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An editorial on the topic haemoglobin mass (Hbmass), red blood cell volume (RBCV) and blood doping is presented. It discusses that blood volume (BV) decline is observed in during spaceflight and artificial microgravity whereas, plasma volume (PV) decline is observed at high altitude. The physical performance is determined by Hbmass and RBCV ad are used as a potential technique for the detection of blood doping. The carbon monoxide (CO) rebreathing method is used for calculating Hbmass.

Introduction: Peak oxygen uptake (V̇O 2peak ) declines by ~7% per 1000 m of increasing altitude, whereas exercise performance seems reduced to a lesser extent. For example, 800-10 000 m track and field performances are decreased by 0.4%-2.4% above 1000 m as compared to below and some studies show similar drops in cycling performance. A greater decline in V̇O 2peak than in endurance performance with altitude suggests a higher fractional utilization of V̇O 2peak (%V̇O 2peak ). Therefore, we hypothesized that the %V̇O 2peak is higher with acute hypoxic exposure than near sea level., Methods: Sixteen lowlanders (8 women, age: 31 ± 7 years [mean ± SD], body mass: 68 ± 8 kg, V̇O 2peak : 60 ± 8 mL min -1  kg -1 ) underwent cycling testing in a hypobaric hypoxic chamber on 6 test days, three conducted at 300 m and three at 2800 m of acute altitude. At both altitudes, V̇O 2peak was determined, and during a 40-min all out maximal effort time trial (TT), mean power output (MPO) and mean V̇O 2 (%V̇O 2peak ) were assessed., Results: V̇O 2peak decreased by 11.2 ± 3.0% (p < 0.001), while MPO during the TT declined by 10.7 ± 3.1% (p < 0.001) at 2800 m as compared to 300 m. During the TT, %V̇O 2peak was higher at altitude, corresponding to 75.9 ± 4.5% at 300 m and 78.8 ± 4.2% at 2800 m (p = 0.011), and cycling economy (mL O 2  kJ -1 ) was poorer (+3.4 ± 2.7%, p < 0.001)., Conclusion: The %V̇O 2peak was higher during a cycling TT at 2800 m of altitude than near sea level, while cycling economy was poorer. This resulted in a similar reduction in performance and V̇O 2peak . Future studies should address the physiological mechanisms underlying the elevated %V̇O 2peak ., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Blood volume (BV) is an important clinical parameter and is usually reported per kg of body mass (BM). When fat mass is elevated, this underestimates BV/BM. One aim was to study if differences in BV/BM related to sex, age, and fitness would decrease if normalized to lean body mass (LBM). The analysis included 263 women and 319 men (age: 10-93 years, body mass index: 14-41 kg/m 2 ) and 107 athletes who underwent assessment of BV and hemoglobin mass (Hb mass ), body composition, and cardiorespiratory fitness. BV/BM was 25% lower (70.3 ± 11.3 and 80.3 ± 10.8 mL/kg BM ) in women than men, respectively, whereas BV/LBM was 6% higher in women (110.9 ± 12.5 and 105.3 ± 11.2 mL/kg LBM ). Hb mass /BM was 34% lower (8.9 ± 1.4 and 11.5 ± 11.2 g/kg BM ) in women than in men, respectively, but only 6% lower (14.0 ± 1.5 and 14.9 ± 1.5 g/kg LBM )/LBM. Age did not affect BV. Athlete's BV/BM was 17.2% higher than non-athletes, but decreased to only 2.5% when normalized to LBM. Of the variables analyzed, LBM was the strongest predictor for BV (R 2  = .72, p < .001) and Hb mass (R 2  = .81, p < .001). These data may only be valid for BV/Hb mass when assessed by CO re-breathing. Hb mass /LBM could be considered a valuable clinical matrix in medical care aiming to normalize blood homeostasis., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Aims: A unique Andean population lives in the highest city of the world (La Rinconada, 5100 m, Peru) and frequently develops a maladaptive syndrome, termed chronic mountain sickness (CMS). Both extreme altitude and CMS are a challenge for the cardiovascular system. This study aims to evaluate cardiac remodelling and pulmonary circulation at rest and during exercise in healthy and CMS highlanders., Methods and Results: Highlanders living permanently at 3800 m (n = 23) and 5100 m (n = 55) with (n = 38) or without CMS (n = 17) were compared with 18 healthy lowlanders. Rest and exercise echocardiography were performed to describe cardiac remodelling, pulmonary artery pressure (PAP), and pulmonary vascular resistance (PVR). Total blood volume (BV) and haemoglobin mass were determined in all people. With the increase in the altitude of residency, the right heart dilated with an impairment in right ventricle systolic function, while the left heart exhibited a progressive concentric remodelling with Grade I diastolic dysfunction but without systolic dysfunction. Those modifications were greater in moderate-severe CMS patients. The mean PAP was higher both at rest and during exercise in healthy highlanders at 5100 m. The moderate-severe CMS subjects had a higher PVR at rest and a larger increase in PAP during exercise. The right heart remodelling was correlated with PAP, total BV, and SpO2., Conclusion: Healthy dwellers at 5100 m exhibit both right heart dilatation and left ventricle concentric remodelling with diastolic dysfunction. Those modifications are even more pronounced in moderate-severe CMS subjects and could represent the limit of the heart's adaptability before progression to heart failure., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise ± metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g., the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty: Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle. Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle. Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.

Aims/hypothesis: The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals., Methods: Glucose-intolerant (2 h OGTT glucose of 7.8-11.0 mmol/l and/or HbA 1c of 39-47 mmol/mol [5.7-6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25-42 kg/m 2 ) individuals were randomly allocated to a placebo study group (PLA, n = 15) or a metformin study group (MET, n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Watt max for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group × time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student's t tests., Results: Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group (∆PLA: -0.7 [95% CI -1.4, 0.0] mmol/l, p = 0.05 and ∆MET: -0.7 [-1.5, -0.0] mmol/l, p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (-0.8 [-1.3, -0.1] mmol/l, p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (-0.9 [-1.6, -0.2] mmol/l, p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p < 0.001). V̇O 2peak increased 15% (4.6 [3.3, 5.9] ml kg -1  min -1 , p < 0.0001) from MEDICATION to TRAINING and body weight decreased (-4.0 [-5.2, -2.7] kg, p < 0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 and p = 0.5, respectively)., Conclusions/interpretation: Metformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities., Funding: The Beckett foundation, A.P Møller Foundation, DDA, the Research Foundation of Rigshospitalet and Trygfonden., Trial Registration: ClinicalTrials.gov (NCT03316690). Graphical abstract.

Total hemoglobin mass (Hb mass ) is routinely assessed in studies by the carbon monoxide (CO) rebreathing. Its clinical application is often hindered due to the consequent rise in carboxyhemoglobin (%HbCO) and the concern of CO toxicity. We tested the reproducibility of the CO rebreathing with a CO dose of 0.5 mL/kg body mass (CO 0.5 ) compared to 1.5 mL/kg (CO 1.5 ) and when shortening the CO rebreathing protocol. Therefore, CO rebreathing was performed 1×/day in eight healthy individuals on four consecutive days. On each day, either CO 0.5 (CO 0.5 -1 and CO 0.5 -2) or CO 1.5 (CO 1.5 -1 and CO 1.5 -2) was administered. Venous blood samples to determine %HbCO and quantify Hb mass were obtained prior to, and at 6 (T 6 ), 8 (T 8 ) and 10 min (T 10 ) of CO rebreathing. This protocol was tested at sea level and at 2320 m to investigate the altitude-related measurement error. At sea level, the mean difference (95% limits of agreement) in Hb mass between CO 0.5 -1 and CO 0.5 -2 was 26 g (-26; 79 g) and between CO 1.5 -1 and CO 1.5 -2, it was 17 g (-18; 52 g) . The respective typical error (TE) corresponded to 2.4% (CO 0.5 ) and 1.5% (CO 1.5 ), while it was 6.5% and 3.0% at 2320 m. With CO 0.5 , shortening the CO rebreathing resulted in a TE for Hb mass of 4.4% (T 8 vs. T 10 ) and 14.1% (T 6 vs T 10 ) and with CO 1.5 , TE was 1.6% and 5.8%. In conclusion, the CO dose and rebreathing time for the CO rebreathing procedure can be decreased at the cost of a measurement error ranging from 1.5-14.1%.

Key Points: Highlanders develop unique adaptative mechanisms to chronic hypoxic exposure, including substantial haemoglobin and haematocrit increases. However, a significant proportion of populations living permanently at high altitude develop maladaptive features known as chronic mountain sickness (CMS). This study aimed to assess the effects of permanent life at high altitude on clinical and haemorheological parameters (blood viscosity and red blood cell aggregation) and to compare clinical and haemorheological parameters of dwellers from the highest city in the world according to CMS severity. Blood viscosity increased with altitude, together with haemoglobin concentration and haematocrit. At 5100 m, highlanders with moderate-to-severe CMS had higher blood viscosity mainly at high shear rate and even at corrected haematocrit (40%), with a lower red blood cell aggregation. Blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit., Abstract: Chronic mountain sickness (CMS) is a condition characterised by excessive erythrocytosis (EE). While EE is thought to increase blood viscosity and subsequently to trigger CMS symptoms, the exact relationship between blood viscosity and CMS symptoms remains incompletely understood. We assessed the effect of living at high altitude on haemoglobin, haematocrit and haemorheological parameters (blood viscosity and red blood cell aggregation), and investigated their relationship with CMS in highlanders living in the highest city in the world (La Rinconada, Peru, 5100 m). Ninety-three men participated in this study: 10 Caucasian lowlanders, 13 Andean highlanders living at 3800 m and 70 Andean highlanders living at 5100 m (35 asymptomatic, CMS score ≤5; 15 with mild CMS, CMS score between 6 and 10; 20 with moderate-to-severe CMS, CMS score >10). Blood viscosity was measured at native and corrected haematocrit (40%). Haemoglobin concentration and haematocrit increased with the altitude of residency. Blood viscosity also increased with altitude (at 45 s -1 : 6.7 ± 0.9 mPa s at sea level, 14.0 ± 2.0 mPa s at 3800 m and 27.1 ± 8.8 mPa s at 5100 m; P < 0.001). At 5100 m, blood viscosity at corrected haematocrit was higher in highlanders with moderate-to-severe CMS (at 45 s -1 : 18.9 ± 10.7 mPa s) than in highlanders without CMS (10.2 ± 5.9 mPa s) or with mild CMS (12.1 ± 6.1 mPa s) (P < 0.05). In conclusion, blood viscosity may contribute to CMS symptomatology but the increased blood viscosity in CMS patients cannot solely be explained by the rise in haematocrit., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Heat acclimation is associated with plasma volume (PV) expansion that occurs within the first week of exposure. However, prolonged effects on hemoglobin mass (Hb mass ) are unclear as intervention periods in previous studies have not allowed sufficient time for erythropoiesis to manifest. Therefore, Hb mass , intravascular volumes, and blood volume (BV)-regulating hormones were assessed with 5½ weeks of exercise-heat acclimation (HEAT) or matched training in cold conditions (CON) in 21 male cyclists [(mean ± SD) age: 38 ± 9 years, body weight: 80.4 ± 7.9 kg, VO 2peak : 59.1 ± 5.2 ml/min/kg]. HEAT ( n = 12) consisted of 1 h cycling at 60% VO 2peak in 40 ° C for 5 days/week in addition to regular training, whereas CON ( n = 9) trained exclusively in cold conditions (<15 ° C). Before and after the intervention, Hb mass and intravascular volumes were assessed by carbon monoxide rebreathing, while reticulocyte count and BV-regulating hormones were measured before, after 2 weeks and post intervention. Total training volume during the intervention was similar ( p = 0.282) between HEAT (509 ± 173 min/week) and CON (576 ± 143 min/week). PV increased ( p = 0.004) in both groups, by 303 ± 345 ml in HEAT and 188 ± 286 ml in CON. There was also a main effect of time ( p = 0.038) for Hb mass with +34 ± 36 g in HEAT and +2 ± 33 g in CON and a tendency toward a higher increase in Hb mass in HEAT compared to CON (time × group interaction: p = 0.061). The Hb mass changes were weakly correlated to alterations in PV ( r = 0.493, p = 0.023). Reticulocyte count and BV-regulating hormones remained unchanged for both groups. In conclusion, Hb mass was slightly increased following prolonged training in the heat and although the mechanistic link remains to be revealed, the increase could represent a compensatory response in erythropoiesis secondary to PV expansion., (Copyright © 2019 Oberholzer, Siebenmann, Mikkelsen, Junge, Piil, Morris, Goetze, Meinild Lundby, Nybo and Lundby.)

Heat acclimation (HA) involves physiological adaptations that directly promote exercise performance in hot environments. However, for endurance-athletes it is unclear if adaptations also improve aerobic capacity and performance in cool conditions, partly because previous randomized controlled trial (RCT) studies have been restricted to short intervention periods. Prolonged HA was therefore deployed in the present RCT study including 21 cyclists [38 ± 2 years, 184 ± 1 cm, 80.4 ± 1.7 kg, and maximal oxygen uptake (VO 2max ) of 58.1 ± 1.2 mL/min/kg; mean ± SE] allocated to either 5½ weeks of training in the heat [HEAT ( n = 12)] or cool control [CON ( n = 9)]. Training registration, familiarization to test procedures, determination of VO 2max , blood volume and 15 km time trial (TT) performance were assessed in cool conditions (14°C) during a 2-week lead-in period, as well as immediately pre and post the intervention. Participants were instructed to maintain total training volume and complete habitual high intensity intervals in normal settings; but HEAT substituted part of cool training with 28 ± 2 sessions in the heat (1 h at 60% VO 2max in 40°C; eliciting core temperatures above 39°C in all sessions), while CON completed all training in cool conditions. Acclimation for HEAT was verified by lower sweat sodium [Na + ], reduced steady-state heart rate and improved submaximal exercise endurance in the heat. However, when tested in cool conditions both peak power output and VO 2max remained unchanged for HEAT (pre 60.0 ± 1.5 vs. 59.8 ± 1.3 mL O 2 /min/kg). TT performance tested in 14°C was improved for HEAT and average power output increased from 298 ± 6 to 315 ± 6 W ( P < 0.05), but a similar improvement was observed for CON (from 294 ± 11 to 311 ± 10 W). Based on the present findings, we conclude that training in the heat was not superior compared to normal (control) training for improving aerobic power or TT performance in cool conditions., (Copyright © 2019 Mikkelsen, Junge, Piil, Morris, Oberholzer, Siebenmann, Lundby and Nybo.)

Blood volume is an integral component of the cardiovascular system, and fundamental to discerning the pathophysiology of multiple cardiovascular conditions leading to exercise intolerance. Based on a systematic search of controlled studies assessing blood volume, in this Personal View we describe how hypovolaemia is a prevalent characteristic of patients with diabetes, irrespective of sex, age, and physical activity levels. Multiple endocrine and haematological mechanisms contribute to hypovolaemia in diabetes. The regulation of intravascular volumes is altered by sustained hyperglycaemia and hypertension. Chronic activation of endocrine systems controlling fluid homeostasis, such as the renin-angiotensin-aldosterone system and vasopressin axis, has a role in progressive kidney desensitisation and diabetic nephropathy. Furthermore, albumin loss from the intravascular compartment reduces the osmotic potential of plasma to retain water. Hypovolaemia also affects the loading conditions and filling of the heart in diabetes. The elucidation of modifiable volumetric traits will plausibly have major health benefits in the diabetes population., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hypoxia increases heart rate (HR) in humans by sympathetic activation and vagal withdrawal. However, in anaesthetized dogs hypoxia increases vagal activity and reduces HR if pulmonary ventilation does not increase and we evaluated whether that observation applies to awake humans. Ten healthy males were exposed to 15 min of normoxia and hypoxia (10.5% O 2 ), while respiratory rate and tidal volume were volitionally controlled at values identified during spontaneous breathing in hypoxia. End-tidal CO 2 tension was clamped at 40 mmHg by CO 2 supplementation. β-Adrenergic blockade by intravenous propranolol isolated vagal regulation of HR. During spontaneous breathing, hypoxia increased ventilation by 3.2 ± 2.1 l/min ( P = 0.0033) and HR by 8.9 ± 5.5 beats/min ( P < 0.001). During controlled breathing, respiratory rate (16.3 ± 3.2 vs. 16.4 ± 3.3 breaths/min) and tidal volume (1.05 ± 0.27 vs. 1.06 ± 0.24 l) were similar for normoxia and hypoxia, whereas the HR increase in hypoxia persisted without (8.6 ± 10.2 beats/min) and with (6.6 ± 5.6 beats/min) propranolol. Neither controlled breathing ( P = 0.80), propranolol ( P = 0.64), nor their combination ( P = 0.89) affected the HR increase in hypoxia. Arterial pressure was unaffected ( P = 0.48) by hypoxia across conditions. The hypoxia-induced increase in HR during controlled breathing and β-adrenergic blockade indicates that hypoxia reduces vagal activity in humans even when ventilation does not increase. Vagal withdrawal in hypoxia seems to be governed by the arterial chemoreflex rather than a pulmonary inflation reflex in humans. NEW & NOTEWORTHY Hypoxia accelerates the heart rate of humans by increasing sympathetic activity and reducing vagal activity. Animal studies have indicated that hypoxia-induced vagal withdrawal is governed by a pulmonary inflation reflex that is activated by the increased pulmonary ventilation in hypoxia. The present findings, however, indicate that humans experience vagal withdrawal in hypoxia even if ventilation does not increase, indicating that vagal withdrawal is governed by the arterial chemoreflex rather than a pulmonary inflation reflex.

Elite endurance athletes possess a high capacity for whole-body maximal fat oxidation (MFO). The aim was to investigate the determinants of a high MFO in endurance athletes. The hypotheses were that augmented MFO in endurance athletes is related to concomitantly increments of skeletal muscle mitochondrial volume density (Mito VD ) and mitochondrial fatty acid oxidation (FAO p ), that is, quantitative mitochondrial adaptations as well as intrinsic FAO p per mitochondria, that is, qualitative adaptations. Eight competitive male cross-country skiers and eight untrained controls were compared in the study. A graded exercise test was performed to determine MFO, the intensity where MFO occurs (Fat Max ), and V ˙ O 2 Max . Skeletal muscle biopsies were obtained to determine Mito VD (electron microscopy), FAO p , and OXPHOS p (high-resolution respirometry). The following were higher (P < 0.05) in endurance athletes compared to controls: MFO (mean [95% confidence intervals]) (0.60 g/min [0.50-0.70] vs 0.32 [0.24-0.39]), Fat Max (46% V ˙ O 2 Max [44-47] vs 35 [34-37]), V ˙ O 2 Max (71 mL/min/kg [69-72] vs 48 [47-49]), Mito VD (7.8% [7.2-8.5] vs 6.0 [5.3-6.8]), FAO p (34 pmol/s/mg muscle ww [27-40] vs 21 [17-25]), and OXPHOS p (108 pmol/s/mg muscle ww [104-112] vs 69 [68-71]). Intrinsic FAO p (4.0 pmol/s/mg muscle w.w/Mito VD [2.7-5.3] vs 3.3 [2.7-3.9]) and OXPHOS p (14 pmol/s/mg muscle ww/Mito VD [13-15] vs 11 [10-13]) were, however, similar in the endurance athletes and untrained controls. MFO and Mito VD correlated (r 2  = 0.504, P < 0.05) in the endurance athletes. A strong correlation between Mito VD and MFO suggests that expansion of Mito VD might be rate-limiting for MFO in the endurance athletes. In contrast, intrinsic mitochondrial changes were not associated with augmented MFO., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Physical inactivity alters glucose homeostasis in skeletal muscle, potentially developing into overt metabolic disease. The present study sought to investigate the role of skeletal muscle capillarization in glucose tolerance and insulin sensitivity (IS) using a classic human model of physical inactivity. Thirteen healthy males (age = 23 ± 2 years) underwent 4 days of full-time supervised and diet-controlled bed rest. Oral glucose tolerance test, indices of IS (quantitative insulin sensitivity check index (QUICKI), Matsuda index), as well as skeletal muscle biopsies with measurement of fiber type distribution, fiber cross-sectional area (FCSA), capillary-to-fiber ratio (C/F ratio), and capillary density (CD) were assessed prior to and after bed rest. Body weight and composition were unaltered by bed rest. Fasting glucose/insulin ratio (G 0 /I 0 ratio) (-25%, P = 0.016), QUICKI (-7%, P = 0.023), and Matsuda index (-24%, P = 0.003) diminished with bed rest. Skeletal muscle FCSA decreased (-737.4 ± 763.2 μm -2 (-12%), P = 0.005) while C/F ratio was preserved, resulting in augmented CD (+93.9 ± 91.5 capillaries·mm -2 (+37%), P = 0.003) with bed rest. No association was detected between changes in skeletal muscle variables and metabolic outcomes. Independently of bed rest-induced effects, a positive linear relationship was detected between C/F ratio and G 0 /I 0 ratio (β = 17.09, P = 0.021). In conclusion, impaired glucose homeostasis with bed rest is not prevented nor associated with enhanced skeletal muscle capillarization in healthy individuals.

Chronic rotator cuff (RC) tears are characterized by retraction, fat accumulation, and atrophy of the affected muscle. These features pose an intractable problem for surgical repair and subsequent recovery, and their prevention may be easier than reversal. Using an established ovine model, we tested the hypothesis that inhibition of the protease calpain mitigates m. infraspinatus atrophy by preservation of the myofibers' structural anchors in the sarcolemma (the costameres). Already 2 weeks of distal tendon release led to a reduction in muscle volume (-11.6 ± 9.1 cm 3 , P = 0.038) and a 8.3% slow-to-fast shift of the fiber area (P = 0.046), which were both entirely abolished by chronic local administration of the calpain inhibitor calpeptin alone, and in combination with sildenafil. Calpain inhibition blunted the retraction of the muscle-tendon unit by 0.8-1.0 cm (P = 0.020) compared with the control group, and prevented cleavage of the costameric protein talin. Calpain 1 and 2 protein levels increased in the medicated groups after 4 weeks, counteracting the efficacy of calpeptin. Hence atrophic changes emerged after 4 weeks despite ongoing treatment. These findings suggest that the early muscular adaptations in the specific case of RC tear in the ovine model are indistinguishable from the atrophy and slow-to-fast fiber transformation observed with conventional unloading and can be prevented for 2 weeks. Concluding, calpain is a potential target to extend the temporal window for reconstruction of the ruptured RC tendon before recovery turns impossible., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Bed rest leads to impaired glucose tolerance. Whether this is linked to maladaptation's in skeletal muscle mitochondrial function and in particular to the level of reactive oxygen species (ROS) is at present unknown. The aim of this longitudinal study was to quantify skeletal muscle mitochondrial function (respiratory capacity and ROS production) together with glucose tolerance after 4 days of strict bed rest in healthy young male subjects (n = 14). Mitochondrial function was determined in permeabilized muscle fibers using high-resolution respirometry and fluorometry, mitochondrial content (citrate synthase [CS] activity) and antioxidant protein expression levels were assessed in parallel to this. Glucose tolerance was determined by means of oral glucose tolerance tests. Intrinsic mitochondrial respiratory capacity was augmented after the bed rest period (CI + II P : 0.43 ± 0.12 vs. 0.55 ± 0.14 [pmol/sec/mg]/CS activity), due to a decreased CS activity (158 ± 39 vs. 129 ± 25 mU/mg dw.). No differences were observed in ROS production (per mg of tissue or when normalized to CS activity). Furthermore, the protein content for catalase was increased while superoxide dismutase and glutathione peroxidase remained unaffected. These findings were accompanied by an impaired glucose tolerance after the bed rest period (Matsuda index: 12 ± 6 vs. 9 ± 5). The change in intrinsic mitochondrial respiratory capacity could be an early indication in the development of impaired glucose tolerance. The increased catalase protein content might explain that no change was seen in ROS production after 4 days of bed rest. Whether these findings can be extrapolated to lifestyle-dependent decrements in physical activity and the development of type-2-diabetes remains unknown., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Introduction: The carbon monoxide (CO) rebreathing method used for the determination of haemoglobin mass (Hb mass ) is associated with blood sample analysis (in this study: Radiometer ABL800). As an alternative hereto the aim of the present study was to evaluate the use of a portable and non-invasive CO pulse oximeter (Rad-57)., Method: With simultaneous determination of CO in the circulation by ABL800 (%HbCO) and Rad-57 (SpCO), Hb mass and blood volume (BV) were determined in duplicates in 24 volunteers. Percentage of typical errors (%TE) within methods and linear correlations between the two procedures were computed., Results: Hb mass (Rad-57 = 798 ± 230 g; ABL800 = 781 ± 192 g) and BV (Rad-57 = 5700 ± 1373 ml; ABL800 = 5581 ± 1096 ml) were similar between methods. However, the %TE for Hb mass was higher (P<0·001) for Rad-57 (5·84 ± 5·29%) than for ABL800 (1·35 ± 1·13%). Similarly, the %TE for BV was higher (P<0·001) for Rad-57 (6·06 ± 5·76%) than for ABL800 (1·48 ± 1·25%). Lower (P<0·05) correlation coefficients between the methods were found when Hb mass  > 905 g and BV > 6193 ml., Conclusion: Assessment of SpCO by Rad-57 resulted in considerably less precise determinations of Hb mass and BV, especially for high values. Thus, non-invasive assessment of Hb mass and BV cannot be recommended for scientific purposes, but may nonetheless be useful in clinical settings., (© 2017 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: Whether arterial stiffness (AS) can be improved by regular exercise in healthy individuals remains equivocal according to cross-sectional and longitudinal studies assessing arterial properties at discrete time points. The purpose of the present study was to pinpoint the time course of training-induced adaptations in central AS., Methods: Aorta characteristic impedance (Zc) and carotid distensibility (CD) were determined with ultrasonography prior to (week 0) and across 8 weeks (weeks 2, 4, and 8) of supervised endurance training (ET) (3 × 60 minutes cycle ergometry sessions per week), in 9 previously untrained healthy normotensive adults (27 ± 4 years) with no history of cardiovascular disease. Exercise capacity was assessed by maximal oxygen consumption (VO2max) elicited by incremental ergometry., Results: VO2max increased throughout the ET intervention (+12% from week 0 to week 8, P < 0.001, P for linear trend <0.001). Systolic blood pressure rose with ET (+7% from week 0 to week 8, P = 0.019, P for linear trend <0.001). Aorta Zc augmented from week 0 to week 8 of ET in all individuals (+38%, P = 0.003, P for linear trend = 0.002). CD did not significantly differ among time points (P = 0.196) although a linear decreasing trend was detected (P = 0.016)., Conclusions: Central AS augments during a conventional ET intervention that effectively enhances aerobic exercise capacity in young individuals. This suggests that normal, healthy elastic arteries are not amendable to improvement unless impairment is present., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Arterial distensibility, an independent predictor of cardiovascular events, is transiently increased with acute hyperglycemia (AHG) in healthy individuals. Whether this response interacts with physical inactivity remains unknown. We examined the effects of short-term bed rest (BR) on the response of carotid artery distensibility (CD) to AHG, and the influence of underlying changes in insulin resistance and blood volume. CD was assessed with ultrasonography before as well as 30 and 120 minutes following ingestion of 75 g of glucose prior to and after 3 days of BR in 15 healthy male volunteers. Plasma insulin/glucose concentrations and blood volumes were concomitantly determined. On day 4 of BR, blood volume was re-established to pre-BR levels by albumin infusion and CD and insulin/glucose concentrations were determined as in the previous experimental days. Basal CD was not affected by BR. AHG increased CD before and after BR but reached a higher peak increment after BR (12% vs 60% at 30 min OGTT, p=0.028). BR also increased the plasma insulin concentration during AHG ( p=0.007). In regression analyses, plasma insulin and glucose concentrations were positively correlated to CD, particularly after BR ( r=0.31, p<0.05). Restoration of the BR-induced loss (5%) in blood volume did not affect the response of CD to AHG. In conclusion, short-term physical inactivity strongly accentuates the initial increase in CD in response to AHG in healthy individuals. This effect is associated with concomitant increases in circulating insulin concentration attributable to early insulin resistance.

The purpose of the present study was to characterize the progression of red blood cell volume (RBCV) expansion and potential volumetric and endocrine regulators of erythropoiesis during endurance training (ET). Nine healthy, untrained volunteers (age = 27 ± 4 yr) underwent supervised ET consisting of 3-4 × 60 min cycle ergometry sessions per week for 8 wk. Plasma volume (PV), RBCV, and overnight fasting hematological markers were determined before and at weeks 2 , 4 , and 8 of ET. In addition, plasma erythropoietin (EPO), cortisol, copeptin, and proatrial natriuretic peptide concentrations were measured during a 3-h morning period at baseline and postexercise at weeks 1 and 8 PV increased from baseline (2,405 ± 335 ml) at weeks 2 , 4 , and 8 (+374 ± 194, +505 ± 156, and +341 ± 160 ml, respectively, P < 0.001). Increases in RBCV from baseline (1,737 ± 442 ml) were manifested at week 4 (+109 ± 114 ml, P = 0.030) and week 8 (+205 ± 109 ml, P = 0.001). Overnight fasting plasma EPO concentration increased from baseline (11.3 ± 4.8 mIU/ml) at week 2 (+2.5 ± 2.8 mIU·ml -1 , P = 0.027) and returned to baseline concentration at weeks 4 and 8 Higher 3-h-postexercise EPO concentration was observed at week 1 (11.6 mIU/ml) compared with week 8 (8.4 ± 3.9 mIU/ml, P = 0.009) and baseline (9.0 ± 4.2 mIU/ml, P = 0.019). Linear relationships between EPO concentration and hematocrit (β = -56.2, P < 0.001) and cortisol (β = 0.037, P < 0.001) were detected throughout the ET intervention. In conclusion, ET leads to mild, transient increases in circulating EPO concentration, concurring with early PV expansion and lowered hematocrit, preceding gradual RBCV enhancement., (Copyright © 2017 the American Physiological Society.)

Objectives: To assess the delivery outcome in a pregnancy with a previous unexplained intra-uterine death by elective induction of labour at term., Methods: An audit of the pregnancy outcome of all women within the catchment area with a current singleton pregnancy; and a previous unexplained or unexplored singleton fetal demise ≥24 weeks (or 500 grams birth weight if gestation unknown) after planned routine induction of labour at full term (39-40 weeks)., Results: During the audit period, 306 patients with a previous intra-uterine fetal death were referred for further management. Of these, 161 had a clear indication for earlier intervention and were excluded from the protocol. Of the remaining 145 patients, 9 met further exclusion criteria and there were 2 patients who defaulted. Forty-two of the remaining study patients (with no known previous medical problems) developed complications during their antenatal course that necessitated a change in clinical management and earlier (<39 weeks) delivery. Of the remaining 92 patients in the audit, 47 (51%) went into spontaneous labour before their induction date; all 92 women delivered without major complications. There were no intra-uterine deaths prior to induction., Conclusions: Careful follow up at a high risk clinic identifies new or concealed maternal or fetal complications in 29% of patients with a previous intra-uterine death and no obvious maternal or fetal disease in the index pregnancy. When all risks are excluded and the pregnancy allowed to progress to full term (39-40 weeks) before an induction is offered, 50% will go into spontaneous labour.