The proteome and phosphoproteome of circulating extracellular vesicle-enriched preparations are associated with characteristic clinical features in type 1 diabetes.

Introduction: There are no validated clinical or laboratory biomarkers to identify and differentiate endotypes of type 1 diabetes (T1D) or the risk of progression to chronic complications. Extracellular vesicles (EVs) have been studied as biomarkers in several different disease states but have not been well studied in T1D. Methods: As the initial step towards circulating biomarker identification in T1D, this pilot study aimed to provide an initial characterization of the proteomic and phosphoproteomic landscape of circulating EV-enriched preparations in participants with established T1D (N=10) and healthy normal volunteers (Controls) (N=7) (NCT03379792) carefully matched by age, race/ethnicity, sex, and BMI. EV-enriched preparations were obtained using EVtrap® technology. Proteins were identified and quantified by LC-MS analysis. Differential abundance and coexpression network (WGCNA), and pathway enrichment analyses were implemented. Results: The detected proteins and phosphoproteins were enriched (75%) in exosomal proteins cataloged in the ExoCarta database. A total of 181 proteins and 8 phosphoproteins were differentially abundant in participants with T1D compared to controls, including some well-known EVproteins (i.e., CD63, RAB14, BSG, LAMP2, and EZR). Enrichment analyses of differentially abundant proteins and phosphoproteins of EV-enriched preparations identified associations with neutrophil, platelet, and immune response functions, as well as prion protein aggregation. Downregulated proteins were involved in MHC class II signaling and the regulation of monocyte differentiation. Potential key roles in T1D for C1q, plasminogen, IL6ST, CD40, HLA-DQB1, HLA-DRB1, CD74, NUCB1, and SAP, are highlighted. Remarkably, WGCNA uncovered two protein modules significantly associated with pancreas size, which may be implicated in the pathogenesis of T1D. Similarly, these modules showed significant enrichment for membrane compartments, processes associated with inflammation and the immune response, and regulation of viral processes, among others. Discussion: This study demonstrates the potential of proteomic and phosphoproteomic signatures of EV-enriched preparations to provide insight into the pathobiology of T1D. The WGCNA analysis could be a powerful tool to discriminate signatures associated with different pathobiological components of the disease.

Exercise and ageing impact the kynurenine/tryptophan pathway and acylcarnitine metabolite pools in skeletal muscle of older adults.

Exercise-induced perturbation of skeletal muscle metabolites is a probable mediator of long-term health benefits in older adults. Although specific metabolites have been identified to be impacted by age, physical activity and exercise, the depth of coverage of the muscle metabolome is still limited. Here, we investigated resting and exercise-induced metabolite distribution in muscle from well-phenotyped older adults who were active or sedentary, and a group of active young adults. Percutaneous biopsies of the vastus lateralis were obtained before, immediately after and 3 h following a bout of endurance cycling. Metabolite profile in muscle biopsies was determined by tandem mass spectrometry. Mitochondrial energetics in permeabilized fibre bundles was assessed by high resolution respirometry and fibre type proportion was assessed by immunohistology. We found that metabolites of the kynurenine/tryptophan pathway were impacted by age and activity. Specifically, kynurenine was elevated in muscle from older adults, whereas downstream metabolites of kynurenine (kynurenic acid and NAD+ ) were elevated in muscle from active adults and associated with cardiorespiratory fitness and muscle oxidative capacity. Acylcarnitines, a potential marker of impaired metabolic health, were elevated in muscle from physically active participants. Surprisingly, despite baseline group difference, acute exercise-induced alterations in whole-body substrate utilization, as well as muscle acylcarnitines and ketone bodies, were remarkably similar between groups. Our data identified novel muscle metabolite signatures that associate with the healthy ageing phenotype provoked by physical activity and reveal that the metabolic responsiveness of muscle to acute endurance exercise is retained [NB]:AUTHOR: Please ensure that the appropriate material has been provide for Table S2, as well as for Figures S1 to S7, as also cited in the text with age regardless of activity levels. KEY POINTS: Kynurenine/tryptophan pathway metabolites were impacted by age and physical activity in human muscle, with kynurenine elevated in older muscle, whereas downstream products kynurenic acid and NAD+ were elevated in exercise-trained muscle regardless of age. Acylcarnitines, a marker of impaired metabolic health when heightened in circulation, were elevated in exercise-trained muscle of young and older adults, suggesting that muscle act as a metabolic sink to reduce the circulating acylcarnitines observed with unhealthy ageing. Despite the phenotypic differences, the exercise-induced response of various muscle metabolite pools, including acylcarnitine and ketone bodies, was similar amongst the groups, suggesting that older adults can achieve the metabolic benefits of exercise seen in young counterparts.

Randomized trial reveals that physical activity and energy expenditure are associated with weight and body composition after RYGB.

OBJECTIVE: This study investigated the associations of both physical activity time (PA) and energy expenditure (EE) with weight and fat mass (FM) loss in patients following Roux-en-Y gastric bypass (RYGB) surgery. METHODS: Ninety-six nondiabetic patients were included in this analysis. Post-RYGB patients were randomized in one of two treatments: A 6-month exercise training program (RYBG+EX) or lifestyle educational classes (RYGB). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography. Components of PA and EE were quantified by a multisensory device. Dose-response relationships of both PA and EE with weight loss and body composition were explored according to quartiles of change in steps per day. RESULTS: Patients in the highest quartiles of steps per day change lost more FM (3rd = -19.5 kg and 4th = -22.7 kg, P < 0.05) and abdominal adipose tissue (4th = -313 cm2 , P < 0.05), maintained skeletal muscle mass (3rd = -3.1 cm2 and 4th = -4.5 cm2 , P < 0.05), and had greater reductions in resting metabolic rate. Decreases in sedentary EE and increases in light EE and age were significant predictors of both Δweight and ΔFM (R2 = 73.8% and R2 = 70.6%, respectively). CONCLUSIONS: Nondiabetic patients who perform higher, yet still modest, amounts of PA following RYGB have greater energy deficits and lose more weight and FM, while maintaining higher skeletal muscle mass.

Functional Capacity and Levels of Physical Activity in Aging: A 3-Year Follow-up.

Over the last decades, the world elderly population has increased exponentially and this tendency will continue during the coming years; from 2000 to 2050, people over 60 will double and those over 80 will quadruple. Loss of independence occurs as people age due to mobility restrictions, frailty, and decreased functional fitness and cognitive abilities. Evidence has shown that appropriate programs and policies contribute to keep older adults healthy and independent over time. The purpose of this chapter is to report the results of our 3-year follow-up study designed to characterize functional physical fitness in a sample of Portuguese community-dwelling older adults to propose a set of functional parameters that decline the most. We studied a group of 43 elderly people, aged 60 and over. Variables assessed on the participants were anthropometric measurements, functional capacity with the Senior Fitness Test battery (muscle strength, aerobic endurance, flexibility, agility, and dynamic balance), handgrip strength, levels of physical activity, and balance. Three years after the first assessment, a second assessment of the same variables was conducted. We analyzed what were the variables that, for this group, were related with a healthier aging and the relation with different physical activity levels. Our study showed that the distance covered in 6-min walk test and handgrip strength seem to explain a great amount of variability on functional variables that have changed on this period (68% of balance, lower and upper functional strength, respectively) and the active participants showed less decrements with aging in anthropometric and functional variables than those inactive or insufficiently active (p < 0.05). Greater importance should be given to prescription of exercise targeting older adults and, specifically, walking and manual activities should be given more attention as components of a community exercise program.

Relationship between muscular strength and sprints with changes of direction.

Sprints with changes of direction (COD) have been traditionally associated with performance in team sports. Jumping tests have been used as predictors of COD; however, there are not too many studies analyzing how dominance affects the best performance of the turn. The purpose of this study was to explore the relationship between tests pertaining to jumps (1 and 2 legs) and COD (right and left turns). Forty-two male students were selected at the Faculty of Physical Education (age: 20.1 ± 3.7 years; weight: 73.4 ± 8.4 kg; body mass index: 23.1 ± 2.6 kg·m(-2); and fat mass: 17.1 ± 8.8%). All the subjects had right leg dominance. The COD tests were assessed using three 10-m sprint tests (90° right and left turns and 180° turn). Jumps were countermovement jumps (CMJs with 1 and 2 legs) and the drop jump (DJ). Pearson coefficient correlation and stepwise regression analyses were performed. Our results showed that both CMJs and DJs were associated with COD. The CMJ with the right leg had the best coefficient correlation with left COD time (r = -0.64; p < 0.01). Also, the CMJ was associated with COD180° time (r = -0.60; p < 0.01). After regression analysis, only right one-leg CMJ and CMJ were predictors of left COD time (adjusted R2 = 0.46; p < 0.01). The main finding of this study was that the CMJ, but not the DJ, was the best predictor of dominant side COD. Jumps are an important component of team sport training because they improve COD performance. However, coaches use several types of jumps during training; our results suggest that jumps similar to the CMJ should be useful tools to improve COD, which helps to specify better training prescription.

Comparing several equations that predict peak VO2 using the 20-m multistage-shuttle run-test in 8-10-year-old children.

This study compared the validity of reported equations as predictors of peak VO(2) in 8-10-year-old children. Participants (90 boys and girls aged 8-10 years) performed the multistage-shuttle-run-test (MSRT) and peak VO(2) was measured in field using a portable gas analyser. The equations that estimated peak VO(2) from the MSRT performance were chosen according to the age range of this study. As follows, the FITNESSGRAM reports and the equations of Leger et al. (Can J Appl Sport Sci 5: 77-84, 1988), Barnett et al. (Pediatr Exerc Sci 5:42-50, 1993), Matsuzaka et al. (Pediatr Exerc Sci 16:113-125, 2004) and Fernhall et al. (Am J Ment Retard 102:602-612, 1998) were used to estimate the peak VO(2) and compared with the directly measured value. The equation of Leger et al. (Can J Appl Sport Sci 5: 77-84, 1988) provided a mean difference (d) of 4.7 ml kg(-1) min(-1) and a 1.0 slope. The equation of Matsuzaka et al. (Pediatr Exerc Sci 16:113-125, 2004)(a) using maximal speed (MS) showed a higher d (5.4) than the remaining using total laps d (4.2). The equation of Barnett et al. (Pediatr Exerc Sci 5:42-50, 1993)(a) that includes triceps skinfold and MS showed the highest d (6.1) but the smallest range (24.1) and slope (0.6). Data from the FITNESSGRAM had the smallest d (1.8 ml kg(-1) min(-1)), but also had the highest range between limits of agreement (28.6 ml kg(-1) min(-1)) and a 1.2 slope. The lowest slope (0.4) and range (22.2 ml kg(-1) min(-1)) were observed using the equation of Fernhall et al. (Am J Ment Retard 102:602-612, 1998). Log transformation of the data revealed that the equations of Matsuzaka et al. (Pediatr Exerc Sci 16:113-125, 2004)(a) (1.1*/÷1.25) and Fernhall et al. (Am J Ment Retard 102:602-612, 1998) (1.17*/÷1.25) showed the closest agreement among all, but they still yield unsatisfactory accuracy.