Milk product intake, muscle strength, and NFKB methylation

Background Muscle atrophy with aging is closely associated with chronic systemic inflammation and lifestyle-related diseases. In the present study, we assessed whether post-exercise milk product intake during 5-month interval walking training (IWT) enhanced the increase in thigh muscle strength and ameliorated susceptibility to inflammation in older women. Methods Subjects [n = 37, 66±5 (standard deviation) yrs] who had been performing IWT for >6 months participated in this study. They were randomly divided into the following 3 groups: IWT alone (CNT, n = 12), IWT + low-dose post-exercise milk product intake (LD, n = 12; 4 g protein and 3 g carbohydrate) or IWT + a 3-times higher dose of milk product intake than the LD group (HD, n = 13). They were instructed to repeat ≥5 sets of fast and slow walking for 3 min each at ≥70% and 40% peak aerobic capacity for walking, respectively, per day for ≥4 days/week. Results After IWT, thigh muscle strength increased in the HD group (8±2%) more than in the CNT group (-2±3%, P = 0.022), despite similar IWT achievements between the groups (P>0.15). Pyrosequencing analysis using whole blood showed that methylation of NFKB1 and NFKB2, master genes of inflammation, was enhanced in the HD group (29±7% and 44 ±11%, respectively) more than in the CNT group (-20±6% and -10±6%, respectively; P<0.001). Moreover, the genome-wide DNA methylation analysis showed that several inflammation-related genes were hyper-methylated in the HD group compared with that in the CNT group, suggesting greater pro-inflammatory cytokine gene suppression in the HD group. Conclusion HD milk product intake after exercise produced a greater percent increase in thigh muscle strength and NFKB1 and NFKB2 gene methylation during IWT in physically active older women

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

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Impact of Carbohydrate-Electrolyte Beverage Ingestion on Heart Rate Response While Climbing Mountain Fuji at ~3000 m

We sought to investigate whether carbohydrate-electrolyte beverage ingestion reduced heart rate (HR) in twenty-three healthy young adults while climbing Mount Fuji at a given exercise intensity. Twenty-three healthy adults were randomly divided into two groups: the tap water (11 males [M] and 1 female [F]) and the carbohydrate-electrolyte group (10 M and 1 F). HR and activity energy expenditure (AEE) were recorded every min. The HRs for the first 30 minutes of climbing were not significantly different between the groups [121 ± 2 beats per min (bpm) in the tap water and 116 ± 3 bpm in the carbohydrate-electrolyte]; however, HR significantly increased with climbing in the tap water group (129 ± 2 bpm) but showed no significant increase in the carbohydrate-electrolyte group (121 ± 3 bpm). In addition, body weight changes throughout two days ascending and descending on Mount Fuji were inversely related to changes in resting HR. Further, individual variation of body weight changes was suppressed by carbohydrate-electrolyte drink. Collectively, carbohydrate-electrolyte beverage intake may attenuate an increase in HR at a given AEE while mountaineering at ~3000 m compared with tap water intake

Effects of Home-Based Interval Walking Training on Thigh Muscle Strength and Aerobic Capacity in Female Total Hip Arthroplasty Patients: A Randomized, Controlled Pilot Study

<div><p></p><p>Due to the reduced physical activity of patients who have undergone total hip arthroplasty (THA), there are no home-based exercise training regimens for preventing muscle atrophy and aerobic capacity impairment in these patients. We examined whether interval walking training (IWT) could prevented these issues. Twenty-eight female patients (∼60 years of age) who had undergone THA more than 2 months prior were randomly divided into IWT (n = 14) and control (CNT, n = 14) groups. The IWT subjects trained at a target of 60 min of fast walking at >70% peak aerobic capacity for walking (O_2peak) per wk for 12 wk, while those in the CNT maintained their previous sedentary life during the same period. We measured the energy expenditure of the daily physical activity, except during sleeping and bathing, every minute and every day during the intervention. We also measured the isometric knee extension (F_EXT) and flexion (F_FLX) forces, O_2peak, and anaerobic threshold during the graded cycling exercise (O_2AT) before and after the intervention. All subjects, except for one in IWT, completed the protocol. F_FLX increased by 23% on the operated side (<i>P</i> = 0.003) and 14% on the non-operated side of IWT (<i>P</i> = 0.006), while it only increased on the operated side of CNT (<i>P</i> = 0.03). The O_2peak and O_2AT in IWT increased by 8% (<i>P</i> = 0.08) and 13% (<i>P</i> = 0.002), respectively, and these changes were significantly higher in the IWT than in CNT group (both, <i>P</i><0.05). In conclusion, IWT might be an effective home-based training regimen for preventing the muscle atrophy from reduced daily physical activity in THA patients.</p><p>Trial Registration</p><p>UMIN-CTR <a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=history&action=list&type=summary&recptno=R000015361&language=E" target="_blank">UMIN000013172</a></p></div

Aerobic capacities before and after training.

<p>Values are given as the mean ± SE. O_2peak, peak aerobic capacity for walking; HR_rest¹, heart rate at rest before starting the exercise for the O_2peak measurement; HR_peak, peak heart rate at O_2peak; O_2AT, anaerobic threshold for cycling; HR_rest², heart rate at rest before starting the exercise for the O_2AT measurement; and HR_AT, heart rate at O_2AT. Significant differences compared to the value before training, *<i>P</i><0.05 and **<i>P</i><0.01.</p><p>Aerobic capacities before and after training.</p