Translational exercise biomedicine最新文献

Notch1 is a mechanosensitive endothelial receptor that responds to vascular wall shear stress. However, data on Notch1 activity in humans remains limited, particularly regarding its role in endothelial function.

Objectives: Accordingly, the purpose of this study was to determine whether Notch1 is associated with the flow-mediated dilatory (FMD) response and whether it is related to aerobic fitness. A secondary purpose was to determine whether Notch1 is related to concentrations of vascular endothelial growth factor (VEGF).

Methods: Sixteen (8M/8F) young (20-30 yrs old) and healthy (BMI: 25 ± 4.2 kg/m², blood pressure: 117 ± 11.63/69 ± 11.25 mmHg) adults participated in the study. Aerobic fitness was determined by cycle V̇O₂ peak. An FMD was performed on the brachial artery, and blood samples were taken from an antecubital vein at rest (baseline) and 1 min after cuff deflation (to align with peak vessel dilation). Concentrations of Notch1 extracellular domain (NECD) and VEGF were determined from plasma using enzyme-linked immunosorbent assays.

Results: In contrast to our hypothesis, concentrations of NECD and VEGF did not change throughout the FMD and were unrelated to allometrically scaled FMD values (p all>0.05). Likewise, there was no relationship between changes in NECD and VEGF (p=0.331, r=0.127). However, the change in NECD across the FMD was moderately (r=0.515) and significantly (p=0.024) correlated with V̇O₂ peak.

Conclusions: These novel data indicate that in healthy young adults, Notch1 activity is linked to aerobic fitness but may not be acutely involved in the shear-mediated vasodilatory response.

Objectives: Aerobic exercise training can increase skeletal muscle mitochondrial content. Supine exercise training with legs above the heart potentially augments these increases. However, the impact of supine exercise training on mitochondrial biogenesis and cardiovascular adaptations remains unclear.

Methods: In this single-centred, randomized, parallel arm trial, 19 recreationally active individuals underwent seven sessions of either supine with legs up (SUP; n=9, 6 females) or upright with legs down (UP; n=10, 7 females) aerobic training on a recumbent bike at 71 ± 7 % and 71 ± 2 % of peak work rate (WR_peak), respectively. The study aimed to test the effects of training with decreased muscle oxygenation on indices of muscle mitochondrial remodelling. Secondary outcomes included exercise performance, muscle oxygenation, and cardiovascular responses.

Results: Secondary outcomes revealed significant interaction effects for time to fatigue (TTF) and WR_peak in the SUP group during supine testing, suggesting enhanced exercise tolerance and performance. No between group interaction effects were observed for upright testing. No clear effects on mitochondrial biogenesis were observed based on expression of mitochondrial protein subunits and transcriptional regulators. Acutely, HR_peak was lower during the SUP Test compared to the UP Test. No central cardiovascular adaptations were observed following training.

Conclusions: Our exploratory analyses showed that supine aerobic training more effectively improves supine exercise tolerance and performance compared with upright training, despite no differences in measured proteins related to mitochondrial biogenesis. Further research is needed to elucidate the mechanisms underlying these postural-specific training effects.

Registration: clinicaltrials.gov: NCT04151095.

Objectives: To examine the effect of the NAD⁺ precursor, nicotinic acid (NA), for improving skeletal muscle status in sedentary older people.

Methods: In a double-blind, randomised, placebo-controlled design, 18 sedentary yet otherwise healthy older (65-75 y) males were assigned to 2-weeks of NA (acipimox; 250 mg × 3 daily, n=8) or placebo (PLA, n=10) supplementation. At baseline, and after week 1 and week 2 of supplementation, a battery of functional, metabolic, and molecular readouts were measured.

Results: Resting and submaximal respiratory exchange ratio was lower (p<0.05) after 2 weeks in the NA group only, but maximal aerobic and anaerobic function and glucose handling were unchanged (p>0.05). Bayesian statistical modelling identified that leak, maximal coupled and maximal uncoupled mitochondrial respiratory states, increased over the 2-week supplemental period in the NA group (probability for a positive change (pd) 85.2, 90.8 and 95.9 %, respectively) but not in PLA. Citrate synthase and protein content of complex II (SDHB) and V (ATP5A) electron transport chain (ETC) components increased over the 2-week period in the NA group only (pd 95.1, 74.5 and 82.3 %, respectively). Mitochondrial and myofibrillar protein synthetic rates remained unchanged in both groups. NA intake altered the muscle transcriptome by increasing the expression of gene pathways related to cell adhesion/cytoskeleton organisation and inflammation/immunity and decreasing pathway expression of ETC and aerobic respiration processes. NAD⁺-specific pathways (e.g., de novo NAD⁺ biosynthetic processes) and genes (e.g., NADSYN1) were uniquely regulated by NA.

Conclusions: NA might be an effective strategy for improving ageing muscle mitochondrial health.

Objectives: To determine how the anti-inflammatory actions of interleukin-10 (IL-10) and IL-6 differ across age and physical activity levels.

Methods: Using a cross-sectional design, fasted blood samples were obtained from younger physically inactive (YI: n=10, age: 22.7 ± 3.7 years, BMI: 24.8 ± 4.8 kg/m², <150 min of weekly moderate-to-vigorous physical activity [MVPA]), younger highly active (YA: n=11 varsity cross country running athletes, 20.7 ± 2.7 years, 21.1 ± 1.8 kg/m², >300 min of weekly MVPA), and older highly active (OA: 12, 56.0 ± 10.3 years, 22.8 ± 3.2 kg/m², >300 min of weekly MVPA) individuals and analyzed for leukocyte counts, IL-10 and IL-6-related signaling, and cytokine secretion ex vivo.

Results: Total white blood cells and monocytes were similar between groups (p=0.8) but YA and OA had lower lymphocyte counts than YI (p<0.01). The ability of IL-10 (1 ng/mL) to phosphorylate signal transducer and activator of transcription 3 (STAT3) in CD14 monocytes was greater in YA vs. YI (p<0.03) despite YA having lower IL-10 receptor expression (p<0.01). IL-6 (10 ng/mL) mediated STAT3 phosphorylation in CD4 lymphocytes was higher in OA compared YI (p<0.01), with a similar tendency observed for YA vs. YI (p=0.08). Despite enhanced responsiveness of STAT3 to IL-10/6 in active individuals, the ability of IL-10/6 to inhibit tumor necrosis factor-alpha (TNF-⍺) secretion from lipopolysaccharide-stimulated whole-blood was similar between groups.

Conclusions: Highly active younger and older individuals demonstrate enhanced IL-10- and IL-6-mediated activation of immune cell STAT3. Although the ability of IL-10/6 to inhibit TNF-⍺ secretion appeared unimpacted by activity level, anti-inflammatory cytokine actions were preserved in older active individuals.

Objectives: To investigate the impact of acute energetic stress (acute HIIE and fasting) on ERRγ, PPARβ, NR1D1, NR4A1, and TFEB in human skeletal muscle.

Methods: The current study performed secondary analyses using muscle biopsy samples from two previously published studies: study 1) leg muscle biopsies from nine men and eight women were obtained pre and 3 h following acute high-intensity interval cycling exercise (HIIE); study 2) leg muscle biopsies were obtained from nine men pre-, during, and post-an 8 h fast with or without 2 h of arm ergometer exercise. RT-PCR was performed on samples from each study to determine the mRNA expression of ERRγ, PPARβ, NR1D1, NR4A1, and TFEB. Additionally, we retrieved data from meta-analyzed human muscle gene expression using the publicly available database MetaMex.

Results: PGC-1α (p<0.01, d=1.98) and NR4A1 (p<0.01, d=1.36) mRNA expression significantly increased while TFEB (p≤0.05, d=0.70) decreased following HIIE. Significant decreases in NR4A1 and NR1D1 mRNA expression were observed following an 8 h fast. Our MetaMex analyses revealed significant increases (p<0.05) in PGC-1α and NR4A1 expression following aerobic and resistance exercise, and in PPARβ expression following resistance exercise.

Conclusions: Our data indicate that acute HIIE stimulates increases in NR4A1 and PGC-1α and decreases in TFEB mRNA expression in human skeletal muscle. Additionally, a short term (8 h) fast reduced the mRNA expression of the transcriptional regulators NR4A1 and NR1D1 - potentially as a mechanism of decreasing mitochondrial biogenesis to reduce energy expenditure during a period of restricted energy availability.