The ELSA trial: single versus combinatory effects of non-prohibited beta-2 agonists on skeletal muscle metabolism, cardio-pulmonary function and endurance performance—study protocol for a randomized 4-way balanced cross-over trial

Background Asthma and/or airway hyper-responsiveness (AHR) are common in elite endurance athletes with a high prevalence rate of beta-2 adrenoreceptor (beta-2) agonists use. Nevertheless, there are data on dose-dependent ergogenic effects of beta-2 agonists suggesting increased muscle strength, endurance and neuromuscular performance. Therefore, most beta-2 agonists belong to the World Anti Doping Agency (WADA) list of prohibited substances and it is tempting to speculate that illegitimate use of beta-2 agonists might be a common practice to boost performance in competitive sports. It is currently unknown whether or not inhaled beta-2 agonists enhance performance by stimulatory effects in skeletal and cardiac muscle. Methods The ELSA trial is a double-blinded, placebo-controlled, randomized, balanced, four-way cross-over study. Study participants (n=24, 12 ♀, 12 ♂) complete four study arms (i.e. periods with treatment A, placebo; B, salbutamol; C, formoterol; D, formoterol + salbutamol) in random order after an initial preliminary testing session. Participants inhale the study medication 20 min before the 10-min time trial (TT; exercise performance test), where participants cycle 10 min at the highest possible workload. Cardiac output is measured continuously. A skeletal muscle biopsy is collected 3 h after the TT. Study endpoints include measures of skeletal muscle expression of nuclear receptors, hormones and cytokine levels, urinary and plasma concentrations of salbutamol and formoterol, circulating cardiac markers, cardiopulmonary function and exercise performance (average power and peak power during the TT). Blood and urine are collected and respiratory testing is performed 24 h post TT. Summary/conclusions This clinical trial evaluates the potential performance-enhancing effects of non-prohibited, not medically indicated inhaled short- and long-acting beta-2 agonists on skeletal muscle gene expression, endocrine regulation, cardiac biomarkers, cardiopulmonary function and acute endurance exercise performance. These data will be used by WADA to adapt the annually published list of prohibited substances (WADA 2021) and will be published in scientific journals

Acute Effects of Single Versus Combined Inhaled β2-Agonists Salbutamol and Formoterol on Time Trial Performance, Lung Function, Metabolic and Endocrine Variables

Background High prevalence rates of β2-agonist use among athletes in competitive sports makes it tempting to speculate that illegitimate use of β2-agonists boosts performance. However, data regarding the potential performance-enhancing effects of inhaled β2-agonists and its underlying molecular basis are scarce. Methods In total, 24 competitive endurance athletes (12f/12m) participated in a clinical double-blinded balanced four-way block cross-over trial to investigate single versus combined effects of β2-agonists salbutamol (SAL) and formoterol (FOR), to evaluate the potential performance enhancement of SAL (1200 µg, Cyclocaps, Pb Pharma GmbH), FOR (36 µg, Sandoz, HEXAL AG) and SAL + FOR (1200 µg + 36 µg) compared to placebo (PLA, Gelatine capsules containing lactose monohydrate, Pharmacy of the University Hospital Ulm). Measurements included skeletal muscle gene and protein expression, endocrine regulation, urinary/serum β2-agonist concentrations, cardiac markers, cardiopulmonary and lung function testing and the 10-min time trial (TT) performance on a bicycle ergometer as outcome variables. Blood and urine samples were collected pre-, post-, 3 h post- and 24 h post-TT. Results Mean power output during TT was not different between study arms. Treatment effects regarding lung function (p < 0.001), echocardiographic (left ventricular end-systolic volume p = 0.037; endocardial global longitudinal strain p < 0.001) and metabolic variables (e.g. NR4A2 and ATF3 pathway) were observed without any influence on performance. In female athletes, total serum β2-agonist concentrations for SAL and FOR were higher. Microarray muscle gene analysis showed a treatment effect for target genes in energy metabolism with strongest effect by SAL + FOR (NR4A2; p = 0.001). Of endocrine variables, follicle-stimulating hormone (3 h Post–Post-TT), luteinizing hormone (3 h Post–Pre-TT) and insulin (Post–Pre-TT) concentrations showed a treatment effect (all p < 0.05). Conclusions No endurance performance-enhancing effect for SAL, FOR or SAL + FOR within the permitted dosages compared to PLA was found despite an acute effect on lung and cardiac function as well as endocrine and metabolic variables in healthy participants. The impact of combined β2-agonists on performance and sex-specific thresholds on the molecular and cardiac level and their potential long-term performance enhancing or health effects have still to be determined. Trial registration: Registered at Eudra CT with the number: 2015-005598-19 (09.12.2015) and DRKS with number DRKS00010574 (16.11.2021, retrospectively registered)

Sedentary Behavior among National Elite Rowers during Off-Training—A Pilot Study

The aim of this pilot study was to analyze the off-training physical activity (PA) profile in national elite German U23 rowers during 31 days of their preparation period. The hours spent in each PA category (i.e., sedentary: &lt;1.5 metabolic equivalents (MET); light physical activity: 1.5–3 MET; moderate physical activity: 3–6 MET and vigorous intense physical activity: &gt;6 MET) were calculated for every valid day (i.e., &gt;480 min of wear time). The off-training PA during 21 weekdays and 10 weekend days of the final 11-week preparation period was assessed by the wrist-worn multisensory device Microsoft Band II (MSBII). A total of 11 rowers provided valid data (i.e., &gt;480 min/day) for 11.6 week days and 4.8 weekend days during the 31 days observation period. The average sedentary time was 11.63 ± 1.25 h per day during the week and 12.49 ± 1.10 h per day on the weekend, with a tendency to be higher on the weekend compared to weekdays (p = 0.06; d = 0.73). The average time in light, moderate and vigorous PA during the weekdays was 1.27 ± 1.15, 0.76 ± 0.37, 0.51 ± 0.44 h per day, and 0.67 ± 0.43, 0.59 ± 0.37, 0.53 ± 0.32 h per weekend day. Light physical activity was higher during weekdays compared to the weekend (p = 0.04; d = 0.69). Based on our pilot study of 11 national elite rowers we conclude that rowers display a considerable sedentary off-training behavior of more than 11.5 h/day

Inter- and intra-unit reliability of the COSMED K5: Implications for multicentric and longitudinal testing.

PurposeTo evaluate the intra-unit (RELINTRA) and inter-unit reliability (RELINTER) of two structurally identical units of the metabolic analyser K5 (COSMED, Rome, Italy) that allows to utilize either breath-by-breath (BBB) or dynamic mixing chamber (DMC) technology.MethodsIdentical flow- and gas-signals were transmitted to both K5s that always operated simultaneously either in BBB- or DMC-mode. To assess RELINTRA and RELINTER, a metabolic simulator was applied to simulate four graded levels of respiration. RELINTRA and RELINTER were expressed as typical error (TE%) and Intraclass Correlation Coefficient (ICC). To assess also inter-unit differences via natural respiratory signals, 12 male athletes performed one incremental bike step test each in BBB- and DMC-mode. Inter-unit differences within biological testing were expressed as percentages.ResultsIn BBB, TE% of RELINTRA ranged 0.30-0.67 vs. RELINTER 0.16-1.39 and ICC ranged 0.57-1.00 vs. 0.09-1.00. In DMC, TE% of RELINTRA ranged 0.38-0.90 vs. RELINTER 0.03-0.86 and ICC ranged 0.22-1.00 vs. 0.52-1.00. Mean inter-unit differences ranged -2.30-2.20% (Cohen's ds (ds) 0.13-1.52) for BBB- and -0.55-0.61% (ds 0.00-0.65) for DMC-mode, respectively. Inter-unit differences for [Formula: see text] and RER were significant (p ConclusionTwo structurally identical K5-units demonstrated accurate RELINTRA with TE < 2.0% and similar RELINTER during metabolic simulation. During biological testing, inter-unit differences for [Formula: see text] and RER in BBB-mode were higher than 2% with partially large ES in BBB. Hence, the K5 should be allocated personally wherever possible. Otherwise, e.g. in multicenter studies, a decrease in total reliability needs to be considered especially when the BBB-mode is applied

The effect of westward travel across five time zones on sleep and subjective jet-lag ratings in athletes before and during the 2015’s World Rowing Junior Championships

This study examined sleep-wake habits and subjective jet-lag ratings of 55 German junior rowers (n = 30 male, 17.8 +/- 0.5 years) before and during the World Rowing Junior Championships 2015 in Rio de Janeiro, Brazil. Athletes answered sleep logs every morning, and Liverpool John Moore's University Jet-Lag Questionnaires each evening and morning. Following an 11-h westward flight with 5-h time shift, advanced bedtimes (-1 h,

Speckle tracking-derived bi-atrial strain before and after eleven weeks of training in elite rowers

The left (LA) and right (RA) atria undergo adaptive remodeling in response to hemodynamic stress not only induced by endurance exercise but also as part of several cardiovascular diseases thereby confounding differential diagnosis. Echocardiographic assessment of the atria with novel speckle tracking (STE)-derived variables broadens the diagnostic spectrum compared to conventional analyses and has the potential to differentiate physiologic from pathologic changes. The purpose of this study was to assess and categorize baseline values of bi-atrial structure and function in elite rowers according to recommended cutoffs, and to assess the cardiac changes occurring with endurance training. Therefore, fifteen elite rowers underwent 2D-echocardiographic analysis of established variables of cardiac structure and function as well as STE-derived variables of bi-atrial function. Measurements were performed at baseline and after eleven weeks of extensive training. 40% of athletes displayed mildly enlarged LA and 47% mildly enlarged RA at baseline, whereas no athlete fell below the lower reference values of LA and RA reservoir strain. Average power during a 2000 m ergometer rowing test (P2000 m) improved from 426 +/- 39 W to 442 +/- 34 W (p = 0.010) but there were no changes of echocardiographic variables following training. In elite rowers, longitudinal bi-atrial strain assessment indicates normal resting function of structurally enlarged atria and thereby may assist to differentiate between exercise-induced versus disease-associated structural cardiac changes in which function is commonly impaired

Eleven-Week Preparation Involving Polarized Intensity Distribution Is Not Superior to Pyramidal Distribution in National Elite Rowers

Polarized (POL) training intensity distribution (TID) emphasizes high-volume low-intensity exercise in zone (Z)1 (&lt; first lactate threshold) with a greater proportion of high-intensity Z3 (&gt;second lactate threshold) compared to Z2 (between first and second lactate threshold). In highly trained rowers there is a lack of prospective controlled evidence whether POL is superior to pyramidal (PYR; i.e., greater volume in Z1 vs. Z2 vs. Z3) TID. The aim of the study was to compare the effect of POL vs. PYR TID in rowers during an 11-wk preparation period. Fourteen national elite male rowers participated (age: 20 ± 2 years, maximal oxygen uptake (V˙O2max): 66 ± 5 mL/min/kg). The sample was split into PYR and POL by varying the percentage spent in Z2 and Z3 while Z1 was clamped to ~93% and matched for total and rowing volume. Actual TIDs were based on time within heart rate zones (Z1 and Z2) and duration of Z3-intervals. The main outcome variables were average power in 2,000 m ergometer-test (P2,000 m), power associated with 4 mmol/L [blood lactate] (P4[BLa]), and V˙O2max. To quantify the level of polarization, we calculated a Polarization-Index as log (%Z1 × %Z3 / %Z2). PYR and POL did not significantly differ regarding rowing or total volume, but POL had a higher percentage of Z3 intensities (6 ± 3 vs. 2 ± 1%; p &lt; 0.005) while Z2 was lower (1 ± 1 vs. 3 ± 2%; p &lt; 0.05) and Z1 was similar (94 ± 3 vs. 93 ± 2%, p = 0.37). Consequently, Polarization-Index was significantly higher in POL (3.0 ± 0.7 vs. 1.9 ± 0.4 a.u.; p &lt; 0.01). P2,000 m did not significantly change with PYR (1.5 ± 1.7%, p = 0.06) nor POL (1.5 ± 2.6%, p = 0.26). V˙O2max did not change (1.7 ± 5.6%, p = 0.52 or 0.6 ± 2.6, p = 0.67) and a small increase in P4[BLa] was observed in PYR only (1.9 ± 4.8%, p = 0.37 or −0.5 ± 4.1%, p = 0.77). Changes from pre to post were not significantly different between groups in any performance measure. POL did not prove to be superior to PYR, possibly due to the high and very similar percentage of Z1 in this study

Speckle tracking-derived bi-atrial strain before and after eleven weeks of training in elite rowers

Abstract The left (LA) and right (RA) atria undergo adaptive remodeling in response to hemodynamic stress not only induced by endurance exercise but also as part of several cardiovascular diseases thereby confounding differential diagnosis. Echocardiographic assessment of the atria with novel speckle tracking (STE)-derived variables broadens the diagnostic spectrum compared to conventional analyses and has the potential to differentiate physiologic from pathologic changes. The purpose of this study was to assess and categorize baseline values of bi-atrial structure and function in elite rowers according to recommended cutoffs, and to assess the cardiac changes occurring with endurance training. Therefore, fifteen elite rowers underwent 2D-echocardiographic analysis of established variables of cardiac structure and function as well as STE-derived variables of bi-atrial function. Measurements were performed at baseline and after eleven weeks of extensive training. 40% of athletes displayed mildly enlarged LA and 47% mildly enlarged RA at baseline, whereas no athlete fell below the lower reference values of LA and RA reservoir strain. Average power during a 2000 m ergometer rowing test (P2000 m) improved from 426 ± 39 W to 442 ± 34 W (p = 0.010) but there were no changes of echocardiographic variables following training. In elite rowers, longitudinal bi-atrial strain assessment indicates normal resting function of structurally enlarged atria and thereby may assist to differentiate between exercise-induced versus disease-associated structural cardiac changes in which function is commonly impaired

Sedentary behavior among national elite rowers during off-training — a pilot study

The aim of this pilot study was to analyze the off-training physical activity (PA) profile in national elite German U23 rowers during 31 days of their preparation period. The hours spent in each PA category (i.e., sedentary: 6 MET) were calculated for every valid day (i.e., >480 min of wear time). The off-training PA during 21 weekdays and 10 weekend days of the final 11-week preparation period was assessed by the wrist-worn multisensory device Microsoft Band II (MSBII). A total of 11 rowers provided valid data (i.e., >480 min/day) for 11.6 week days and 4.8 weekend days during the 31 days observation period. The average sedentary time was 11.63 ± 1.25 h per day during the week and 12.49 ± 1.10 h per day on the weekend, with a tendency to be higher on the weekend compared to weekdays (p = 0.06; d = 0.73). The average time in light, moderate and vigorous PA during the weekdays was 1.27 ± 1.15, 0.76 ± 0.37, 0.51 ± 0.44 h per day, and 0.67 ± 0.43, 0.59 ± 0.37, 0.53 ± 0.32 h per weekend day. Light physical activity was higher during weekdays compared to the weekend (p = 0.04; d = 0.69). Based on our pilot study of 11 national elite rowers we conclude that rowers display a considerable sedentary off-training behavior of more than 11.5 h/day

Effects of Training Status and Exercise Mode on Global Gene Expression in Skeletal Muscle

The aim of this study was to investigate differences in skeletal muscle gene expression of highly trained endurance and strength athletes in comparison to untrained individuals at rest and in response to either an acute bout of endurance or strength exercise. Endurance (ET, n = 8, VO2max 67 &plusmn; 9 mL/kg/min) and strength athletes (ST, n = 8, 5.8 &plusmn; 3.0 training years) as well as untrained controls (E-UT and S-UT, each n = 8) performed an acute endurance or strength exercise test. One day before testing (Pre), 30 min (30&prime;Post) and 3 h (180&prime;Post) afterwards, a skeletal muscle biopsy was obtained from the m. vastus lateralis. Skeletal muscle mRNA was isolated and analyzed by Affymetrix-microarray technology. Pathway analyses were performed to evaluate the effects of training status (trained vs. untrained) and exercise mode-specific (ET vs. ST) transcriptional responses. Differences in global skeletal muscle gene expression between trained and untrained were smaller compared to differences in exercise mode. Maximum differences between ET and ST were found between Pre and 180&prime;Post. Pathway analyses showed increased expression of exercise-related genes, such as nuclear transcription factors (NR4A family), metabolism and vascularization (PGC1-&alpha; and VEGF-A), and muscle growth/structure (myostatin, IRS1/2 and HIF1-&alpha;. The most upregulated genes in response to acute endurance or strength exercise were the NR4A genes (NR4A1, NR4A2, NR4A3). The mode of acute exercise had a significant effect on transcriptional regulation Pre vs. 180&prime;Post. In contrast, the effect of training status on human skeletal muscle gene expression profiles was negligible compared to strength or endurance specialization. The highest variability in gene expression, especially for the NR4A-family, was observed in trained individuals at 180&prime;Post. Assessment of these receptors might be suitable to obtain a deeper understanding of skeletal muscle adaptive processes to develop optimized training strategies