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Reducing NF-κB Signaling Nutritionally is Associated with Expedited Recovery of Skeletal Muscle Function After Damage.
Jameson, TSO, Pavis, GF, Dirks, ML, Lee, BP, Abdelrahman, DR, Murton, AJ, Porter, C, Alamdari, N, Mikus, CR, Wall, BT, et al
The Journal of clinical endocrinology and metabolism. 2021;(7):2057-2076
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Abstract
CONTEXT The early events regulating the remodeling program following skeletal muscle damage are poorly understood. OBJECTIVE The objective of this study was to determine the association between myofibrillar protein synthesis (myoPS) and nuclear factor-kappa B (NF-κB) signaling by nutritionally accelerating the recovery of muscle function following damage. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS Healthy males and females consumed daily postexercise and prebed protein-polyphenol (PP; n = 9; 4 females) or isocaloric maltodextrin placebo (PLA; n = 9; 3 females) drinks (parallel design) 6 days before and 3 days after 300 unilateral eccentric contractions of the quadriceps during complete dietary control. MAIN OUTCOME MEASURES Muscle function was assessed daily, and skeletal muscle biopsies were taken after 24, 27, and 36 hours for measurements of myoPS rates using deuterated water, and gene ontology and NF-κB signaling analysis using a quantitative reverse transcription PCR (RT-qPCR) gene array. RESULTS Eccentric contractions impaired muscle function for 48 hours in PLA intervention, but just for 24 hours in PP intervention (P = 0.047). Eccentric quadricep contractions increased myoPS compared with the control leg during postexercise (24-27 hours; 0.14 ± 0.01 vs 0.11 ± 0.01%·h-1, respectively; P = 0.075) and overnight periods (27-36 hours; 0.10 ± 0.01 vs 0.07 ± 0.01%·h-1, respectively; P = 0.020), but was not further increased by PP drinks (P > 0.05). Protein-polyphenol drinks decreased postexercise and overnight muscle IL1R1 (PLA = 2.8 ± 0.4, PP = 1.1 ± 0.4 and PLA = 1.9 ± 0.4, PP = 0.3 ± 0.4 log2 fold-change, respectively) and IL1RL1 (PLA = 4.9 ± 0.7, PP = 1.6 ± 0.8 and PLA = 3.7 ± 0.6, PP = 0.7 ± 0.7 log2 fold-change, respectively) messenger RNA expression (P < 0.05) and downstream NF-κB signaling compared with PLA. CONCLUSION Protein-polyphenol drink ingestion likely accelerates recovery of muscle function by attenuating inflammatory NF-κB transcriptional signaling, possibly to reduce aberrant tissue degradation rather than increase myoPS rates.
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Role of nitric oxide signaling in the antidepressant mechanism of action of ketamine: A randomized controlled trial.
Bevilacqua, L, Charney, A, Pierce, CR, Richards, SM, Jha, MK, Glasgow, A, Brallier, J, Kirkwood, K, Bagiella, E, Charney, DS, et al
Journal of psychopharmacology (Oxford, England). 2021;(2):124-127
Abstract
Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects. Studies suggest that inhibition of nitric oxide synthesis plays a role in the mechanism of action of ketamine. This randomized, placebo-controlled study investigated whether co-administration of sodium nitroprusside, a nitric oxide donor, compared to placebo, would attenuate the antidepressant and dissociative effects of ketamine. Sixteen ketamine responders were randomized to a double-blind infusion of ketamine co-administered with placebo or sodium nitroprusside. Our findings show no difference between the two conditions suggesting that the nitric oxide pathway may not play a primary role in ketamine's antidepressant or dissociative effects. The study is registered at clinicaltrials.gov (NCT03102736).
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Beneficial Effect of Ubiquinol on Hematological and Inflammatory Signaling during Exercise.
Diaz-Castro, J, Moreno-Fernandez, J, Chirosa, I, Chirosa, LJ, Guisado, R, Ochoa, JJ
Nutrients. 2020;(2)
Abstract
Strenuous exercise (any activity that expends six metabolic equivalents per minute or more causing sensations of fatigue and exhaustion to occur, inducing deleterious effects, affecting negatively different cells), induces muscle damage and hematological changes associated with high production of pro-inflammatory mediators related to muscle damage and sports anemia. The objective of this study was to determine whether short-term oral ubiquinol supplementation can prevent accumulation of inflammatory mediators and hematological impairment associated to strenuous exercise. For this purpose, 100 healthy and well-trained firemen were classified in two groups: Ubiquinol (experimental group), and placebo group (control). The protocol was two identical strenuous exercise tests with rest period between tests of 24 h. Blood samples were collected before supplementation (basal value) (T1), after supplementation (T2), after first physical exercise test (T3), after 24 h of rest (T4), and after second physical exercise test (T5). Hematological parameters, pro- and anti-inflammatory cytokines and growth factors were measured. Red blood cells (RBC), hematocrit, hemoglobin, VEGF, NO, EGF, IL-1ra, and IL-10 increased in the ubiquinol group while IL-1, IL-8, and MCP-1 decreased. Ubiquinol supplementation during high intensity exercise could modulate inflammatory signaling, expression of pro-inflammatory, and increasing some anti-inflammatory cytokines. During exercise, RBC, hemoglobin, hematocrit, VEGF, and EGF increased in ubiquinol group, revealing a possible pro-angiogenic effect, improving oxygen supply and exerting a possible protective effect on other physiological alterations.
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Whey Protein Hydrolysate Increases Amino Acid Uptake, mTORC1 Signaling, and Protein Synthesis in Skeletal Muscle of Healthy Young Men in a Randomized Crossover Trial.
Moro, T, Brightwell, CR, Velarde, B, Fry, CS, Nakayama, K, Sanbongi, C, Volpi, E, Rasmussen, BB
The Journal of nutrition. 2019;(7):1149-1158
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Abstract
BACKGROUND Muscle protein synthesis (MPS) can be stimulated by ingestion of protein sources, such as whey, casein, or soy. Protein supplementation can enhance muscle protein synthesis after exercise and may preserve skeletal muscle mass and function in aging adults. Therefore, identifying protein sources with higher anabolic potency is of high significance. OBJECTIVE The aim of this study was to determine the anabolic potency and efficacy of a novel whey protein hydrolysate mixture (WPH) on mechanistic target of rapamycin complex 1 (mTORC1) signaling and skeletal MPS in healthy young subjects. METHODS Ten young men (aged 28.7 ± 3.6 y, 25.2 ± 2.9 kg/m2 body mass index [BMI]) were recruited into a double-blind two-way crossover trial. Subjects were randomized to receive either 0.08 g/kg of body weight (BW) of WPH or an intact whey protein (WHEY) mixture during stable isotope infusion experiments. Fractional synthetic rate, leucine and phenylalanine kinetics, and markers of amino acid sensing were assessed as primary outcomes before and 1-3 h after protein ingestion using a repeated measures mixed model. RESULTS Blood leucine concentration, delivery of leucine to muscle, transport of leucine from blood into muscle and intracellular muscle leucine concentration significantly increased to a similar extent 1 h after ingestion of both mixtures (P < 0.05). Phosphorylation of S6K1 (i.e. a marker of mTORC1 activation) increased equally by ∼20% 1-h postingestion (P < 0.05). Ingestion of WPH and WHEY increased mixed MPS similarly in both groups by ∼43% (P < 0.05); however, phenylalanine utilization for synthesis increased in both treatments 1-h postingestion but remained elevated 3-h postingestion only in the WPH group (P < 0.05). CONCLUSIONS We conclude that a small dose of WPH effectively increases leucine transport into muscle, activating mTORC1 and stimulating MPS in young men. WPH anabolic potency and efficacy for promoting overall muscle protein anabolism is similar to WHEY, an intact protein source. This trial was registered at clinicaltrials.gov as NCT03313830.
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Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma.
Ronellenfitsch, MW, Zeiner, PS, Mittelbronn, M, Urban, H, Pietsch, T, Reuter, D, Senft, C, Steinbach, JP, Westphal, M, Harter, PN
Acta neuropathologica communications. 2018;(1):81
Abstract
Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
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Differential T Cell Signaling Pathway Activation by Tacrolimus and Belatacept after Kidney Transplantation: Post Hoc Analysis of a Randomised-Controlled Trial.
Kannegieter, NM, Hesselink, DA, Dieterich, M, de Graav, GN, Kraaijeveld, R, Baan, CC
Scientific reports. 2017;(1):15135
Abstract
Pharmacokinetic immunosuppressive drug monitoring poorly correlates with clinical outcomes after solid organ transplantation. A promising method for pharmacodynamic monitoring of tacrolimus (TAC) in T cell subsets of transplant recipients might be the measurement of (phosphorylated) p38MAPK, ERK1/2 and Akt (activated downstream of the T cell receptor) by phospho-specific flow cytometry. Here, blood samples from n = 40 kidney transplant recipients (treated with either TAC-based or belatacept (BELA)-based immunosuppressive drug therapy) were monitored before and throughout the first year after transplantation. After transplantation and in unstimulated samples, p-p38MAPK and p-Akt were inhibited in CD8+ T cells and p-ERK in CD4+ T cells but only in patients who received TAC-based therapy. After activation with PMA/ionomycin, p-p38MAPK and p-AKT were significantly inhibited in CD4+ and CD8+ T cells when TAC was given, compared to pre-transplantation. Eleven BELA-treated patients had a biopsy-proven acute rejection, which was associated with higher p-ERK levels in both CD4+ and CD8+ T cells compared to patients without rejection. In conclusion, phospho-specific flow cytometry is a promising tool to pharmacodynamically monitor TAC-based therapy. In contrast to TAC-based therapy, BELA-based immunosuppression does not inhibit key T cell activation pathways which may contribute to the high rejection incidence among BELA-treated transplant recipients.
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Acute low-intensity cycling with blood-flow restriction has no effect on metabolic signaling in human skeletal muscle compared to traditional exercise.
Smiles, WJ, Conceição, MS, Telles, GD, Chacon-Mikahil, MP, Cavaglieri, CR, Vechin, FC, Libardi, CA, Hawley, JA, Camera, DM
European journal of applied physiology. 2017;(2):345-358
Abstract
PURPOSE Autophagy is an intracellular degradative system sensitive to hypoxia and exercise-induced perturbations to cellular bioenergetics. We determined the effects of low-intensity endurance-based exercise performed with blood-flow restriction (BFR) on cell signaling adaptive responses regulating autophagy and substrate metabolism in human skeletal muscle. METHODS In a randomized cross-over design, nine young, healthy but physically inactive males completed three experimental trials separated by 1 week of recovery consisting of either a resistance exercise bout (REX: 4 × 10 leg press repetitions, 70% 1-RM), endurance exercise (END: 30 min cycling, 70% VO2peak), or low-intensity cycling with BFR (15 min, 40% VO2peak). A resting muscle biopsy was obtained from the vastus lateralis 2 weeks prior to the first exercise trial and 3 h after each exercise bout. RESULTS END increased ULK1Ser757 phosphorylation above rest and BFR (~37 to 51%, P < 0.05). Following REX, there were significant elevations compared to rest (~348%) and BFR (~973%) for p38γ MAPKThr180/Tyr182 phosphorylation (P < 0.05). Parkin content was lower following BFR cycling compared to REX (~20%, P < 0.05). There were no exercise-induced changes in select markers of autophagy following BFR. Genes implicated in substrate metabolism (HK2 and PDK4) were increased above rest (~143 to 338%) and BFR cycling (~212 to 517%) with END (P < 0.001). CONCLUSION A single bout of low-intensity cycling with BFR is insufficient to induce intracellular "stress" responses (e.g., high rates of substrate turnover and local hypoxia) necessary to activate skeletal muscle autophagy signaling.
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Effects of DHA Supplementation on Vascular Function, Telomerase Activity in PBMC, Expression of Inflammatory Cytokines, and PPARγ-LXRα-ABCA1 Pathway in Patients With Type 2 Diabetes Mellitus: Study Protocol for Randomized Controlled Clinical Trial.
Toupchian, O, Sotoudeh, G, Mansoori, A, Djalali, M, Keshavarz, SA, Nasli-Esfahani, E, Alvandi, E, Koohdani, F
Acta medica Iranica. 2016;(7):410-7
Abstract
Docosahexaenoic acid (DHA), as an omega-3 fatty acid, in a natural ligand of peroxisome proliferator-activated receptors (PPARs). Regarding the combinative effects of Nutrigenomics and Nutrigenetics and due to the lack of in vivo studies conducted using natural ligands of PPARs, we aimed to evaluate the effects of DHA supplementation on vascular function, telomerase activity, and PPARγ-LXRα-ABCA1 pathway, in patients with type 2 diabetes mellitus (T2DM), based on the Pro12Ala polymorphism in PPARγ encoding gene. 72 T2DM patients (36 dominant and 36 recessive allele carriers), aged 30-70, with body mass index of 18.5 to 35 kg/m2, will be participated in this double blind randomized controlled trial. In each group, stratification will be performed based on sex and age and participants will be randomly assigned to receive 2.4 g/day DHA or placebo (paraffin) for 8 weeks. PPARγ genotyping will be carried out using PCR-RFLP method; Telomerase activity will be estimated by PCR-ELISA TRAP assay; mRNA expression levels of target genes will be assessed using real time PCR. Serum levels of ADMA, sCD163 and adiponectin, will be measured using ELISA commercial kits. The present study is designed in order to help T2DM patients to modify their health conditions based on their genetic backgrounds, and to recommend the proper food ingredients as the natural agonists for PPARs in order to prevent and treat metabolic abnormalities of the disease.
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Melatonin Pathway and Atenolol-Related Glucose Dysregulation: Is There a Correlation?
Chang, SW, Gong, Y, McDonough, CW, Langaee, TY, Nasiri Kenari, N, Beitelshees, AL, Gums, JG, Chapman, AB, Turner, ST, Johnson, JA, et al
Clinical and translational science. 2016;(2):114-22
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Abstract
Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol-related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6-sulfatoxymelatonin (aMT6s) was measured pre- and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 ± 10.1mg/dl, P = 0.02) and decreased aMT6s (-4.5 ± 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post-atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0×10(-4)). PRKCB is involved in the melatonin-insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol-related hyperglycemia.
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Similar mitochondrial signaling responses to a single bout of continuous or small-sided-games-based exercise in sedentary men.
Mendham, AE, Duffield, R, Coutts, AJ, Marino, FE, Boyko, A, McAinch, AJ, Bishop, DJ
Journal of applied physiology (Bethesda, Md. : 1985). 2016;(6):1326-1334
Abstract
This study assessed the mitochondrial related signaling responses to a single bout of noncontact, modified football (touch rugby), played as small-sided games (SSG), or cycling (CYC) exercise in sedentary, obese, middle-aged men. In a randomized, crossover design, nine middle-aged, sedentary, obese men completed two, 40-min exercise conditions (CYC and SSG) separated by a 21-day recovery period. Heart rate (HR) and ratings of perceived exertion (RPE) were collected during each bout. Needle biopsies from the vastus lateralis muscle were collected at rest and 30 and 240 min postexercise for analysis of protein content and phosphorylation (PGC-1α, SIRT1, p53, p53Ser15, AMPK, AMPKThr172, CAMKII, CAMKIIThr286, p38MAPK, and p38MAPKThr180/Tyr182) and mRNA expression (PGC-1α, p53, NRF1, NRF2, Tfam, and cytochrome c). A main effect of time effect for both conditions was evident for HR, RPE, and blood lactate (P < 0.05), with no condition by time interaction (P > 0.05). Both conditions increased PGC1-α protein and mRNA expression at 240 min (P < 0.05). AMPKThr172 increased 30 min post CYC (P < 0.05), with no change in SSG (P > 0.05). CYC increased p53 protein content at 240 min to a greater extent than SSG (P < 0.05). mRNA expression of NRF2 decreased in both conditions (P < 0.05). No condition by time interactions were evident for mRNA expression of Tfam, NRF1, cytochrome c, and p53. The similar PGC-1α response between intensity-matched conditions suggests both conditions are of similar benefit for stimulating mitochondrial biogenesis. Differences between conditions regarding fluctuation in exercise intensity and type of muscle contraction may explain the increase of p53 and AMPK within CYC and not SSG (noncontact, modified football).