TGF-β Induction of miR-143/145 Is Associated to Exercise Response by Influencing Differentiation and Insulin Signaling Molecules in Human Skeletal Muscle

Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-β1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-β1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (n = 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-β signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR-143/145 cluster targets. Elevated TGF-β signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-β and finetuned IRS1 suppression by miR-143-3p.

The Effect of a Single Bout of Exercise on Vitamin B2 Status Is Not Different between High- and Low-Fit Females

High-fitness individuals have been suggested to be at risk of a poor vitamin B2 (riboflavin) status due to a potentially higher vitamin B2 demand, as measured by the erythrocyte glutathione reductase (EGR) activation coefficient (EGRAC). Longer-term exercise interventions have been shown to result in a lower vitamin B2 status, but studies are contradictory. Short-term exercise effects potentially contribute to discrepancies between studies but have only been tested in limited study populations. This study investigated if vitamin B2 status, measured by EGRAC, is affected by a single exercise bout in females who differ in fitness levels, and that represents long-term physical activity. At baseline and overnight after a 60-min cycling bout at 70% V·O2peak, EGR activity and EGRAC were measured in 31 young female adults, divided into a high-fit (V·O2peak ≥ 47 mL/kg/min, N = 15) and low-fit (V·O2peak ≤ 37 mL/kg/min, N = 16) group. A single exercise bout significantly increased EGR activity in high-fit and low-fit females (Ptime = 0.006). This response was not affected by fitness level (Ptime*group = 0.256). The effect of exercise on EGRAC was not significant (Ptime = 0.079) and not influenced by EGR activity. The exercise response of EGRAC was not significantly different between high-fit and low-fit females (Ptime*group = 0.141). Thus, a single exercise bout increased EGR activity, but did not affect EGRAC, indicating that vitamin B2 status was not affected. The exercise response on EGRAC and EGR did not differ between high-fit and low-fit females.

Translational Value of Exercise in Routine Care Following Hematopoietic Stem Cell Transplantation: A Retrospective Analysis

Purpose: Exercise is an effective adjuvant therapy to address many of the symptoms experienced by Hematopoietic Stem Cell Transplant (HSCT) recipients. However, there is little translational research examining meaningful clinical effects. A retrospective analysis of a community-embedded exercise program based at a large urban comprehensive cancer hospital was conducted, with the aim of establishing the translational value of exercise in a clinical setting. A secondary aim was to determine the impact of baseline function on exercise response. Methods: The Living Well Program is an evidence-based program supervised by Accredited Exercise Physiologists, delivered through the Chris O’Brien Lifehouse. HSCT recipients are prescribed individualised, once-weekly 1-hour aerobic, resistance and balance training. Changes in physical function (6-minute walk distance, strength, and balance), fatigue, and quality of life measures from baseline to post-intervention were analysed, and also assessed in relation to session attendance. Participants were then stratified as low- or high-function for each measure of physical function. Results: Data from 48 participants (male n=27, age=54.3±11.7-years) was included in the analysis. Significant improvements were found for all outcome measures, with improvements exceeding minimal clinically important differences for 6-minute walk distance (6MWD) and 30-second sit-to-stand. Greater session attendance correlated with improvements in 6MWD and strength outcomes. Exercise response was greater among those with lower baseline scores for 6MWD only (p<0.001).Conclusions: An existing exercise program embedded in cancer care was successful in eliciting improvements that are both significant and clinically relevant. Further investigations into key factors that influence the efficacy of these programs are required.

Elevated Left and Right Atrial Pressures Long‐Term After Atrial Septal Defect Correction: An Invasive Exercise Hemodynamic Study

Background Despite correction of the atrial septal defect (ASD), patients experience atrial fibrillation frequently and have increased morbidity and mortality. We examined physical capacity, cardiac performance, and invasive hemodynamics in patients with corrected ASD. Methods and Results Thirty‐eight corrected patients with isolated secundum ASD and 19 age‐matched healthy controls underwent right heart catheterization at rest and during exercise with simultaneous expired gas assessment and echocardiography. Maximum oxygen uptake was comparable between groups (ASD 32.7±7.7 mL O 2 /kg per minute, controls 35.2±7.5 mL O 2 /kg per minute, P =0.3), as was cardiac index at both rest and peak exercise. In contrast, pulmonary artery wedge v wave pressures were increased at rest and peak exercise (rest: ASD 14±4 mm Hg, controls 10±5 mm Hg, P =0.01; peak: ASD 25±9 mm Hg, controls 14±9 mm Hg, P =0.0001). The right atrial v wave pressures were increased at rest but not at peak exercise. The transmural filling pressure gradient (TMFP) was higher at peak exercise among patients with ASD (10±6 mm Hg, controls 7±3 mm Hg, P =0.03). One third of patients with ASD demonstrated an abnormal hemodynamic exercise response defined as mean pulmonary artery wedge pressure ≥25 mm Hg and/or mean pulmonary artery pressure ≥35 mm Hg at peak exercise. These patients had significantly elevated peak right and left atrial a wave pressures, right atrial v wave pressures, pulmonary artery wedge v wave pressures, and transmural filling pressure compared with both controls and patients with ASD with a normal exercise response. Conclusions Patients with corrected ASD present with elevated right and in particular left atrial pressures at rest and during exercise despite preserved peak exercise capacity. Abnormal atrial compliance and systolic atrial function could predispose to the increased long‐term risk of atrial fibrillation. Registration Information clinicaltrials.gov. Identifier: NCT03565471.

Indicators of response to exercise training: a systematic review and meta-analysis

BackgroundMeans-based analysis of maximal rate of oxygen consumption (VO2max) has traditionally been used as the exercise response indicator to assess the efficacy of endurance (END), high intensity interval (HIIT) and resistance exercise training (RET) for improving cardiorespiratory fitness and whole-body health. However, considerable heterogeneity exists in the interindividual variability response to the same or different training modalities.ObjectivesWe performed a systematic review and meta-analysis to investigate exercise response rates in the context of VO2max: (1) in each training modality (END, HIIT and RET) versus controls, (2) in END versus either HIIT or RET and (3) exercise response rates as measured by VO2max versus other indicators of positive exercise response in each exercise modality.MethodsThree databases (EMBASE, MEDLINE, CENTRAL) and additional sources were searched. Both individual response rate and population average data were incorporated through continuous data, respectively. Of 3268 identified manuscripts, a total of 29 studies were suitable for qualitative synthesis and a further 22 for quantitative. Stratification based on intervention duration (less than 12 weeks; more than or equal to 12 weeks) was undertaken.ResultsA total of 62 data points were procured. Both END and HIIT training exhibited differential improvements in VO2max based on intervention duration. VO2max did not adequately differentiate between END and HIIT, irrespective of intervention length. Although none of the other exercise response indicators achieved statistical significance, LT and HRrest demonstrated common trajectories in pooled and separate analyses between modalities. RET data were highly limited. Heterogeneity was ubiquitous across all analyses.ConclusionsThe potential for LT and HRrest as indicators of exercise response requires further elucidation, in addition to the exploration of interventional and intrinsic sources of heterogeneity.

A methodology for an acute exercise clinical trial called dementia risk and dynamic response to exercise

Exercise likely has numerous benefits for brain and cognition. However, those benefits and their causes remain imprecisely defined. If the brain does benefit from exercise it does so primarily through cumulative brief, “acute” exposures over a lifetime. The Dementia Risk and Dynamic Response to Exercise (DYNAMIC) clinical trial seeks to characterize the acute exercise response in cerebral perfusion, and circulating neurotrophic factors in older adults with and without the apolipoprotein e4 genotype (APOE4), the strongest genetic predictor of sporadic, late onset Alzheimer’s disease. DYNAMIC will enroll 60 older adults into a single moderate intensity bout of exercise intervention, measuring pre- and post-exercise cerebral blood flow (CBF) using arterial spin labeling, and neurotrophic factors. We expect that APOE4 carriers will have poor CBF regulation, i.e. slower return to baseline perfusion after exercise, and will demonstrate blunted neurotrophic response to exercise, with concentrations of neurotrophic factors positively correlating with CBF regulation. Preliminary findings on 7 older adults and 9 younger adults demonstrate that the experimental method can capture CBF and neurotrophic response over a time course. This methodology will provide important insight into acute exercise response and potential directions for clinical trial outcomes.ClinicalTrials.gov NCT04009629, Registered 05/07/2019.

Myokine Responses to Exercise in a Rat Model of Low/High Adaptive Potential

IntroductionAssuming myokines underlie some of the health benefits of exercise, we hypothesised that ‘high responder trainer’ (HRT) rats would exhibit distinct myokine profiles to ‘low responder trainers’ (LRT), reflecting distinct health and adaptive traits.MethodsBlood was collected from LRT and HRT (N=8) rats at baseline (BL), immediately (0h), 1h, and 3h after running; repeated after 3-wks training. Myokines were analysed by ELISA (i.e. BDNF/Fractalkine/SPARC/Irisin/FGF21/Musclin/IL-6).ResultsAt baseline, Musclin (LRT: 84 ± 24 vs HRT: 26 ± 3 pg/ml, P=0.05) and FGF21 (LRT: 133 ± 34 vs HRT: 63.5 ± 13 pg/ml, P=0.08) were higher in LRT than HRT. Training increased Musclin in HRT (26 ± 3 to 54 ± 9 pg/ml, P&lt;0.05) and decreased FGF21 in LRT (133 ± 34 to 60 ± 28 pg/ml, P&lt;0.05). Training increased SPARC (LRT: 0.8 ± 0.1 to 2.1 ± 0.6 ng/ml, P&lt;0.05; HRT: 0.7 ± 0.06 to 1.8 ± 0.3 ng/ml, P=0.06) and Irisin (LRT 0.62 ± 0.1 to 2.6 ± 0.4 ng/ml, P&lt;0.01; HRT 0.53 ± 0.1 to 2.8 ± 0.7 ng/ml, P&lt;0.01) while decreasing BDNF (LRT: 2747 ± 293 to 1081 ± 330 pg/ml, P&lt;0.01; HRT: 1976 ± 328 to 797 ± 160 pg/ml, P&lt;0.05). Acute exercise response of Musclin (AUC) was higher in LRT vs HRT (306 ± 74 vs. 88 ± 12 pg/ml×3h-1, P&lt;0.01) and elevated in HRT after training (221 ± 31 pg/ml×3h-1, P&lt;0.01). Training elevated SPARC (LRT: 2.4 ± 0.1 to 7.7 ± 1.3 ng/ml×3h-1, P&lt;0.05; HRT: 2.5 ± 0.13 to 11.2 ± 2.2 ng/ml×3h-1, P&lt;0.001) and Irisin (LRT: 1.34 ± 0.3 to 9.6 ± 1.7 ng/ml×3h-1, P&lt;0.001; HRT: 1.5 ± 0.5 to 12.1 ± 1.9 ng/ml×3h-1, P&lt;0.0001).ConclusionExercise training alters how myokines are secreted in response to acute exercise. Myokine responses were not robustly linked to adaptive potential in aerobic capacity, making them an unlikely regulator of adaptive traits.