チョウジカン ジキュウセイ ウンドウ パフォーマンス ニ タウリン トウヨ ガ オヨボス エイキョウ

筑波大学博士 (体育科学) 学位論文・平成23年5月31日授与 (乙第2547号)筑波大学（University of Tsukuba）201

N-acetyltaurine and Acetylcarnitine Production for the Mitochondrial Acetyl-CoA Regulation in Skeletal Muscles during Endurance Exercises

During endurance exercises, a large amount of mitochondrial acetyl-CoA is produced in skeletal muscles from lipids, and the excess acetyl-CoA suppresses the metabolic flux from glycolysis to the TCA cycle. This study evaluated the hypothesis that taurine and carnitine act as a buffer of the acetyl moiety of mitochondrial acetyl-CoA derived from the short- and long-chain fatty acids of skeletal muscles during endurance exercises. In human subjects, the serum concentrations of acetylated forms of taurine (NAT) and carnitine (ACT), which are the metabolites of acetyl-CoA buffering, significantly increased after a full marathon. In the culture medium of primary human skeletal muscle cells, NAT and ACT concentrations significantly increased when they were cultured with taurine and acetate or with carnitine and palmitic acid, respectively. The increase in the mitochondrial acetyl-CoA/free CoA ratio induced by acetate and palmitic acid was suppressed by taurine and carnitine, respectively. Elevations of NAT and ACT in the blood of humans during endurance exercises might serve the buffering of the acetyl-moiety in mitochondria by taurine and carnitine, respectively. The results suggest that blood levels of NAT and ACT indicate energy production status from fatty acids in the skeletal muscles of humans undergoing endurance exercise

Preliminary Clinical Evaluation of Toxicity and Efficacy of A New Astaxanthin-rich Haematococcus pluvialis Extract

Astaxanthin (Ax), a carotenoid ubiquitously distributed in microorganisms, fish, and crustaceans, has been known to be a potent antioxidant and hence exhibit various physiological effects. We attempted in these studies to evaluate clinical toxicity and efficacy of long-term administration of a new Ax product, by measuring biochemical and hematological blood parameters and by analyzing brain function (using CogHealth and P300 measures). Ax-rich Haematococcus pluvialis extracts equivalent to 4, 8, 20 mg of Ax dialcohol were administered to 73, 38, and 16 healthy adult volunteers, respectively, once daily for 4 weeks to evaluate safety. Ten subjects with age-related forgetfulness received an extract equivalent to 12 mg in a daily dosing regimen for 12 weeks to evaluate efficacy. As a result, no abnormality was observed and efficacy for age-related decline in cognitive and psychomotor functions was suggested

Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats

Taurine enhances physical performance; however, the underlying mechanism remains unclear. This study examined the effect of taurine on the overtime dynamics of blood glucose concentration (BGC) during endurance exercise in rats. Male F344 rats were subjected to transient treadmill exercise until exhaustion following 3 weeks of taurine supplementation or non-supplementation (TAU and CON groups). Every 10 min during exercise, BGC was measured in blood collected through cannulation of the jugular vein. Gluconeogenesis-, lipolysis-, and fatty acid oxidation-related factors in the plasma, liver, and skeletal muscles were also analyzed after 120-min run. Exercise time to exhaustion was significantly longer with taurine supplementation. BGC in the two groups significantly increased by 40 min and gradually and significantly decreased toward the respective exhaustion point. The decline in BGC from the peak at 40 min was significantly slower in the TAU group. The time when the once-increased BGC regressed to the 0-time level was significantly and positively correlated with exercise time until exhaustion. At the 120-min point, where the difference in BGC between the two groups was most significant, plasma free fatty acid concentration and acetyl-carnitine and N-acetyltaurine concentrations in skeletal muscle were significantly higher in the TAU group, whereas glycogen and glucogenic amino acid concentrations and G6Pase activity in the liver were not different between the two groups. Taurine supplementation enhances endurance capacity by delaying the decrease in BGC toward exhaustion through increases of lipolysis in adipose tissues and fatty acid oxidation in skeletal muscles during endurance exercise

骨格筋糖代謝ならびにアミノ酸代謝関連の遺伝子発現に及ぼすタウリン投与の影響

骨格筋の糖代謝ならびにセリン・グリシン・スレオニンのアミノ酸代謝の遺伝子発現に及ぼすタウリン投与の影響を明らかにすることを目的とした。ラットへ2週間タウリンを経口投与し、腓腹筋内側頭白色部の遺伝子発現をDNAマイクロアレイ法にて網羅的に解析を行った。その結果、タウリン投与によって、骨格筋の糖代謝ならびにセリン・グリシン・スレオニンのアミノ酸代謝には影響を及ぼさなかった。タウリン投与のエネルギー代謝への影響は骨格筋よりむしろ肝臓など他の臓器への作用が関連する可能性が示唆された

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Exercise Intensity during Olympic-Distance Triathlon in Well-Trained Age-Group Athletes: An Observational Study

The aim of this study was to examine the exercise intensity during the swimming, cycling, and running legs of nondraft legal, Olympic-distance triathlons in well-trained, age-group triathletes. Seventeen male triathletes completed incremental swimming, cycling, and running tests to exhaustion. Heart rate (HR) and workload corresponding to aerobic and anaerobic thresholds, maximal workloads, and maximal HR (HRmax) in each exercise mode were analyzed. HR and workload were monitored throughout the race. The intensity distributions in three HR zones for each discipline and five workload zones in cycling and running were quantified. The subjects were then assigned to a fast or slow group based on the total race time (range, 2 h 07 min–2 h 41 min). The mean percentages of HRmax in the swimming, cycling, and running legs were 89.8% ± 3.7%, 91.1% ± 4.4%, and 90.7% ± 5.1%, respectively, for all participants. The mean percentage of HRmax and intensity distributions during the swimming and cycling legs were similar between groups. In the running leg, the faster group spent relatively more time above HR at anaerobic threshold (AnT) and between workload at AnT and maximal workload. In conclusion, well-trained male triathletes performed at very high intensity throughout a nondraft legal, Olympic-distance triathlon race, and sustaining higher intensity during running might play a role in the success of these athletes

Exercise Intensity during Olympic-Distance Triathlon in Well-Trained Age-Group Athletes: An Observational Study

The aim of this study was to examine the exercise intensity during the swimming, cycling, and running legs of nondraft legal, Olympic-distance triathlons in well-trained, age-group triathletes. Seventeen male triathletes completed incremental swimming, cycling, and running tests to exhaustion. Heart rate (HR) and workload corresponding to aerobic and anaerobic thresholds, maximal workloads, and maximal HR (HRmax) in each exercise mode were analyzed. HR and workload were monitored throughout the race. The intensity distributions in three HR zones for each discipline and five workload zones in cycling and running were quantified. The subjects were then assigned to a fast or slow group based on the total race time (range, 2 h 07 min–2 h 41 min). The mean percentages of HRmax in the swimming, cycling, and running legs were 89.8% ± 3.7%, 91.1% ± 4.4%, and 90.7% ± 5.1%, respectively, for all participants. The mean percentage of HRmax and intensity distributions during the swimming and cycling legs were similar between groups. In the running leg, the faster group spent relatively more time above HR at anaerobic threshold (AnT) and between workload at AnT and maximal workload. In conclusion, well-trained male triathletes performed at very high intensity throughout a nondraft legal, Olympic-distance triathlon race, and sustaining higher intensity during running might play a role in the success of these athletes