Fatigue-induced Orosomucoid 1 Acts on C-C Chemokine Receptor Type 5 to Enhance Muscle Endurance.
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ABSTRACT:
SUBMITTER: Lei H
PROVIDER: S-EPMC4703980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gender differences in fatigue manifest as females being more prone to feel exhaustion and having lower muscle endurance. However, the mechanisms of these effects remain unclear. We investigated whether orosomucoid, an endogenous anti-fatigue protein that enhances muscle endurance, is involved in this regulation. Female rats exhibited lower muscle endurance, and this gender difference disappeared in orosomucoid-1-deficient mice. Female rats also exhibited weaker orosomucoid induction in serum, liver and muscle in response to fatigue compared with male rats. Ovariectomy elevated orosomucoid levels and increased swimming time, and estrogen replenishment reversed these effects. Exogenous estrogen treatment in male and female mice produced opposite effects. Estrogen decreased orosomucoid expression and its promoter activity in C2C12 muscle and Chang liver cells in vitro, and estrogen receptor or p38 mitogen-activated protein kinase blockade abolished this effect. Therefore, estrogen negatively regulates orosomucoid expression that is responsible for the weaker muscle endurance in females.
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Project description:BackgroundOrosomucoid (ORM) is a positive acute phase protein verified to be upregulated in various forms of exercise-induced fatigued (EIF) rodents. However, its association with EIF among human beings remained unknown. This study aimed to explore the association between serum ORM and EIF triggered by military basic combat training (BCT).MethodsThe degree of EIF were measured by Borg's Rating of Perceived Exertion Scale (Borg-RPE-Scale®) as RPE score after BCT. Fifty-three male recruits were classified into three groups according to the RPE score: (1) group 1 (slight fatigue group): RPE score after BCT < 13; (2) group 2 (moderate fatigue group): RPE score after BCT = 13 or 14; (3) group 3 (severe fatigue group): RPE score after BCT > 14. The levels of blood ORM, lactate (LAC), cortisol and C-reactive protein (CRP) were determined before and after BCT. The diagnostic value of ORM was evaluated by receiver operating characteristic (ROC) curve analysis and logistic regression.ResultsAfter BCT, the level of LAC, CRP, and cortisol increased among all groups, but the changes had no significant between-group difference (all p > 0.05). The level of ORM had a specific significant increase in group 3 (p = 0.039), and the changes of ORM (ΔORM) had significant difference among groups (p = 0.033). ROC curve analysis showed that the estimated area under ROC curve for ΔORM was 0.724 (p = 0.009) with the recommended optimal cut-off value as 0.2565 mg/mL. Logistic analysis showed that recruits with ΔORM ≥ 0.2565 mg/mL had higher odds for suffering from severe EIF, 5.625 times (95% CI 1.542-20.523, p = 0.009) as large as those with ΔORM < 0.2565 mg/mL.ConclusionORM might be a promising biomarker of severe EIF triggered by BCT among male recruits. Its potential optimal cut-off value regarding ΔORM was recommended to be 0.2565 mg/mL.
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Project description:Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.
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Project description:Endurance exercise training can promote an adaptive muscle fiber transformation and an increase of mitochondrial biogenesis by triggering scripted changes in gene expression. However, no transcription factor has yet been identified that can direct this process. We describe the engineering of a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This was achieved by targeted expression of an activated form of peroxisome proliferator-activated receptor delta (PPARdelta) in skeletal muscle, which induces a switch to form increased numbers of type I muscle fibers. Treatment of wild-type mice with PPARdelta agonist elicits a similar type I fiber gene expression profile in muscle. Moreover, these genetically generated fibers confer resistance to obesity with improved metabolic profiles, even in the absence of exercise. These results demonstrate that complex physiologic properties such as fatigue, endurance, and running capacity can be molecularly analyzed and manipulated.
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Project description:The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained anti-tumoral activity and prolonged animal survival only when co-expressing C-X-C chemokine receptor type 6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.
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Project description:(1) Background: Extracellular nicotinamide phosphoribosyltrasferase (eNAMPT) is released by various cell types with pro-tumoral and pro-inflammatory properties. In cancer, eNAMPT regulates tumor growth through the activation of intracellular pathways, suggesting that it acts through a putative receptor, although its nature is still elusive. It has been shown, using surface plasma resonance, that eNAMPT binds to the C-C chemokine receptor type 5 (CCR5), although the physiological meaning of this finding is unknown. The aim of the present work was to characterize the pharmacodynamics of eNAMPT on CCR5. (2) Methods: HeLa CCR5-overexpressing stable cell line and B16 melanoma cells were used. We focused on some phenotypic effects of CCR5 activation, such as calcium release and migration, to evaluate eNAMPT actions on this receptor. (3) Results: eNAMPT did not induce ERK activation or cytosolic Ca2+-rises alone. Furthermore, eNAMPT prevents CCR5 internalization mediated by Rantes. eNAMPT pretreatment inhibits CCR5-mediated PKC activation and Rantes-dependent calcium signaling. The effect of eNAMPT on CCR5 was specific, as the responses to ATP and carbachol were unaffected. This was strengthened by the observation that eNAMPT inhibited Rantes-induced Ca2+-rises and Rantes-induced migration in a melanoma cell line. (4) Conclusions: Our work shows that eNAMPT binds to CCR5 and acts as a natural antagonist of this receptor.
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Project description:The development of localized muscle fatigue has classically been described by the nonlinear intensity-endurance time (ET) curve (Rohmert, 1960; El Ahrache et al., 2006). These empirical intensity-ET relationships have been well-documented and vary between joint regions. We previously proposed a three-compartment biophysical fatigue model, consisting of compartments (i.e. states) for active (M(A)), fatigued (M(F)), and resting (M(R)) muscles, to predict the decay and recovery of muscle force (Xia and Frey Law, 2008). The purpose of this investigation was to determine optimal model parameter values, fatigue (F) and recovery (R), which define the "flow rate" between muscle states and to evaluate the model's accuracy for estimating expected intensity-ET curves. Using a grid-search approach with modified Monte Carlo simulations, over 1 million F and R permutations were used to predict the maximum ET for sustained isometric tasks at 9 intensities ranging from 10% to 90% of maximum in 10% increments (over 9 million simulations total). Optimal F and R values ranged from 0.00589 (F(ankle)) and 0.0182 (R(ankle)) to 0.00058 (F(shoulder)) and 0.00168 (R(shoulder)), reproducing the intensity-ET curves with low mean RMS errors: shoulder (2.7s), hand/grip (5.6s), knee (6.7s), trunk (9.3s), elbow (9.9s), and ankle (11.2s). Testing the model at different task intensities (15-95% maximum in 10% increments) produced slightly higher errors, but largely within the 95% prediction intervals expected for the intensity-ET curves. We conclude that this three-compartment fatigue model can be used to accurately represent joint-specific intensity-ET curves, which may be useful for ergonomic analyses and/or digital human modeling applications.
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Project description:The chemokine-like receptor-1 (CMKLR1) is a G protein-coupled receptor that is activated by chemerin, a secreted plasma leukocyte attractant and adipokine. Previous studies identified that CMKLR1 is expressed in skeletal muscle in a stage-specific fashion during embryogenesis and in adult mice; however, its function in skeletal muscle remains unclear. Based on the established function of CMKLR1 in cell migration and differentiation, we investigated the hypothesis that CMKLR1 regulates the differentiation of myoblasts into myotubes. In C(2)C(12) mouse myoblasts, CMKLR1 expression increased threefold with differentiation into multinucleated myotubes. Decreasing CMKLR1 expression by adenoviral-delivered small-hairpin RNA (shRNA) impaired the differentiation of C(2)C(12) myoblasts into mature myotubes and reduced the mRNA expression of myogenic regulatory factors myogenin and MyoD while increasing Myf5 and Mrf4. At embryonic day 12.5 (E12.5), CMKLR1 knockout (CMKLR1(-/-)) mice appeared developmentally delayed and displayed significantly lower wet weights and a considerably diminished myotomal component of somites as revealed by immunolocalization of myosin heavy chain protein compared with wild-type (CMKLR1(+/+)) mouse embryos. These changes were associated with increased Myf5 and decreased MyoD protein expression in the somites of E12.5 CMKLR1(-/-) mouse embryos. Adult male CMKLR1(-/-) mice had significantly reduced bone-free lean mass and weighed less than the CMKLR1(+/+) mice. We conclude that CMKLR1 is essential for myogenic differentiation of C(2)C(12) cells in vitro, and the CMKLR1 null mice have a subtle skeletal muscle deficit beginning from embryonic life that persists during postnatal life.
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Project description:In modern developed societies, heavy physical demands are decreasing and getting replaced by longer periods of static, low-exertion activities such as sitting or standing. To counteract this lack of physical activity, more and more people are engaging in physical activity through exercise and training. Virtually opposite training modalities are endurance and strength. We asked if back muscle endurance capacity is influenced by training mode. 38 healthy male subjects (age range 19-31 years, mean age 22.6 years) were investigated: sedentary (Control, n = 12), endurance trained (ET, n = 13), and strength trained participants (ST, n = 13). They underwent a ten-minutes isometric extension task at 50% of their upper body weight. Surface EMG was measured in the low-back region utilizing quadratic 4*4 monopolar electrode montages per side. Relative amplitude and mean frequency changes were analysed with respect to electrode position and group during the endurance task. Eight ST subjects failed to complete the endurance task. Relative amplitude and frequency changes were largest in the ST group, followed by Control and ET groups (amplitude: F 6.389, p 0.004, frequency: F 11.741, p<0.001). Further, independent of group largest amplitude increase was observed for the most upper and laterally positioned electrodes. Mean frequency changes showed no systematic spatial distribution pattern. Although, in the light of an aging population, strength training has its merits our results question the functional suitability of frequent and isolated high-impact strength training for everyday endurance requirements like doing the dishes. Fatigue related amplitude elevations are systematically distributed in the back region, showing least fatigue signs for the most caudal and medial, i.e. the lumbar paravertebral region.
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