptosis pathway of both death receptors and mitochondria in acute exhausted rats. METHODS:Male SD rats were randomly divided into 4 groups (n=6): control group(Con), acute exhaustive swimming group (EE), low-dose and high-dose Sal pre-treatment exhaustive swimming group (SLE, SHE). Rats were treated with Sal solution (15 or 30 mg/(kg·d)) or 0.9%NaCl (3 ml/(kg·d)) by intraperitoneal injection for 15 d, respectively. The Con group did not carry out swimming training. The next day after the end of intraperitoneal administration, the rats in EE, SLE and SHE group were forced to swim until they were exhausted followed the standard of Thomas. After the end of exhaustive exercise, the rats were anesthetized and the blood samples and hearts were collected immediately. The myocardial ischemia and hypoxia area and myocardial apoptosis index (AI) were also observed. Serum ischemia modified albumin (IMA), cardiac troponin I (cTnI), brain natriuretic peptide(BNP) and myocardial cell Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2) were determined. The expressions of myocardial TNF receptor superfamily member 6 (Fas), cytochrome C (Cyto-c), aspartate proteolytic enzyme-3(Caspase-3), aspartate proteolytic enzyme-8(Caspase-8), and aspartate proteolytic enzyme-9(Caspase-9) were detected. RESULTS:Compared with the Con group, the myocardial ischemia and hypoxia area in EE group was increased significantly. The serum levels of IMA, cTnI and BNP, AI and Bax levels and cardiac Fas, Cyto-C, Caspase-3, Caspase-8 and Caspase-9 protein expressions of EE group were also increased significantly (P＜0.01), while the protein expression of Bcl-2 in cardiac tissues was decreased significantly (P＜0.01). Compared with the EE group, the myocardial ischemia and hypoxia area, serum levels of IMA, cTnI and BNP, AI and Bax levels, and the protein expressions of cardiac Fas, Cyto-C, Caspase-3, Caspase-8 and Caspase-9 in Sal group were all decreased significantly(P＜0.01). while the protein expression of cardiac Bcl-2 in Sal group were increased significantly (P＜0.01). CONCLUSION:Sal plays a role in protecting myocardial cell through reducing the myocardial ischemia and inhibiting myocardial cell apoptosis in exhaustive exercise rats. The mechanism of reducing myocardial cell apoptosis may be related to inhibiting the expressions of Fas, Cyto-C, Caspase-3, Caspase-8, Caspase-9 and increasing the expression of Bcl-2.
10.12047/j.cjap.5691.2019.080
PROMIS Fatigue short forms are reliable and valid in adults with rheumatoid arthritis.
Bingham Iii Clifton O,Gutierrez Anna Kristina,Butanis Alessandra,Bykerk Vivian P,Curtis Jeffrey R,Leong Amye,Lyddiatt Anne,Nowell W Benjamin,Orbai Ana Maria,Bartlett Susan J
Journal of patient-reported outcomes
BACKGROUND:Fatigue is prevalent and impactful in rheumatoid arthritis (RA). There is no standardized measure for its assessment nor data concerning the performance of PROMIS-Fatigue short forms (SFs) in people with RA. We evaluated the construct validity of 4-, 7-, and 8-item PROMIS-Fatigue SFs in RA patients across the range of disease activity. METHODS:Adult RA patients were recruited from an online patient community and an observational cohort from three academic medical centers. Measures included PROMIS-Fatigue SFs, other PROMIS measures, and other patient reported outcomes including RAND-36 Vitality, Fatigue NRS, and patient global assessment of disease activity. Other measures from the observational cohort included 28-joint swollen and tender joints, physician global assessment, and the composite RA clinical disease activity index (CDAI). RESULTS:Two-hundred online participants and 348 participants from the observational cohort were included. PROMIS Fatigue SF scores spanned the measurement continuum and correlated highly with each other (r's ≥ 0.91) and other fatigue measures (r's ≥ 0.85). PROMIS-Fatigue SF scores were highly and inversely associated with Physical Function and Participation (r's - 0.77 to - 0.78), and moderately-highly and positively correlated with pain, sleep disturbance, anxiety, and depression (r's 0.60 to 0.75). PROMIS-Fatigue SF scores showed dose-response relationships across fatigue severity descriptors and CDAI categories. CONCLUSIONS:These results provide robust evidence supporting the construct validity of the 4, 7, and 8-item PROMIS-Fatigue SFs. They capture fatigue across the spectrum of RA disease activity in diverse groups of individuals and should be considered for use as patient-centered assessments of disease control and treatment efficacy.
10.1186/s41687-019-0105-6
Fatigued breast cancer survivors and gene polymorphisms in the inflammatory pathway.
Reinertsen Kristin V,Grenaker Alnæs Grethe I,Landmark-Høyvik Hege,Loge Jon H,Wist Erik,Kristensen Vessela N,Fosså Sophie D,Edvardsen Hege
Brain, behavior, and immunity
Chronic fatigue (CF) in breast cancer survivors (BCSs) has been associated with increased serum C-reactive protein-levels (CRP), pro-inflammatory cytokines and cytokine gene single nucleotide polymorphisms (SNPs). Still, there are few studies on these topics, and due to small study-cohorts the possibility to adjust for other conditions related to inflammatory processes, e.g. depression, has been limited. In 302 BCSs, examined approximately four years after treatment for breast cancer stage II/III, data on high sensitivity (hs)CRP, leukocytes and mRNA interleukin (IL)1β and IL6R expression, depression and chronic fatigue were available. Three years thereafter, 236 BCSs were re-examined. The associations between fatigue and SNPs in inflammation-related genes; IL1β (rs16944), IL6 (rs1800795), IL6receptor (rs4129267, rs4845617, rs2228145), CRP (rs2794521, rs3091244) were investigated, together with the relations between SNPs in IL6R,IL1β and CRP genes and mRNA blood expression levels of IL6R and IL1β and serum hsCRP-levels, respectively. All analyses were repeated after exclusion of depressed individuals and separating BCSs with persistent fatigue from never-fatigued individuals. Even after exclusion of depressed individuals neither the SNPs nor the mRNA IL1β and IL6R expression levels were associated with chronic or persistent fatigue. In the subset of persistent fatigued and never-fatigued individuals the CRP SNP (rs3091244) was associated with hsCRP level (p=0.02). IL1β and IL6R mRNA expression levels were not related to the IL1β and IL6R genotypes. In a large cohort of BCSs the investigated SNPs in inflammation-related genes were not associated with fatigue, though subset analyses indicated an association between the CRP SNP (rs3091244) and serum hsCRP.
10.1016/j.bbi.2011.04.001
Effects of Mongolian Warm Acupuncture on iNOS/NO and Inflammatory Cytokines in the Hippocampus of Chronic Fatigue Rats.
Frontiers in integrative neuroscience
The inducible nitric oxide synthase/nitric oxide (iNOS/NO) signaling pathway and inflammatory cytokines play important roles in the pathogenesis of exercise-induced fatigue. Studies have found that Mongolian warm acupuncture (WA) could alleviate exercise-induced fatigue. However, the exact mechanisms underlying its effects remain unclear. In the present study, we investigated the effects of Mongolian WA on iNOS/NO signaling pathway and proinflammatory cytokines in a chronic exhaustive swimming-induced fatigue rat model. Animals were randomly divided into Control group, Ctrl + WA group, Model group, and Model + WA group. The body weight, exhaustive swimming time test, and Morris water maze test were performed before and after the chronic exhaustive swimming. The serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and iNOS were detected by enzyme linked immunosorbent assay (ELISA). The mRNA expressions of IL-1β, IL-6, TNF-α, IFN-γ, and iNOS in the hippocampus were measured by real-time polymerase chain reaction (RT-PCR). Moreover, the protein expression of iNOS in the hippocampus was measured by western blot, and the NO productions in the serum and hippocampus were detected by Griess reaction system. Chronic exhaustive exercise significantly reduced the body weight and exhaustive swimming time, and induced impairment in learning and memory, and which were reversed by WA treatment. Chronic exhaustive exercise also increased the expressions of iNOS and proinflammatory cytokines, while WA treatment significantly decreased the level of iNOS and proinflammatory cytokines. However, chronic exhaustive exercise did not affect the NO production. These findings demonstrated that WA could alleviate the chronic exhaustive swimming-induced fatigue and improve the learning and memory ability, and the actions might be related to the reduction of inflammatory response and iNOS expression.
10.3389/fnint.2019.00078
Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions.
Kavanagh Justin J,McFarland Amelia J,Taylor Janet L
The Journal of physiology
KEY POINTS:Animal preparations have revealed that moderate synaptic release of serotonin (5-HT) onto motoneurones enhances motor activity via activation of 5-HT receptors, whereas intense release of 5-HT causes spillover of 5-HT to extrasynaptic 5-HT receptors on the axon initial segment to reduce motoneurone activity. We explored if increasing extracellular concentrations of endogenously released 5-HT (via the selective serotonin reuptake inhibitor paroxetine) influences the ability to perform unfatigued and fatigued maximal voluntary contractions in humans. Following the ingestion of paroxetine, voluntary muscle activation and torque generation increased during brief unfatigued maximal contractions. In contrast, the ability to generate maximal torque with increased 5-HT availability was compromised under fatigued conditions, which was consistent with paroxetine-induced reductions in motoneurone excitability and voluntary muscle activation. This is the first in vivo human study to provide evidence that 5-HT released onto the motoneurones could play a role in central fatigue. ABSTRACT:Brief stimulation of the raphe-spinal pathway in the turtle spinal cord releases serotonin (5-HT) onto motoneurones to enhance excitability. However, intense release of 5-HT via prolonged stimulation results in 5-HT spillover to the motoneurone axon initial segment to activate inhibitory 5-HT receptors, thus providing a potential spinal mechanism for exercise-induced central fatigue. We examined how increased extracellular concentrations of 5-HT affect the ability to perform brief, as well as sustained, maximal voluntary contractions (MVCs) in humans. Paroxetine was used to enhance 5-HT concentrations by reuptake inhibition, and three studies were performed. Study 1 (n = 14) revealed that 5-HT reuptake inhibition caused an ∼4% increase in elbow flexion MVC. However, when maximal contractions were sustained, time-to-task failure was reduced and self-perceived fatigue was higher with enhanced availability of 5-HT. Study 2 (n = 11) used twitch interpolation to reveal that 5-HT-based changes in motor performance had a neural basis. Enhanced 5-HT availability increased voluntary activation for the unfatigued biceps brachii and decreased voluntary activation of the biceps brachii by 2-5% following repeated maximal elbow flexions. The final study (n = 8) investigated whether altered motoneurone excitability may contribute to 5-HT changes in voluntary activation. F-waves of the abductor digiti minimi (ADM) were unaffected by paroxetine for unfatigued muscle and marginally affected following a brief 2-s MVC. However, F-wave area and persistence were significantly decreased following a prolonged 60-s MVC of the ADM. Overall, high serotonergic drive provides a spinal mechanism by which higher concentrations of 5-HT may contribute to central fatigue.
10.1113/JP277148
Genistein attenuates genioglossus muscle fatigue under chronic intermittent hypoxia by down-regulation of oxidative stress level and up-regulation of antioxidant enzyme activity through ERK1/2 signaling pathway.
Ding Wh,Liu Yh
Oral diseases
OBJECTIVE:This study aims to investigate the effects of genistein on contractile properties of genioglossus under chronic intermittent hypoxia (CIH) conditions and its relationship with oxidative stress, antioxidant enzyme, and ERK1/2 signaling pathway. MATERIALS AND METHODS:Fifty female Sprague-Dawley rats were randomly divided into five groups 1 week after ovariectomy: the normal control group, the CIH group, the CIH with low-dose, medium-dose, and high-dose genistein groups. Rats in the latter four groups were exposed to CIH for 5 weeks. Twitch tension, tetanic tension, and fatigue resistance of genioglossus were investigated. Malondialdehyde (MDA) and mitochondrial reactive oxygen species (ROS), enzymatic activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and ERK1/2 were detected. RESULTS:Muscle fatigue resistance and enzymatic activity of GPx, CAT, and SOD were reduced after CIH exposure and improved by different doses of genistein at different degrees. CIH increased the level of ROS and MDA, and they were returned to normal by genistein. The expression of phospho-ERK1/2 is opposite to the changes in muscle fatigue resistance. CONCLUSION:Chronic intermittent hypoxia decreases fatigue resistance of genioglossus, and genistein treatment reverses the fatigability of genioglossus by down-regulation of oxidative stress level and up-regulation of antioxidant enzymatic activity probably through ERK1/2 signaling pathway.
10.1111/j.1601-0825.2011.01822.x
Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity.
Panossian Alexander,Wikman Georg
Current clinical pharmacology
The aim of this review article is to assess the level of scientific evidence presented by clinical trials of adaptogens in fatigue, and to provide a rationale at the molecular level for verified effects. Strong scientific evidence is available for Rhodiola rosea SHR-5 extract, which improved attention, cognitive function and mental performance in fatigue and in chronic fatigue syndrome. Good scientific evidence has been documented in trails in which Schisandra chinensis and Eleutherococcus senticosus increased endurance and mental performance in patients with mild fatigue and weakness. Based on their efficacy in clinical studies, adaptogens can be defined as a pharmacological group of herbal preparations that increase tolerance to mental exhaustion and enhance attention and mental endurance in situations of decreased performance. The beneficial stress-protective effect of adaptogens is related to regulation of homeostasis via several mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the control of key mediators of stress response such as molecular chaperons (e.g. Hsp70), stress-activated c-Jun N-terminal protein kinase (JNK1), Forkhead Box O transcription factor DAF-16, cortisol and nitric oxide (NO). The key point of action of phytoadaptogens appears to be their up-regulating and stress-mimetic effects on the "stress-sensor" protein Hsp70, which plays an important role in cell survival and apoptosis. Hsp70 inhibits the expression of NO synthase II gene and interacts with glucocorticoid receptors directly and via the JNK pathway, thus affecting the levels of circulating cortisol and NO. Prevention of stress-induced increase in NO, and the associated decrease in ATP production, results in increased performance and endurance. Adaptogen-induced up-regulation of Hsp70 triggers stress-induced JNK-1 and DAF-16-mediated pathways regulating the resistance to stress and resulting in enhanced mental and physical performance and, possibly, increased longevity.
10.2174/157488409789375311
Multiple determinants and consequences of cohesion fatigue in mammalian cells.
Molecular biology of the cell
Cells delayed in metaphase with intact mitotic spindles undergo cohesion fatigue, where sister chromatids separate asynchronously, while cells remain in mitosis. Cohesion fatigue requires release of sister chromatid cohesion. However, the pathways that breach sister chromatid cohesion during cohesion fatigue remain unknown. Using moderate-salt buffers to remove loosely bound chromatin cohesin, we show that "cohesive" cohesin is not released during chromatid separation during cohesion fatigue. Using a regulated protein heterodimerization system to lock different cohesin ring interfaces at specific times in mitosis, we show that the Wapl-mediated pathway of cohesin release is not required for cohesion fatigue. By manipulating microtubule stability and cohesin complex integrity in cell lines with varying sensitivity to cohesion fatigue, we show that rates of cohesion fatigue reflect a dynamic balance between spindle pulling forces and resistance to separation by interchromatid cohesion. Finally, while massive separation of chromatids in cohesion fatigue likely produces inviable cell progeny, we find that short metaphase delays, leading to partial chromatid separation, predispose cells to chromosome missegregation. Thus, complete separation of one or a few chromosomes and/or partial separation of sister chromatids may be an unrecognized but common source of chromosome instability that perpetuates the evolution of malignant cells in cancer.
10.1091/mbc.E18-05-0315
Altered Cd8+ T lymphocyte Response Triggered by Arginase 1: Implication for Fatigue Intensification during Localized Radiation Therapy in Prostate Cancer Patients.
Saligan Leorey N,Lukkahatai Nada,Zhang Zhang-Jin,Cheung Chi Wai,Wang Xiao-Min
Neuropsychiatry
Fatigue, the most common side effect of cancer treatments, is observed to intensify during external-beam radiation therapy (EBRT). The underlying molecular mechanisms remain unclear. This study investigated the differentially expressed genes/proteins and their association with fatigue intensification during EBRT. Fatigue scores measured by FACT-F and peripheral blood were collected prior to treatment (baseline D), at midpoint (days 19-21, D21) and endpoint (days 38-42, D42) from men (n=30) with non-metastatic prostate cancer undergoing EBRT. RNA extracted from peripheral blood was used for gene expression analysis. Plasma arginase I and arginine were examined using ELISA and liquid chromatography-tandem mass spectrometry. Differences in fatigue scores, gene and protein expression between times points following EBRT were analyzed by one way ANOVA followed by Post Hoc t-test. Fatigue scores decreased significantly from baseline (44.6 ± 8.1) to midpoint (37.3 ± 10.6, 0.000, low scores indicating high fatigue) and to endpoint (37.4 ± 10.1, p=0.001) during EBRT. (encoding arginase type 1) was significantly up regulated from baseline to midpoint of EBRT (fold change =2.41, <0.05) whereas genes associated with the adaptive immune functional pathway () were significantly downregulated >2-fold between the study time points. The changes in gene expression were associated with patient reported fatigue intensity. Moreover, the upregulation of was negatively correlated with the absolute lymphocyte count (R=0.561, =0.01) only in the high level of fatigue group (n=17) during EBRT. Increased expression is known to result in arginine deficiency, which leads to immunosuppression by impairing lymphocyte proliferation and activation. EBRT-induced upregulation may play an essential role in fatigue intensification via the arginine deficiency and suppression of T-cell proliferation pathways. These findings may provide novel insights into the molecular-genetic mechanisms underlying the development and intensification of cancer treatment-related fatigue.
10.4172/Neuropsychiatry.1000454
Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?
Meeus Mira,Mistiaen Wilhelm,Lambrecht Luc,Nijs Jo
Anticancer research
Cancer and chronic fatigue syndrome (CFS) are both characterised by fatigue and severe disability. Besides fatigue, certain aspects of immune dysfunctions appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunctions in CFS and cancer is provided. Special emphasis is given to the relationship between immune dysfunctions and fatigue. Abnormalities in ribonuclease (RNase) L and hyperactivation of nuclear factor kappa beta (NF-kappaB) are present in CFS and in prostate cancer. Malfunctioning of natural killer (NK) cells has long been recognised as an important factor in the development and reoccurrence of cancer, and has been documented repeatedly in CFS patients. The dysregulation of the RNase L pathway, hyperactive NF-kappaB leading to disturbed apoptotic mechanisms and oxidative stress or excessive nitric oxide, and low NK activity may play a role in the two diseases and in the physiopathology of the common symptom fatigue. However, in cancer the relation between the immune dysfunctions and fatigue has been poorly studied. Immunological abnormalities to such as a dysregulated RNase L pathway, hyperactive NF-kappaB, increased oxidative stress and reduced NK cytotoxicity, among others, are present in both diseases. These anomalies may be part of the physiopathology of some of the common complaints, such as fatigue. Further studies to confirm the hypotheses given here are warranted.
Liver-brain interactions in inflammatory liver diseases: implications for fatigue and mood disorders.
D'Mello Charlotte,Swain Mark G
Brain, behavior, and immunity
Chronic inflammatory liver diseases are often accompanied by behavior alterations including fatigue, mood disorders, cognitive dysfunction and sleep disturbances. These altered behaviors can adversely affect patient quality of life. The communication pathways between the inflamed liver and the brain that mediate changes in central neural activity leading to behavior alterations during liver inflammation are poorly understood. Neural and humoral communication pathways have been most commonly implicated as driving peripheral inflammation to brain signaling. Classically, the cytokines TNFα, IL-1β and IL-6 have received the greatest scientific attention as potential mediators of this communication pathway. In mice with liver inflammation we have identified a novel immune-mediated liver-to-brain communication pathway whereby CCR2(+) monocytes found within the peripheral circulation transmigrate into the brain parenchyma in response to MCP-1/CCL2 expressing activated microglia. Inhibition of cerebral monocyte infiltration in these mice significantly improved liver inflammation associated sickness behaviors. Importantly, in recent work we have found that at an earlier time point, when cerebral monocyte infiltration is not evident in mice with liver inflammation, increased monocyte:cerebral endothelial cell adhesive interactions are observed using intravital microscopy of the brain. These monocyte:cerebral endothelial cell adhesive interactions are P-selectin mediated, and inhibition of these interactions attenuated microglial activation and sickness behavior development. Delineating the pathways that the periphery uses to communicate with the brain during inflammatory liver diseases, and the central neurotransmitter systems that are altered through these communication pathways (e.g., serotonin, corticotrophin releasing hormone) to give rise to liver inflammation-associated sickness behaviors, will allow for the identification of novel therapeutic targets to decrease the burden of debilitating symptoms in these patients.
10.1016/j.bbi.2013.10.009
High-density lipoprotein cholesterol is associated with multiple sclerosis fatigue: A fatigue-metabolism nexus?
Browne Richard W,Jakimovski Dejan,Ziliotto Nicole,Kuhle Jens,Bernardi Francesco,Weinstock-Guttman Bianca,Zivadinov Robert,Ramanathan Murali
Journal of clinical lipidology
BACKGROUND:Fatigue is a frequent symptom in multiple sclerosis (MS). The role of cholesterol and lipids in MS fatigue has not been investigated. OBJECTIVE:To investigate the associations of cholesterol biomarkers and serum neurofilament light chain (sNfL) with fatigue in relapsing-remitting MS. METHODS:This cross-sectional study included 75 relapsing-remitting MS patients (69% female, mean age ± SD: 49.6 ± 11 years and median Expanded Disability Status Scale score: 2.0). Fatigue, disability, and depression were assessed with Fatigue Severity Scale (FSS), Expanded Disability Status Scale, and the Beck Depression Index-Fast Screen, respectively. sNfL was measured using single-molecule array technology. Plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and an apolipoprotein panel data were obtained. Soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), chemokine (C-C motif) ligand 5 (CCL5 or RANTES), and CCL18 levels were measured to assess inflammation. RESULTS:The mean FSS was 4.27 ± 1.73, and 57% had severe fatigue status (SFS, FSS ≥ 4.0). In regression analyses adjusted for age, sex, disability, and depression, lower FSS and SFS were associated with greater HDL-C (P = .006 for FSS, and P = .016 for SFS) and lower TC to HDL-C ratio (P = .011 for FSS, and P = .009 for SFS). Apolipoprotein A-II was also associated with FSS (P = .022). sNfL, CCL5, CCL18, sICAM-1, and sVCAM-1 levels were not associated with fatigue after adjusting for disability and depression. CONCLUSIONS:TC to HDL-C ratio is associated with MS fatigue. Our results implicate a potential role for the HDL-C pathway in MS fatigue and could provide possible targets for the treatment of MS fatigue.
10.1016/j.jacl.2019.06.003
Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue.
Bower Julienne E,Ganz Patricia A,Irwin Michael R,Arevalo Jesusa M G,Cole Steve W
Brain, behavior, and immunity
Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n=11) and non-fatigued controls (n=10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p<.05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors.
10.1016/j.bbi.2010.09.010
Virtual Screening of Potential Anti-fatigue Mechanism of Polygonati Rhizoma Based on Network Pharmacology.
Wang Ze-Feng,Hu Ye-Qing,Wu Qi-Guo,Zhang Rui
Combinatorial chemistry & high throughput screening
BACKGROUND AND OBJECTIVE:A large number of people are facing the danger of fatigue due to the fast-paced lifestyle. Fatigue is common in some diseases, such as cancer. The mechanism of fatigue is not definite. Traditional Chinese medicine is often used for fatigue, but the potential mechanism of Polygonati Rhizoma (PR) is still not clear. This study attempts to explore the potential anti-fatigue mechanism of Polygonati Rhizoma through virtual screening based on network pharmacology. METHODS:The candidate compounds of PR and the known targets of fatigue are obtained from multiple professional databases. PharmMapper Server is designed to identify potential targets for the candidate compounds. We developed a Herbal medicine-Compound-Disease-Target network and analyzed the interactions. Protein-protein interaction network is developed through the Cytoscape software and analyzed by topological methods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment are carried out by DAVID Database. Finally, we develop Compound-Target-Pathway network to illustrate the anti-fatigue mechanism of PR. RESULTS:This approach identified 12 active compounds and 156 candidate targets of PR. The top 10 annotation terms for GO and KEGG were obtained by enrichment analysis with 35 key targets. The interaction between E2F1 and PI3K-AKT plays a vital role in the anti-fatigue effect of PR due to this study. CONCLUSION:This study demonstrates that PR has multi-component, multi-target and multipathway effects.
10.2174/1386207322666191106110615
[Synthesis reduction of central neurotransmitter 5-hydroxytryptamine by branched chain amino acid and associated antagonists improves postoperative fatigue syndrome].
Dong Qiantong,Zhang Xiaodong,Yu Zhen,Yan Jingyi,Chen Xiaolei
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery
OBJECTIVE:To observe the change of postoperative fatigue in rats after the effect of branched chain amino acid(BCAA) and associated antagonists on central neurotransmitter 5-HT metabolic pathway, and to investigate the role of 5-HT in the development of postoperative fatigue syndrome(POFS). METHODS:Fifty SD rats were randomly divided into sham operation group(C group, n=10), model group(M group, n=10), L-type amino acid transporter inhibitor group(L group, n=10), 5-HT uptake inhibitor group(F group, n=10) and branched chain amino acids(B group, n=10). The rats in the C group and the M group were injected with normal saline, while other three groups were respectively injected with BCH, fluoxetine, BCAA(val:leucine:isoleucine=5:3:2), on preoperative 1 h, postoperative day 1, 2, 3, 4. The rats, except for those in the C group, underwent resection of 70% of the middle small intestine with end-to-end anastomosis. General status of the rats was observed before and after surgery. Morris water maze test, including the hidden platform test and search space test (detecting the learning ability of rats) and tail suspension test (detecting physical endurance of rats) were used to evaluate the degree of POFS from postoperative day 1 to day 7. Concentration of tryptophan(TRP), 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) in different position of brain(hippocampus, striatum, hypothalamus) of rats were measured by high performance liquid chromatography(HPLC) at postoperative day 8. RESULTS:As compared to the M group, other four groups showed better general condition and less fatigue. In the hidden platform test, M group showed the least time of crossing platform as compared to other four groups(all P<0.05). Meanwhile, M group and B group performed the longer incubation period than C group and L group(all P<0.05). In search space test, M group and B group showed less time of crossing platform, but there were no significant differences among the groups(all P>0.05). In tail suspension test, M group and F group showed lower score of physical strength than L group and B group(all P<0.05). Levels of TRP in the L, F, B groups were lower compared to the M group(all P<0.01) in brain tissue. The least concentration of striatum 5-HT was found in the C group but there were no significant differences among the M, L, F and B groups. Level of 5-HIAA in the M group, only in hypothalamus, was higher than that in the F group(P<0.05), but no significant differences between the M group and the L and B groups were found. CONCLUSION:BCAA and associated antagonists (BCH, fluoxetine) can improve POFS by reducing the absorption of TRP that results in decreased synthesis of central 5-HT.
Enhanced serotonin availability amplifies fatigue perception and modulates the TMS-induced silent period during sustained low-intensity elbow flexions.
Thorstensen Jacob R,Taylor Janet L,Tucker Murray G,Kavanagh Justin J
The Journal of physiology
KEY POINTS:During maximal effort contractions, intense serotonin release via the raphe-spinal pathway spills over from the somato-dendritic compartment to activate inhibitory 5-HT receptors on the axon initial segment of motoneurons to reduce motoneuronal output. We investigated whether the same mechanism of central fatigue is present for low-intensity contractions, whereby weak serotonergic drive over an extended period may cause accumulation of serotonin and exacerbate central fatigue. Enhanced availability of serotonin did not directly influence motor pathways or motor performance during prolonged submaximal contraction. However, perceptions of muscle fatigue were greater, and the fatigue-induced lengthening of the silent period elicited via motor cortical stimulation was reduced with enhanced availability of serotonin. We propose that sustained low-intensity serotonergic neurotransmission influences supraspinal processes associated with fatigue, without directly influencing the output of the motor system during submaximal exercise. ABSTRACT:Enhanced availability of serotonin (5-HT) exacerbates central fatigue that occurs during maximal effort contractions. However, it is unknown if 5-HT release contributes to central fatigue during prolonged submaximal contractions. Hence, we assessed the effect that enhanced availability of 5-HT has on sustained low-intensity fatiguing contractions. Fifteen individuals (22.3 ± 2.1 years) ingested the 5-HT reuptake inhibitor paroxetine in a human, double-blinded, placebo-controlled, repeated-measures design. Participants performed a low-intensity isometric elbow flexion for 30 min (15% of maximal voluntary contraction, MVC). Throughout the protocol, brief MVCs were performed and muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of the brachial plexus, and motor point stimulation of the biceps were obtained. Ratings of perceived fatigue were also acquired. Paroxetine did not influence torque or voluntary activation during brief MVCs performed throughout the low-intensity contraction. However, paroxetine increased the perception of fatigue throughout the contraction (P = 0.005), and shortened the biceps silent period elicited via TMS during sustained submaximal contraction (P = 0.003) and brief MVCs (P = 0.011). Overall, it appears that prolonged low-intensity contractions do not cause intense 5-HT release onto motoneurons, and therefore, 5-HT does not activate inhibitory extra-synaptic 5-HT receptors of motoneurons to reduce their output. Although motor performance was unaffected by paroxetine, perceived fatigue was greater and intracortical inhibitory activity was reduced following the enhancement of endogenous concentrations of 5-HT during sustained submaximal contraction. Thus, 5-HT affects supraspinal processes during low-intensity contractions without directly altering motor pathways projecting to the muscle.
10.1113/JP279347
Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation.
Cotel Florence,Exley Richard,Cragg Stephanie J,Perrier Jean-François
Proceedings of the National Academy of Sciences of the United States of America
Motor fatigue induced by physical activity is an everyday experience characterized by a decreased capacity to generate motor force. Factors in both muscles and the central nervous system are involved. The central component of fatigue modulates the ability of motoneurons to activate muscle adequately independently of the muscle physiology. Indirect evidence indicates that central fatigue is caused by serotonin (5-HT), but the cellular mechanisms are unknown. In a slice preparation from the spinal cord of the adult turtle, we found that prolonged stimulation of the raphe-spinal pathway--as during motor exercise--activated 5-HT1A receptors that decreased motoneuronal excitability. Electrophysiological tests combined with pharmacology showed that focal activation of 5-HT1A receptors at the axon initial segment (AIS), but not on other motoneuronal compartments, inhibited the action potential initiation by modulating a Na(+) current. Immunohistochemical staining against 5-HT revealed a high-density innervation of 5-HT terminals on the somatodendritic membrane and a complete absence on the AIS. This observation raised the hypothesis that a 5-HT spillover activates receptors at this latter compartment. We tested it by measuring the level of extracellular 5-HT with cyclic voltammetry and found that prolonged stimulations of the raphe-spinal pathway increased the level of 5-HT to a concentration sufficient to activate 5-HT1A receptors. Together our results demonstrate that prolonged release of 5-HT during motor activity spills over from its release sites to the AIS of motoneurons. Here, activated 5-HT1A receptors inhibit firing and, thereby, muscle contraction. Hence, this is a cellular mechanism for central fatigue.
10.1073/pnas.1216150110
Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome.
Rajeevan Mangalathu S,Dimulescu Irina,Murray Janna,Falkenberg Virginia R,Unger Elizabeth R
Human immunology
Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11K single nucleotide polymorphisms (SNPs) following the manufacturer's protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5' UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study.
10.1016/j.humimm.2015.06.014
Localized External Beam Radiation Therapy (EBRT) to the Pelvis Induces Systemic IL-1Beta and TNF-Alpha Production: Role of the TNF-Alpha Signaling in EBRT-Induced Fatigue.
McDonald Tasha L,Hung Arthur Y,Thomas Charles R,Wood Lisa J
Radiation research
Prostate cancer patients undergoing localized external beam radiation therapy (EBRT) can experience a progressive increase in fatigue, which can affect physical functioning and quality of life. The purpose of this study was to develop a mouse EBRT prostate cancer treatment model with which to determine the role of pro-inflammatory cytokines in the genesis of EBRT-related fatigue. We assessed voluntary wheel-running activity (VWRA) as a proxy for fatigue, food intake and body weight in male C57BL/6 mice undergoing EBRT to the pelvis. In the first experiment, anesthetized male C57BL/6 mice underwent fractionated EBRT to the pelvis for a total dose of 68.2 Gy, thereby mimicking a clinically relevant therapeutic dose and frequency. The day after the last treatment, levels of IL-1β and TNF-α in plasma along with mRNA levels in liver, colon and whole brain were measured. EBRT-induced fatigue resulted in reduced body weight, diminished food intake, and increased plasma and tissue levels of IL-1β and TNF-α. In a follow-up experiment, we used TNF-α-deficient mice to further delineate the role of TNF-α signaling in EBRT-induced sickness behavior. EBRT-induced changes in fatigue, food intake and body weight were no different between TNF-α deficient mice and their wild-type counterparts. Taken together our data demonstrate that a clinically relevant localized irradiation of the pelvis induces a systemic IL-1β and TNF-α response and sickness behavior in mice, but the TNF-α signaling pathway alone does not independently mediate these effects.
10.1667/RR14072.1
Evaluating the Role of Mitochondrial Function in Cancer-related Fatigue.
Journal of visualized experiments : JoVE
Fatigue is a common and debilitating condition that affects most cancer patients. To date, fatigue remains poorly characterized with no diagnostic test to objectively measure the severity of this condition. Here we describe an optimized method for assessing mitochondrial function of PBMCs collected from fatigued cancer patients. Using a compact extracellular flux system and sequential injection of respiratory inhibitors, we examined PBMC mitochondrial functional status by measuring basal mitochondrial respiration, spare respiratory capacity, and energy phenotype, which describes the preferred energy pathway to respond to stress. Fresh PBMCs are readily available in the clinical setting using standard phlebotomy. The entire assay described in this protocol can be completed in less than 4 hours without the involvement of complex biochemical techniques. Additionally, we describe a normalization method that is necessary for obtaining reproducible data. The simple procedure and normalization methods presented allow for repeated sample collection from the same patient and generation of reproducible data that can be compared between time points to evaluate potential treatment effects.
10.3791/57736
C-reactive protein predicts fatigue independently of depression in breast cancer patients prior to chemotherapy.
Pertl Maria M,Hevey David,Boyle Noreen T,Hughes Martina M,Collier Sonya,O'Dwyer Anne-Marie,Harkin Andrew,Kennedy M John,Connor Thomas J
Brain, behavior, and immunity
Heightened inflammatory activity has been proposed as a mechanism for the development of cancer-related fatigue (CRF), a common and distressing condition that can negatively affect quality of life. Inflammation is also implicated in the pathogenesis of depression, and depression is a strong predictor of CRF. Thus, the role of the pro-inflammatory cytokine network in CRF may be mediated by depression or both conditions may share similar underlying physiological processes. The current study investigated associations between fatigue, depression and inflammatory cytokine (IFN-γ, IL-6, TNF-α) and CRP concentrations, as well as kynurenine pathway (KP) activation, in 61 breast cancer patients prior to chemotherapy. Changes in inflammatory markers and KP activation over time were also explored, and associations with changes in fatigue and depression were examined. Higher levels of CRP were significantly correlated with fatigue and depression before chemotherapy; nevertheless, CRP predicted fatigue independently of depression. Although greater kynurenine concentrations were associated with increased immune activation, there was no evidence that the KP played a role in fatigue or depression. Furthermore, no relationships emerged between either fatigue or depression and IFN-γ, IL-6, or TNF-α before chemotherapy. Nevertheless, kynurenine levels pre- and post-treatment significantly predicted changes in depression, suggesting that heightened KP activation may contribute to depressive symptoms in patients treated for cancer. In addition, IL-6 significantly covaried with fatigue. These preliminary findings provide some support for the idea that low-grade inflammation contributes to the development of CRF, independently of depression; however, there was no evidence that this is mediated by KP activity.
10.1016/j.bbi.2013.07.177
mGluR5 mediates post-radiotherapy fatigue development in cancer patients.
Feng Li Rebekah,Fernández-Martínez Juan Luis,Zaal Kristien J M,deAndrés-Galiana Enrique J,Wolff Brian S,Saligan Leorey N
Translational psychiatry
Cancer-related fatigue (CRF) is a common burden in cancer patients and little is known about its underlying mechanism. The primary aim of this study was to identify gene signatures predictive of post-radiotherapy fatigue in prostate cancer patients. We employed Fisher Linear Discriminant Analysis (LDA) to identify predictive genes using whole genome microarray data from 36 men with prostate cancer. Ingenuity Pathway Analysis was used to determine functional networks of the predictive genes. Functional validation was performed using a T lymphocyte cell line, Jurkat E6.1. Cells were pretreated with metabotropic glutamate receptor 5 (mGluR5) agonist (DHPG), antagonist (MPEP), or control (PBS) for 20 min before irradiation at 8 Gy in a Mark-1 γ-irradiator. NF-κB activation was assessed using a NF-κB/Jurkat/GFP Transcriptional Reporter Cell Line. LDA achieved 83.3% accuracy in predicting post-radiotherapy fatigue. "Glutamate receptor signaling" was the most significant (p = 0.0002) pathway among the predictive genes. Functional validation using Jurkat cells revealed clustering of mGluR5 receptors as well as increased regulated on activation, normal T cell expressed and secreted (RANTES) production post irradiation in cells pretreated with DHPG, whereas inhibition of mGluR5 activity with MPEP decreased RANTES concentration after irradiation. DHPG pretreatment amplified irradiation-induced NF-κB activation suggesting a role of mGluR5 in modulating T cell activation after irradiation. These results suggest that mGluR5 signaling in T cells may play a key role in the development of chronic inflammation resulting in fatigue and contribute to individual differences in immune responses to radiation. Moreover, modulating mGluR5 provides a novel therapeutic option to treat CRF.
10.1038/s41398-018-0161-3
Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome.
Journal of neuroinflammation
BACKGROUND:The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1β and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue. METHODS:We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated. RESULTS:Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1β and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1β production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1β levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1β levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered. CONCLUSIONS:These findings suggest that LPS-induced fatigue is an IL-1β-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.
10.1186/s12974-016-0539-1
Gene Expression, and Fatigue in Puerto Rican Men during Radiotherapy for Prostate Cancer: an Exploratory Study.
Gonzalez Velda J,Saligan Leorey N,Fridley Brooke L,Ortiz-Zuazaga Humberto,Aaronson Lauren S
Puerto Rico health sciences journal
OBJECTIVE:To examine the trajectory of fatigue experienced by 26 Puerto Rican (PR) men over the course of External Beam Radiation Therapy (EBRT) and to assess gene expression changes from baseline to midpoint of EBRT using microarray technology. Design/Research Approach- Prospective exploratory and comparative design study. Setting- RT facility located in San Juan, PR. Sample/Participants-26 PR men with non-metastatic prostate cancer. METHODS:Participants completed 2 paper forms: demographics and the Spanish version of the 13-item FACT-fatigue at baseline, midpoint, and end of EBRT. Wholeblood samples were collected at baseline and at midpoint of EBRT. Descriptive data was analyzed using t-test, Wilcoxon, and Friedman test for repeated measures. Gene expression data was analyzed using the LIMMA package in R; the functional network analysis was conducted using Ingenuity Pathway analysis. Main Research Variable-Fatigue scores, gene expression. RESULTS:Subjects were of ages 52-81 with fatigue scores that remained unchanged during EBRT (baseline=42.38, SD=9.34; midpoint=42.11, SD=8.93, endpoint=43.04, SD=8.62). Three hundred seventy-three genes (130-up regulated and 243-down regulated) were differentially expressed from baseline to mid-point of EBRT (FDR<0.01). The top distinct canonical pathways of the differentially expressed probesets (p<0.0001) were: "Phospholipase C Signaling," "Role of NFAT in Regulation of the Immune Response," and "Gαq Signaling." CONCLUSION:While fatigue did not worsen over the course of EBRT for this sample as a group, there was variability in fatigue across the sample. It is possible that the over expression of the SESN3 gene, known to suppress oxidative damage, may have contributed to the attenuation of fatigue in this clinical population.
-glucan Salecan Improves Exercise Performance and Displays Anti-Fatigue Effects through Regulating Energy Metabolism and Oxidative Stress in Mice.
Xu Xi,Ding Yijian,Yang Yunxia,Gao Yan,Sun Qi,Liu Junhao,Yang Xiao,Wang Junsong,Zhang Jianfa
Nutrients
Fatigue induced by prolonged exercise not only leads to the decrease of exercise capacity, but also might be the cause of many diseases. In consideration of the side effects of pharmacological drugs, dietary supplements seem to be a better choice to ameliorate exercise-induced fatigue. The present study aimed to investigate the anti-fatigue effect of Salecan, a novel water-soluble -glucan, during exercise and explore the underlying mechanisms. Male Institute of Cancer Research (ICR) mice were divided into five groups, including the Rest group and the other four Swim-groups treated with Salecan at 0, 25, 50, and 100 mg/kg/day for four weeks. Salecan treatment markedly increased the exhaustive swimming time of mice in the forced swimming test. Exercise fatigue and injury-related biochemical biomarkers including lactate, blood urea nitrogen (BUN), creatinine kinase (CK), alanine transaminase (ALT), and aspartate transaminase (AST) were ameliorated by Salecan. Salecan reversed the decreased serum glucose levels and glycogen contents caused by exercise. In addition, Salecan improved oxidative stress induced by exercise through regulating Nrf2/HO⁻1/Trx signaling pathway. Thus, the beneficial effects of Salecan against fatigue may be due to its positive effects on energy metabolism and antioxidation defence. Our results suggest that Salecan could be a novel potential candidate for anti-fatigue dietary supplements.
10.3390/nu10070858
Prevention of postoperative fatigue syndrome in rat model by ginsenoside Rb1 via down-regulation of inflammation along the NMDA receptor pathway in the hippocampus.
Chen Wei-Zhe,Liu Shu,Chen Fan-Feng,Zhou Chong-Jun,Yu Jian,Zhuang Cheng-Le,Shen Xian,Chen Bi-Cheng,Yu Zhen
Biological & pharmaceutical bulletin
Postoperative fatigue syndrome (POFS) is a common complication which decelerates recovery after surgery. The present study investigated the anti-fatigue effect of ginsenoside Rb1 (GRb1) through the inflammatory cytokine-mediated N-methyl-D-aspartate (NMDA) receptor pathway. A POFS rat model was created by major small intestinal resection and assessed with an open field test. Real-time quantitative polymerase chain reaction, western blot analysis, high performance liquid chromatography and a transmission electron microscopic analysis were used to determine typical biochemical parameters in the hippocampus. Our results showed that POFS rats exhibited fatigue associated with an increased expression of inflammatory cytokines and NMDA receptor 1, higher (kynurenine)/(tryptophan) and (kynurenine)/(kynurenic acid) on postoperative days 1 and 3, and an increased expression of indoleamine 2,3-dioxygenase (IDO) on postoperative day 1. Degenerated neurons were found in the hippocampus of POFS rats. The NMDA receptor antagonist MK801 had a significant effect on central fatigue on postoperative day 1. GRb1 had no effect on IDO or tryptophan metabolism, but exhibited a significant effect on POFS by inhibiting the expression of inflammatory cytokines and NMDA receptor 1. These data suggested that inflammatory cytokines could activate tryptophan metabolism to cause POFS through the NMDA receptor pathway. GRb1 had an anti-fatigue effect on POFS by reducing inflammatory cytokines and NMDA receptors.
10.1248/bpb.b14-00599
The Toll-Like Receptor Radical Cycle Pathway: A New Drug Target in Immune-Related Chronic Fatigue.
Lucas Kurt,Morris Gerwyn,Anderson George,Maes Michael
CNS & neurological disorders drug targets
In this review we discuss that peripheral and central activation of the Toll-like receptor 2/4 (TLR2/4) Radical Cycle may underpin the pathophysiology of immune-related chronic fatigue secondary to other medical diseases and conditions. The TLR Radical Cycle plays a role in illnesses and conditions that are disproportionately commonly comorbid with secondary chronic fatigue, including a) neuroinflammatory disorders, e.g. Parkinson's disease, stroke, depression, psychological stressors, and b) systemic disorders, e.g. (auto)immune disorders, chronic obstructive pulmonary disease, ankylosing spondylitis, chronic kidney disease, inflammatory bowel disease, cardiovascular disease, incl. myocardial infarction, cancer and its treatments. Increased TLR signaling is driven by activated immuneinflammatory and oxidative and nitrosative stress pathways, pathogen derived molecular patterns, including lipopolysaccharides, and damage associated molecular patterns (DAMPs). Newly formed redox-derived DAMPs, secondary to oxidative processes, may further activate the TLR complex leading to an auto-amplifying TLR Radical feedback loop. Increased gut permeability with translocation of gram negative bacteria and LPS, which activates the TLR Radical Cycle, is another pathway that may play a role in most of the abovementioned diseases and the secondary fatigue accompanying them. It is concluded that secondary fatigue may be associated with activation of the TLR Radical Cycle pathway due to activated immune-inflammatory pathways, classical and redox-derived DAMPs and PAMPs plays a role in its pathophysiology. Such an activation of the TLR Radical Cycle pathway may also explain why the abovementioned conditions are primed for an increased expression of secondary chronic fatigue. Targeting the TLR Radical Cycle pathway may be an effective method to treat TLR-Radical Cycle-related diseases such as secondary chronic fatigue.
10.2174/1871527314666150317224645
Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy.
Wright Fay,Hammer Marilyn,Paul Steven M,Aouizerat Bradley E,Kober Kord M,Conley Yvette P,Cooper Bruce A,Dunn Laura B,Levine Jon D,DEramo Melkus Gail,Miaskowski Christine
Cytokine
Fatigue, a highly prevalent and distressing symptom during chemotherapy (CTX), demonstrates diurnal and interindividual variability in severity. Little is known about the associations between variations in genes involved in inflammatory processes and morning and evening fatigue severity during CTX. The purposes of this study, in a sample of oncology patients (N=543) with breast, gastrointestinal (GI), gynecological (GYN), or lung cancer who received two cycles of CTX, were to determine whether variations in genes involved in inflammatory processes were associated with inter-individual variability in initial levels as well as in the trajectories of morning and evening fatigue. Patients completed the Lee Fatigue Scale to determine morning and evening fatigue severity a total of six times over two cycles of CTX. Using a whole exome array, 309 single nucleotide polymorphisms SNPs among the 64 candidate genes that passed all quality control filters were evaluated using hierarchical linear modeling (HLM). Based on the results of the HLM analyses, the final SNPs were evaluated for their potential impact on protein function using two bioinformational tools. The following inflammatory pathways were represented: chemokines (3 genes); cytokines (12 genes); inflammasome (11 genes); Janus kinase/signal transducers and activators of transcription (JAK/STAT, 10 genes); mitogen-activated protein kinase/jun amino-terminal kinases (MAPK/JNK, 3 genes); nuclear factor-kappa beta (NFkB, 18 genes); and NFkB and MAP/JNK (7 genes). After controlling for self-reported and genomic estimates of race and ethnicity, polymorphisms in six genes from the cytokine (2 genes); inflammasome (2 genes); and NFkB (2 genes) pathways were associated with both morning and evening fatigue. Polymorphisms in six genes from the inflammasome (1 gene); JAK/STAT (1 gene); and NFkB (4 genes) pathways were associated with only morning fatigue. Polymorphisms in three genes from the inflammasome (2 genes) and the NFkB (1 gene) pathways were associated with only evening fatigue. Taken together, these findings add to the growing body of evidence that suggests that morning and evening fatigue are distinct symptoms.
10.1016/j.cyto.2016.12.023
Anti-fatigue effect of aqueous extract of Hechong (Tylorrhynchus heterochaetus) via AMPK linked pathway.
Yang Ziqing,Sunil Christudas,Jayachandran Muthukumaran,Zheng Xuchu,Cui Kuopeng,Su Yuepeng,Xu Baojun
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
Tylorrhynchus heterochaetus (Hechong in Chinese) has been used in Chinese traditional medicine for treating various diseases. This study was aimed to assess the anti-fatigue effect of T. heterochaetus on Kunming mice and its primary mechanism of action using forced running, rotating rod and weight-loaded swimming tests. Low (2.70 mg/0.5 mL/20 g), medium (5.41 mg/0.5 mL/20 g) and high (6.58 mg/0.5 mL/20 g) doses of T. heterochaetus aqueous extract were treated to mice for 28 days. Among the doses, the low and medium doses showed significant (p ≤ 0.05) anti-fatigue effect on the weight-loaded swimming test. Also, T. heterochaetus extract showed significant (p ≤ 0.05) effects on fatigue-related blood parameters by increasing the GLU, TG and LDH levels and decreasing the LA, CK and BUN levels. The levels of liver and skeletal muscle glycogen were also significantly (p ≤ 0.05) increased after treatment. Further, on Western blot analysis, it has been found that T. heterochaetus enhanced the expressions of AMPK and PGC-1α in the liver and skeletal muscles of mice. From the study, our outcomes suggest that T. heterochaetus possess an anti-fatigue effect through the AMPK-linked pathway and thereby it can regularize the energy metabolism.
10.1016/j.fct.2019.111043
Anti-fatigue effect of anwulignan via the NRF2 and PGC-1α signaling pathway in mice.
Zhang Xinyun,Jing Shu,Lin Huijiao,Sun Wei,Jiang Weihai,Yu Chunyan,Sun Jinghui,Wang Chunmei,Chen Jianguang,Li He
Food & function
OBJECTIVE:To examine the anti-fatigue function of anwulignan from Schisandra and its underlying mechanism. METHODS:After an excessive fatigue mouse model was created, anwulignan was administered to the mice, and its effect on exercise tolerance was studied by the weight-bearing swimming test, rotarod test, grip strength test, and tail suspension test. The biochemical indicators closely related to fatigue, including blood urea nitrogen (BUN), lactic acid (LD), lactate dehydrogenase (LDH), and creatine kinase (CK) in the serum; liver glycogen (LG) in the liver tissue; muscle glycogen (MG); inorganic phosphate (Pi) and Annexin V in the gastrocnemius; superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities; malondialdehyde (MDA), catalase (CAT), and thiobarbituric acid reactive substances (TBARS); and the 8-hydroxy-2-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) content in both serum and the gastrocnemius were detected. Morphological changes were also observed. The anti-fatigue-related proteins of the NRF2/ARE, Bcl2, and PGC-1α pathways in the gastrocnemius of the mice were detected by western blot. RESULTS:Anwulignan significantly increased the exercise tolerance by decreasing BUN, LD, LDH, CK, Pi, MDA, TBARS, 8-OHdG, ROS, and Annexin V levels and increasing LG, MG, SOD, CAT, and GSH-Px levels, significantly upregulated the expression of NRF2 and Bcl2 proteins, which are anti-oxidation and anti-apoptosis regulators, and also activated the p38MAPK-PGC-1α pathway. CONCLUSION:Anwulignan can increase exercise tolerance and relieve fatigue in an excessive fatigue mouse model. The underlying mechanism may be through its regulatory effect on the NRF2 and PGC-1α signaling pathway. This study will provide scientific data for anwulignan to be developed as a novel and efficient component in anti-oxidant or anti-fatigue health food.
10.1039/c9fo01182j
Ginsenoside Rb1 improves postoperative fatigue syndrome by reducing skeletal muscle oxidative stress through activation of the PI3K/Akt/Nrf2 pathway in aged rats.
Zhuang Cheng-Le,Mao Xiang-Yu,Liu Shu,Chen Wei-Zhe,Huang Dong-Dong,Zhang Chang-Jing,Chen Bi-Cheng,Shen Xian,Yu Zhen
European journal of pharmacology
Ginsenoside Rb1 is reported to possess anti-fatigue activity, but the mechanisms remain unknown. The aim of this study was to investigate the molecular mechanisms responsible for the anti-fatigue effect of ginsenoside Rb1 on postoperative fatigue syndrome induced by major small intestinal resection (MSIR) in aged rat. Aged rats with MSIR were administrated with ginsenoside Rb1 (15 mg/kg) once a day from 3 days before surgery to the day of sacrifice, or with saline as corresponding controls. Rats without MSIR but going through the same surgery procedure were administrated with saline as blank controls. Anti-fatigue effect was assessed by an open field test; superoxide dismutase, reactive oxygen species and malondialdehyde in skeletal muscle were determined. The mRNA levels of Akt2 and Nrf2 in skeletal muscle were measured by real-time quantitative PCR. The activation of Akt and Nrf2 was examined by western blot and immunohistofluorescence. Our results revealed that ginsenoside Rb1 significantly increased the journey and the rearing frequency, decreased the time of rest in aged rats with MSIR. In addition, ginsenoside Rb1 significantly reduced reactive oxygen species and malondialdehyde release and increased the superoxide dismutase activity of skeletal muscle in aged rats with MSIR. Ginsenoside Rb1 also increased the expression of Akt2 and Nrf2 mRNA, up-regulated Akt phosphorylation and Nrf2 nuclear translocation. These findings indicate that ginsenoside Rb1 has an anti-fatigue effect on postoperative fatigue syndrome in aged rat, and the mechanism possibly involves activation of the PI3K/Akt pathway with subsequent Nrf2 nuclear translocation and induction of antioxidant enzymes.
10.1016/j.ejphar.2014.06.040
Fatigue in inflammatory rheumatic disorders: pathophysiological mechanisms.
Korte S Mechiel,Straub Rainer H
Rheumatology (Oxford, England)
Today, inflammatory rheumatic disorders are effectively treated, but many patients still suffer from residual fatigue. This work presents pathophysiological mechanisms of fatigue. First, cytokines can interfere with neurotransmitter release at the preterminal ending. Second, a long-term increase in serum concentrations of proinflammatory cytokines increase the uptake and breakdown of monoamines (serotonin, noradrenaline and dopamine). Third, chronic inflammation can also decrease monoaminergic neurotransmission via oxidative stress (oxidation of tetrahydrobiopterin [BH4]). Fourth, proinflammatory cytokines increase the level of enzyme indoleamine-2, 3-dioxygenase activity and shunt tryptophan away from the serotonin pathway. Fifth, oxidative stress stimulates astrocytes to inhibit excitatory amino acid transporters. Sixth, astrocytes produce kynurenic acid that acts as an antagonist on the α7-nicotinic acetylcholine receptor to inhibit dopamine release. Jointly, these actions result in increased glutamatergic and decreased monoaminergic neurotransmission. The above-described pathophysiological mechanisms negatively affect brain functioning in areas that are involved in fatigue.
10.1093/rheumatology/kez413