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Abstract Objective To assess the effectiveness of an exercise intervention, in addition to standard care, in preventing or delaying insulin prescription in women with gestational diabetes mellitus (GDM). Design Randomised controlled trial. Setting University hospital. Population Pregnant women at 25–35 weeks of gestation diagnosed with GDM. Methods Women in the intervention group participated in weekly, supervised, 30–45 min exercise sessions and were encouraged to accumulate more than 5000 steps per day, tracked by a pedometer, in addition to receiving usual care. The control group received standard care only. Main outcome measure Insulin prescription. Results From February 2008 through April 2013, 109 women were randomized into the intervention group (n = 57) or the usual care group (n = 52). Two women in the intervention group were excluded from the analysis (one was randomised in error and one was lost to follow-up). Six women never attended the exercise sessions, and two attended fewer than two sessions. However, two-third of women were considered as compliant to the intervention (attended more than 50% of sessions and/or averaged more than 5000 steps/day). The incidence of insulin prescription did not differ between the groups: 31 women (56%) in the intervention group versus 24 women (46%) in the control group (RR 1.22, 95% CI 0.84 to 1.78). The median time from randomization to insulin prescription was also similar between groups (14 days in the intervention group and 13 days in the control group). Conclusion This study did not demonstrate that an exercise program reduces or delays insulin prescription in women with GDM. Low adherence to the intervention, a small sample size, and the short duration of the program may explain the lack of observed benefit. Registered At clinicaltrials.gov, NCT03174340, 02/06/2017

Objective: The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-LeuTAA) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-LeuTAA, on mitochondrial metabolism and pancreatic islet functions. Methods: We used antisense oligonucleotides to reduce mt-tRF-LeuTAA levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-LeuTAA inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-LeuTAA silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays. Results: Our study unveils a modulation of mt-tRF-LeuTAA levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-LeuTAA interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-LeuTAA in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-LeuTAA impairs insulin secretion of rat and human pancreatic β-cells. Conclusions: Our findings indicate that mt-tRF-LeuTAA interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion.

Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of the mitochondrial electron transfer system with respiration render it an appropriate hub for coordinating cellular adaption to changes in oxygen levels. How changes in respiration under functional hypoxia (i.e., when intracellular O2 levels limit mitochondrial respiration) are relayed by the electron transfer system to impact mitochondrial adaption and remodeling after hypoxic exposure remains poorly defined. This is largely due to challenges integrating findings under controlled and defined O2 levels in studies connecting functions of isolated mitochondria to humans during physical exercise. Here we present experiments under conditions of hypoxia in isolated mitochondria, myotubes and exercising humans. Performing steady-state respirometry with isolated mitochondria we found that oxygen limitation of respiration reduced electron flow and oxidative phosphorylation, lowered the mitochondrial membrane potential difference, and decreased mitochondrial calcium influx. Similarly, in myotubes under functional hypoxia mitochondrial calcium uptake decreased in response to sarcoplasmic reticulum calcium release for contraction. In both myotubes and human skeletal muscle this blunted mitochondrial adaptive responses and remodeling upon contractions. Our results suggest that by regulating calcium uptake the mitochondrial electron transfer system is a hub for coordinating cellular adaption under functional hypoxia.

Objectives: This study aims to quantify the cross-sectional and prospective associations between quality of life (QoL) and moderate-to-vigorous physical activity (MVPA).Methods: This study was based on the Swiss children’s Objectively measured PHYsical Activity cohort. The primary endpoint is the overall QoL score and its six dimensions. The main predictor is the average time spent in MVPA per day. Linear mixed effects and linear regression models respectively were used to investigate the cross-sectional and prospective associations between MVPA and QoL.Results: There were 352 participants in the study with complete data from baseline (2013–2015) and follow-up (2019). MVPA was positively associated with overall QoL and physical wellbeing (p = 0.023 and 0.002 respectively). The between-subject MVPA was positively associated with the overall QoL, physical wellbeing, and social wellbeing (p = 0.030, 0.017, and 0.028 respectively). Within-subject MVPA was positively associated with physical wellbeing and functioning at school (p = 0.039 and 0.013 respectively). Baseline MVPA was not associated with QoL 5 years later.Conclusion: Future longitudinal studies should employ shorter follow-up times and repeat measurements to assess the PA and QoL association.

Introduction Athletes increasingly engage in repeated sprint training that consists of repeated short all-out effort (< 10 s) interspersed by short recoveries (< 60 s). When performed in hypoxia (repeated sprints in hypoxia, RSH), it may lead to greater training effect than in normoxia (RSN). However, the mechanisms underlying this superior training effect of RSH are unclear. Specifically, the role of muscle metabolic response to RSH is still debated and results are heterogeneous. Clarifying the molecular pathways of skeletal muscle adaptations to RSH may thus provide new insights into the role of hypoxia-induced response to training. Methods Two groups of healthy young men (randomized) performed three training sessions/week for three weeks. Each training session consisted in six series of six sprints (6 s effort/24 s rest) in either normoxia (RSN, n = 7) or normobaric hypoxia (FiO2 = ~13%, RSH, n = 9). Before and after the training period, vastus lateralis muscle biopsies, a repeated sprint ability (RSA) test and a Wingate test were performed. Metabolic muscle adaptations were studied with proteomics and western blotting. Results RSN and RSH similarly improved power output (p < 0.05) during the RSA test (RSN: + 7.2 ± 7.7% vs. RSH: + 7.9 ± 6.6%) and the Wingate test (RSN: + 1.3 ± 3.6% vs. RSH: + 4.4 ± 5.0%). Proteomics revealed a decrease in several processes involved in oxidative phosphorylation, confirmed by Western Blot with a reduction (p < 0.05) in complexes I (- 19 ± 30%) and V (- 15 ± 24%) protein levels in response to both RSN and RSH. RSN and RSH increased (p < 0.05) protein levels of the hypoxia inducible factor 1α (HIF-1α, + 111 ± 50%) and vascular endothelial growth factor A (VEGFa, + 91 ± 60%). Protein levels of the glycolytic enzyme hexokinase II increased (+ 119 ± 183%, p < 0.05) after both training types. Only RSH induced increased glucose transporter 4 (GLUT4, + 31 ± 18%, p < 0.05) protein level, suggesting specific glycolytic adaptations in response to hypoxia, supported by proteomics data. This specific adaptation may be triggered through the signaling of S100A protein family as we observed an increased S100A13 protein level (+ 467 ± 353%, p < 0.05) and Akt phosphorylation (+ 21 ± 21%, time x group interaction, p < 0.05) as well as several other S100A proteins in proteomics only after RSH training. Discussion/Conclusion To conclude, RSH did not exhibit in greater performance improvement compared to RSN. However, it further improved the glycolytic phenotype compared to RSN, possibly through specific S100A13 proteins signaling. Thus, we suggest that the reported superiority of RSH to RSN in the literature may stem from superior glycolytic adaptations triggered through the activation of a specific pathway involving S100A13 protein. The potential role of S100A13 protein in skeletal muscle adaptative responses to exercise is novel and the present results open new research perspectives in this field.

IntroductionQuality of life (QoL) is an important health indicator among children and adolescents. Evidence on the effect of physical activity (PA)-related behaviors on QoL among youth remains inconsistent. Conventional accelerometer-derived PA metrics and guidelines with a focus on whole weeks may not adequately characterize QoL relevant PA behavior.ObjectiveThis study aims to a) identify clusters of accelerometer-derived PA profiles during weekend days among children and adolescents living in Switzerland, b) assess their cross-sectional and predictive association with overall QoL and its dimensions, and c) investigate whether the associations of QoL with the newly identified clusters persist upon adjustment for the commonly used PA metrics moderate-to-vigorous physical activity (MVPA) and time spent in sedentary behavior (SB).MethodsThe population-based Swiss children's Objectively measured PHYsical Activity (SOPHYA) cohort among children and adolescents aged 6 to 16 years was initiated at baseline in 2013. PA and QoL information was obtained twice over a five-year follow-up period. The primary endpoint is the overall QoL score and its six dimension scores obtained by KINDL® questionnaire. The primary predictor is the cluster membership of accelerometer-derived weekend PA profile. Clusters were obtained by applying the k-medoid algorithm to the distance matrix of profiles obtained by pairwise alignments of PA time series using the Dynamic Time Warping (DTW) algorithm. Secondary predictors are accelerometer-derived conventional PA metrics MVPA and SB from two combined weekend days. Linear regression models were applied to assess a) the cross-sectional association between PA cluster membership and QoL at baseline and b) the predictive association between PA cluster membership at baseline and QoL at follow-up, adjusting for baseline QoL.ResultsThe study sample for deriving PA profile clusters consisted of 51.4% girls and had an average age of 10.9 [SD 2.5] years). The elbow and silhouette methods indicated that weekend PA profiles are best classified in two or four clusters. The most differentiating characteristic for the two-clusters classification ("lower activity" and "high activity"), and the four-clusters classification ("inactive", "low activity", "medium activity", and "high activity"), respectively was the participant's mean counts per 15-seconds epoch. Participants assigned to high activity clusters were younger and more often male. Neither the clustered PA profiles nor MVPA or SB were cross-sectionally or predictively associated with overall QoL. The only association of a conventional PA metrics with QoL while adjusting for cluster membership was observed between MVPA during the weekend days and social well-being with a mean score difference of 2.4 (95%CI: 0.3 to 4.5; p = 0.025).ConclusionThe absence of strong associations of PA metrics for the weekend with QoL, except for the positive association between MVPA during the weekend days and social well-being, is in line with results from two randomized studies not showing efficacy of PA interventions on youth QoL. But because PA decreases with age, its promotion and relevance to QoL remain important research topics. Larger longitudinal study samples with more than two follow-up time points of children and adolescents are needed to derive new novel accelerometer-derived PA profiles and to associate them with QoL dimensions.