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Physical activity and sports play major roles in the overall health status of humans. It is well known that regular exercise helps to lower the risk for a broad variety of health problems, such as cardiovascular disease, type 2 diabetes, and cancer. Being physically active induces a wide variety of molecular adaptations, for example fiber type switches or other metabolic alterations, in skeletal muscle tissue. These adaptations are based on exercise-induced changes to the skeletal muscle transcriptome. Understanding their nature is crucial to improve the development of exercise-based therapeutic strategies. Recent research indicates that specifically epigenetic mechanisms, i.e., pathways that induce changes in gene expression patterns without altering the DNA base sequence, might play a major role in controlling skeletal muscle transcriptional patterns. Epigenetic mechanisms include DNA and histone modifications, as well as expression of specific microRNAs. They can be modulated by environmental factors or external stimuli, such as exercise, and eventually induce specific and fine-tuned changes to the transcriptional response. In this review, we highlight current knowledge on epigenetic changes induced in exercising skeletal muscle, their target genes, and resulting phenotypic changes. In addition, we raise the question of whether epigenetic modifications might serve as markers for the design and management of optimized and individualized training protocols, as prognostic tools to predict training adaptation, or even as targets for the design of “exercise mimics”.

Work-related musculoskeletal disorders (WMSDs) are prevalent in occupations characterised by high repetition and high force demands. Both factors not only evoke inflammatory and degenerative processes in affected musculoskeletal tissue, but also systemic responses identified by biomarkers in blood serum. Clarifying methodological aspects of biomarkers may provide insights into their predictive role in the pathway of developing WMSDs. This study will primarily assess reliability of systemic inflammatory biomarkers (CRP, TNF-α, IL-6, IL-1β) and immune cell reactivity by repeated measures in workers with constant workloads over time. This observational cross-sectional study will include two groups of workers: exposed group including workers exposed to higher upper-extremity physical workloads, especially affecting the elbow/forearm/hand-area; unexposed group, including office workers exposed to lower upper-extremity physical workloads. Recruited persons are screened against eligibility criteria followed by a medical anamnesis and blood analysis. Enrolled participants undergo nine repeated measurements once every two weeks, taking blood among others. Blood analyses will determine values of systemic inflammatory biomarkers and reactivity of immune cells. The absolute test-retest reliability of biomarkers and immune cell reactivity over time is assessed by the intra-class correlation coefficient applying two-way mixed-effects models. The relative test-retest reliability is assessed by the standard error of measurement. Knowledge of and models currently describing the pathological role of systemic inflammatory biomarkers are based on highly-controlled laboratory rat experiments. This study has the strength of assessing a human population under real-life conditions. The major challenge is in participant recruitment given the intensive and complex study design. The results of this study could provide fundamentals for initiating a cohort study and be used for developing work-related stress-recovery concepts for occupations with different physical demands to identify workers who may be at risk for developing WMSDs. German Clinical Trials Register (DRKS00031872, 25 May 2023).

PurposeWe investigated the cardiovascular individual response to 6 weeks (3×/week) of work-matched within the severe-intensity domain (high-intensity interval training, HIIT) or moderate-intensity domain (moderate-intensity continuous training, MICT). In addition, we analyzed the cardiovascular factors at baseline underlying the response variability.Methods42 healthy sedentary participants were randomly assigned to HIIT or MICT. We applied the region of practical equivalence-method for identifying the levels of responders to the maximal oxygen uptake (V̇O2max) response. For investigating the influence of cardiovascular markers, we trained a Bayesian machine learning model on cardiovascular markers.ResultsDespite that HIIT and MICT induced significant increases in V̇O2max, HIIT had greater improvements than MICT (p < 0.001). Greater variability was observed in MICT, with approximately 50% classified as “non-responder” and “undecided”. 20 “responders”, one “undecided” and no “non-responders” were observed in HIIT. The variability in the ∆V̇O2max was associated with initial cardiorespiratory fitness, arterial stiffness, and left-ventricular (LV) mass and LV end-diastolic diameter in HIIT; whereas, microvascular responsiveness and right-ventricular (RV) excursion velocity showed a significant association in MICT.ConclusionOur findings highlight the critical influence of exercise-intensity domains and biological variability on the individual V̇O2max response. The incidence of “non-responders” in MICT was one third of the group; whereas, no “non-responders” were observed in HIIT. The incidence of “responders” was 11 out of 21 participants in MICT, and 20 out of 21 participants in HIIT. The response in HIIT showed associations with baseline fitness, arterial stiffness, and LV-morphology; whereas, it was associated with RV systolic function in MICT.

Background Multimorbidity is a major problem in Europe, increasing the need for prevention and rehabilitation programs. In Germany no guidelines have been developed that focus on patients with multiple chronic non-communicable diseases (NCDs). Benefits of physical activity (PA) and exercise in NCDs have been proven, but most interventions focus on single conditions. The evaluation of the effectiveness, efficiency and safety of PA programs in patients suffering from multiple NCDs and the feasibility of the implementation within the health care service remain open research questions. Methods The multi-site randomized controlled pragmatic trial includes 320 sedentary subjects with at least two of the following NCDs, either manifested or in a pre-stage with evident risk factors: Cardio-vascular disease, Diabetes mellitus type 2, knee/ hip osteoarthritis and obesity. Participants will be recruited from general practitioners and medical specialists and randomized to standard care of a statutory health insurance or MultiPill-Exercise . Standard care includes a choice of one or a maximum of two 8- to 12-week health programs, including nutrition, exercise, relaxation or special disease management programs. MultiPill-Exercise is based on the bio-psycho-social health model, considering a person-oriented perspective in light of given individual characteristics and context factors. The 24-weeks intervention focuses on aerobic and strengthening exercises in line with the WHO PA recommendations. Psychological and pedagogical elements along with behavior change techniques are implemented to ease the initiation and maintenance of exercise participation and lifestyle change, including nutrition. Primary outcome will be short- and long-term PA measured with the European Health Interview Survey-Physical Activity Questionnaire (EHIS-PAQ). Secondly, the effectiveness of the program on generic, disease specific, economic, and exercise behavioral parameters, as well as program adherence and safety will be evaluated. Discussion Results of this trial evaluate the PA intervention program in people with multiple NCDs in a real-life scenario. It will serve as a proof of concept with the opportunity of translation into routine practice. This approach, as a multi-site RCT with its rigorous methods and standardized operating procedures for the conduction of the intervention, will allow valid conclusions for the implementation of PA interventions in people with multimorbidity. Trial registration The trial was registered at www.drks.de (ID: DRKS00025033 ) on 30th September 2021.

Lifestyle-related diseases, such as overweight/obesity, diabetes mellitus type 2 (T2DM), cardiovascular disease, or osteoarthritis, are a major health burden in Western societies. Due to common risk factors, most patients suffer from multimorbidity, i.e., have been diagnosed with more than one of these diseases. Physical activity (PA) is known to have a positive effect on all of these diseases; however, little is known about the effects of PA on patients with multimorbidity. In particular, so far, no reliable biomarkers have been found to predict and monitor the effects of PA-based lifestyle intervention programs on these subjects. Employing a metabolomics approach with dried blood spots, we analyzed the concentrations of different metabolites in subjects with multimorbidity over the course of the lifestyle intervention program MultiPill-Exercise. We found increased concentrations of all tested amino acids (AAs), total carnitine (Cx), and short- (C2-C6) and long- (>C12) chain acylcarnitines (ACs) after 12 weeks (t1) and/or 24 weeks (t2) of intervention. When correlating baseline (t0) metabolite concentrations with changes in physiological and clinical parameters, we observed associations of various metabolite concentrations with changes in metabolic and cardiovascular parameters. When analyzing metabolite acute reactions in response to exhaustive exercise (ergometer test), however, few overall changes were observed. Nevertheless, a significant negative correlation was found between the mobilization of medium-chain acylcarnitines (MC-ACs) at t2 and changes in peak power output (PPO) between t0 and t2. Taken together, these data suggest that specific AAs and ACs might be candidate biomarkers to predict and monitor the effects of PA-based lifestyle intervention programs in subjects with multimorbidity, a hypothesis that should be further tested in larger cohorts.

microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females (n = 6) before and after a single submaximal bout of endurance exercise (‘reference training’). Subsequently, participants were subjected to a structured training program, consisting of six weeks of moderate-intensity continuous endurance training (MICT) and six weeks of high-intensity interval training (HIIT) in randomized order. In vastus lateralis muscle, we found significant downregulation of myomiRs, specifically miR-1, 133a-3p, and -5p, -133b, and -499a-5p. Similarly, exercise-associated miRs-23a-3p, -378a-5p, -128-3p, -21-5p, -107, -27a-3p, -126-3p, and -152-3p were significantly downregulated, whereas miR-23a-5p was upregulated. Furthermore, in an untargeted approach for differential expression in response to acute exercise, we identified n = 35 miRs that were downregulated and n = 20 miRs that were upregulated by factor 4.5 or more. Remarkably, KEGG pathway analysis indicated central involvement of this set of miRs in fatty acid metabolism. To reproduce these data in a larger cohort of all-female subjects (n = 29), qPCR analysis was carried out on n = 15 miRs selected from the microarray, which confirmed their differential expression. Furthermore, the acute response, i.e., the difference between miR concentrations before and after the reference training, was correlated with changes in maximum oxygen uptake (V̇O2max) in response to the training program. Here, we found that miRs-199a-3p and -19b-3p might be suitable acute-response candidates that correlate with individual degrees of training adaptation in females.

Diabetes prevention programs focus on people with prediabetes because they have a greater risk of developing type 2 diabetes mellitus than people with normal blood glucose levels. Weight management can reduce this risk. However, in our largely sedentary society, there is less enthusiasm for regular exercise. Whole-body electromyostimulation (WB-EMS) is a training technology that provides exercise-like effects by inducing muscle contractions using electrical currents. There is evidence that local EMS can improve glucose metabolism. Several studies investigated the effect of WB-EMS on cardiometabolic risk factors including blood glucose control in a population of individuals with metabolic syndrome. However, to the best of our knowledge, there is no randomized controlled trial examining the preliminary efficacy of WB-EMS on hemoglobin A (HbA ) levels in individuals with prediabetes. The objective of this randomized controlled trial is to pilot procedures for a randomized controlled trial testing WB-EMS training on glycemic changes in sedentary adults with prediabetes. A total of 60 community-dwelling sedentary adults aged 40-65 years with prediabetes will be randomized to one of 3 arms: WB-EMS + an activity tracker and a lifestyle education program (LEP) focusing on diabetes prevention, an activity tracker and LEP, or LEP only, with 20 individuals in each arm. The WB-EMS training will consist of 1.5×20 minutes per week. The intervention will last 16 weeks. As a pilot study, our main outcomes concern the number of participants who will be recruited, and comply with intervention and follow-up. The primary efficacy outcome of interest includes hemoglobin A . The intention-to-treat analysis will be conducted with the objective of providing CI estimation of treatment effects. The recruitment of study participants started in February 2024. At the time of submission of this protocol for publication, the recruitment was still ongoing. As of October 2024, a total of 42 participants were allocated to the study groups. The anticipated date of recruitment completion is July 2025. The results of this trial will provide valuable evidence for future investigations comparing the efficacy of the WB-EMS intervention with traditional exercise training to improve glycemic control in this population. ClinicalTrials.gov NCT06188481; https://clinicaltrials.gov/study/NCT06188481. DERR1-10.2196/68761.

The evaluation of the maximal oxygen uptake (V˙O2max) following exercise training is the classical assessment of training effectiveness. Research has lacked in investigating whether individuals that do not respond to the training intervention (V˙O2max), also do not improve in other health‐related parameters. We aimed to investigate the cardiovascular and metabolic adaptations (i.e., performance, body composition, blood pressure, vascular function, fasting blood markers, and resting cardiac function and morphology) to exercise training among participants who showed different levels of V˙O2max responsiveness. Healthy sedentary participants engaged in a 6‐week exercise training program, three times a week. Our results showed that responders had a greater increase in peak power output, second lactate threshold, and microvascular responsiveness, whereas non‐responders had a greater increase in cycling efficiency. No statistical differences were observed in body composition, blood pressure, fasting blood parameters, and resting cardiac adaptations. In conclusion, our study showed, for the first time, that in addition to the differences in the V˙O2max, a greater increase in microvascular responsiveness in responders compared to non‐responders was observed. Additionally, responders and non‐responders did not show differences in the adaptations on metabolic parameters. There is an increasing need for personalized training prescription, depending on the target clinical outcome. The evaluation of the maximal oxygen uptake (V˙O2max) following exercise training is the classical assessment of training effectiveness. Research has lacked in investigating whether individuals that do not respond to the training intervention (V˙O2max), also do not improve in other health‐related parameters. Our results showed that responders had a greater increase than non‐responders in peak power output, second lactate threshold, and microvascular responsiveness, whereas non‐responders had a greater increase in cycling efficiency than responders.

Background: Physical activity induces a range of physiological and molecular adaptations, particularly affecting skeletal muscle and the cardiovascular system, regulating both tissue architecture and metabolic pathways. Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may serve as potential biomarkers for these adaptations. Here, we analyzed piRNA patterns in the context of exercise. Methods: This study selected eight participants of the iReAct study (DRKS00017446) for piRNA analysis. Baseline assessments included demographic profiling and fitness evaluation, particularly maximal oxygen uptake (V̇O2max) assessment. In addition, blood samples were collected pre- and (for six of the eight participants) post- standard reference training sessions. Subsequently, subjects underwent 6-week training protocols, employing standardized high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) regimens. Next, RNA sequencing was conducted to identify differentially expressed piRNAs, and correlation analyses were performed between piRNA expression patterns and training-associated changes in V̇O2max. Finally, to identify piRNAs potentially of interest in the context of exercise, different screening procedures were applied. Results: There were unique and specific changes in individual piRNA expression levels in response to exercise. In addition, we could define correlations of piRNA expression patterns, namely of piR-32886, piR-33151, piR-12547, and piR-33074, with changes in V̇O2max. These correlations did not reach significance in the small sample size of this pilot study, but might be verified in larger, confirming studies. Conclusions: This hypothesis-generating study identifies characteristic piRNA patterns in the context of exercise. Their significance as biomarkers is yet to be determined.

Physical activity and exercise induce a complex pattern of adaptation reactions in a broad variety of tissues and organs, particularly the cardiovascular and the musculoskeletal systems. The underlying mechanisms, however, specifically the molecular changes that occur in response to training, are still incompletely understood. Animal models help to systematically elucidate the mechanisms of exercise adaptation. With regard to endurance‐based running exercise in mice, two basic regimens have been established: forced treadmill running (FTR), usually consisting of several sessions per week, and voluntary wheel running (VWR). However, the effects of these two programs on skeletal muscle molecular adaptation patterns have never been directly compared. To address this issue, in a pilot study, we analyzed the effects of two ten‐week training regimens in juvenile, male, C57BL/6 mice: moderate‐intensity forced treadmill running three‐times‐a‐week, employing a protocol that has been widely used in similar studies before, and voluntary wheel running. Our data suggest that there are similarities, but also characteristic differences in the molecular responses of different skeletal muscle species to the two training regimens. In particular, we found that VWR induces a significant fiber type shift toward more type IIX fibers in the slow, oxidative soleus muscle (p = .0053), but not in the other three muscles analyzed. In addition, while training‐induced expression patterns of the two metabolic markers Ppargc1a, encoding Pgc‐1α (peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha) and Nr4a3 (nuclear receptor subfamily 4 group A member 3) were roughly similar, downregulation of the Mstn (myostatin) gene and the “atrogene” Fbox32 could only be observed in response to VWR in specific muscles, such as in the gastrocnemius (p = .0015 for Mstn) and in the tibialis anterior (p = .0053 for Fbox32) muscles, suggesting that molecular adaptation reactions to the two training regimens show distinct characteristics. Forced treadmill and voluntary wheel running have differential effects on mouse skeletal muscle, specifically with regard to expression of exercise‐associated genes and miRNAs. In addition, effects differ significantly between individual muscle types.