Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition: A Randomized Crossover Clinical Trial.

Importance: Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration. Objective: To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC. Design, Setting, and Participants: In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited. Interventions: After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise. Main Outcomes and Measures: The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC. Results: Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: -6.8 mL/kg/min; 95% CI, -10.7 to -2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: -37 Nm; 95% CI, -67 to -7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, -26.5 minutes/d; 95% CI, -42.0 to -11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing. Conclusions and Relevance: In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC. Trial Registration: ClinicalTrials.gov Identifier: NCT05445830.

[Challanges and possibilities with space travel]. / Rymdmedicin: utmaningar och möjligheter med rymdfärder.

Human space flight poses several challenges to human health, such as microgravity, space radiation, and prolonged confinement. Humans are anatomically and physiologically adapted to the gravitation on earth, and microgravity affects crucial functions. We review the pathophysiological consequences of spaceflight on the sensomotoric, cardiovascular, cerebral, and musculoskeletal systems, as well as effects of space radiation and psychosocial considerations. We also look at the medical capabilities in space, and different research methods on earth and in space.

Increased maximal oxygen uptake after sprint-interval training is mediated by central haemodynamic factors as determined by right heart catheterization.

There is a lack of knowledge regarding the contribution of central and peripheral factors to the increases in VO2max following sprint-interval training (SIT). This study investigated the importance of maximal cardiac output (Qmax ) in relation to VO2max improvements following SIT and the relative importance of the hypervolemic response on Qmax and VO2max . We also investigated whether systemic O2 extraction increased with SIT as has been previously suggested. Healthy men and women (n = 9) performed 6 weeks of SIT. State-of-the-art measurements: right heart catheterization, carbon monoxide rebreathing and respiratory gas exchange analysis were used to assess Qmax , arterial O2 content (ca O2 ), mixed venous O2 content (cv O2 ), blood volume (BV) and VO2max before and after the intervention. In order to assess the relative contribution of the hypervolemic response to the increases in VO2max , BV was re-established to pre-training levels by phlebotomy. Following the intervention, VO2max , BV and Qmax increased by 11% (P < 0.001), 5.4% (P = 0.013) and 8.8% (P = 0.004), respectively. cv O2 decreased by 12.4% (P = 0.011) and systemic O2 extraction increased by 4.0% (P = 0.009) during the same period, both variables were unaffected by phlebotomy (P = 0.589 and P = 0.548, respectively). After phlebotomy, VO2max and Qmax reverted back to pre-intervention values (P = 0.064 and P = 0.838, respectively) and were significantly lower compared with post-intervention (P = 0.016 and P = 0.018, respectively). The decline in VO2max after phlebotomy was linear to the amount of blood removed (P = 0.007, R = -0.82). The causal relationship between BV, Qmax and VO2max shows that the hypervolemic response is a key mediator of the increases in VO2max following SIT. KEY POINTS: Sprint-interval training (SIT) is an exercise model involving supramaximal bouts of exercise interspersed with periods of rest known for its efficiency in improving maximal oxygen uptake (VO2max ). In contrast to the commonly accepted view where central haemodynamic adaptations are considered to be the key mediators of increases in VO2max there have been propositions highlighting peripheral adaptations as the main mediators in the context of SIT-induced changes in VO2max . By combining right heart catheterization, carbon monoxide rebreathing and phlebotomy, this study shows that increases in maximal cardiac output due to the expansion of the total blood volume is a major explanatory factor for the improvement in VO2max following SIT, with a smaller contribution from improved systemic oxygen extraction. The present work not only clarifies a controversy in the field by using state-of-the-art methods, but also encourages future research to investigate regulatory mechanisms that could explain how SIT can lead to improvements in VO2max and maximal cardiac output similar to those that have previously been reported for traditional endurance exercise.

Influence of gravity on biomechanics in flywheel squat and leg press.

Resistance exercise on Earth commonly involves both body weight and external load. When developing exercise routines and devices for use in space, the absence of body weight is not always adequately considered. This study compared musculoskeletal load distribution during two flywheel resistance knee-extension exercises, performed in the direction of (vertical squat; S) or perpendicular to (horizontal leg press; LP) the gravity vector. Eleven participants performed these two exercises at a given submaximal load. Motion analysis and musculoskeletal modelling were used to compute joint loads and to simulate a weightless situation. The flywheel load was more than twice as high in LP as in S (p < 0.001). Joint moments and forces were greater during LP than during S in the ankle, hip and lower back (p < 0.01) but were similar in the knee. In the simulated weightless situation, hip and lower-back loadings in S were higher than corresponding values at Earth gravity (p ≤ 0.01), whereas LP joint loads did not increase. The results suggest that LP is a better terrestrial analogue than S for knee-extension exercise in weightlessness and that the magnitude and direction of gravity during resistance exercise should be considered when designing and evaluating countermeasure exercise routines and devices for space.

Improvements in Maximal Oxygen Uptake After Sprint-Interval Training Coincide with Increases in Central Hemodynamic Factors.

INTRODUCTION: Sprint-interval training has been shown to improve maximal oxygen uptake, in part through peripheral muscle adaptations that increase oxygen utilization. In contrast, the adaptations of central hemodynamic factors in this context remain unexplored. PURPOSE: The aim of the current study was to explore the effects of sprint-interval training on maximal oxygen uptake and central hemodynamic factors. METHODS: Healthy men and women (n = 29; mean age, 27 ± 5 yr; height, 175 ± 8 cm; body mass, 72.5 ± 12.0 kg) performed 6 wk of sprint-interval training consisting of three weekly sessions of 10-min low-intensity cycling interspersed with 3 × 30-s all-out sprints. Maximal oxygen uptake, total blood volume, and maximal cardiac output were measured before and after the intervention. RESULTS: Maximal oxygen uptake increased by 10.3% (P < 0.001). Simultaneously, plasma volume, blood volume, total hemoglobin mass, and cardiac output increased by 8.1% (276 ± 234 mL; P < 0.001), 6.8% (382 ± 325 mL; P < 0.001), 5.7% (42 ± 41 g; P < 0.001), and 8.5% (1.0 ± 0.9 L·min-1; P < 0.001), respectively. Increased total hemoglobin mass along with measures of body surface area had a significant impact on the improvements in maximal oxygen uptake. CONCLUSIONS: Six weeks of sprint-interval training results in significant increases in hemoglobin mass, blood volume, and cardiac output. Because these changes were associated with marked improvements in maximal oxygen uptake, we conclude that central hemodynamic adaptations contribute to the improvement in maximal oxygen uptake during sprint-interval training.

Differential responsiveness of glabrous and nonglabrous skin to local transmural pressure elevations: impact of 5 weeks of iterative local pressure loading.

We examined the in vivo pressure-flow relationship in human cutaneous vessels during acute and repeated elevations of local transmural pressure. In 10 healthy men, red blood cell flux was monitored simultaneously on the nonglabrous skin of the forearm and the glabrous skin of a finger during a vascular pressure provocation, wherein the blood vessels of an arm were exposed to a wide range of stepwise increasing distending pressures. Forearm skin blood flux was relatively stable at slight and moderate elevations of distending pressure, whereas it increased approximately three- to fourfold at the highest levels (P = 0.004). Finger blood flux, on the contrary, dropped promptly and consistently throughout the provocation (P < 0.001). Eight of the subjects repeated the provocation trial after a 5-wk pressure-training regimen, during which the vasculature in one arm was exposed intermittently (40 min, 3 times/wk) to increased transmural pressure (from +65 mmHg week 1 to +105 mmHg week 5). The training regimen diminished the pressure-induced increase in forearm blood flux by ∼34% (P = 0.02), whereas it inhibited the reduction in finger blood flux (P < 0.001) in response to slight and moderate distending pressure elevations. The present findings demonstrate that during local pressure perturbations, the cutaneous autoregulatory function is accentuated in glabrous compared with in the nonglabrous skin regions. Prolonged intermittent regional exposures to augmented intravascular pressure blunt the responsiveness of the glabrous skin but enhance arteriolar pressure resistance in the nonglabrous skin.

Comparison of Joint and Muscle Biomechanics in Maximal Flywheel Squat and Leg Press.

The aim was to compare the musculoskeletal load distribution and muscle activity in two types of maximal flywheel leg-extension resistance exercises: horizontal leg press, during which the entire load is external, and squat, during which part of the load comprises the body weight. Nine healthy adult habitually strength-training individuals were investigated. Motion analysis and inverse dynamics-based musculoskeletal modelling were used to compute joint loads, muscle forces, and muscle activities. Total exercise load (resultant ground reaction force; rGRF) and the knee-extension net joint moment (NJM) were slightly and considerably greater, respectively, in squat than in leg press (p ≤ 0.04), whereas the hip-extension NJM was moderately greater in leg press than in squat (p = 0.03). Leg press was performed at 11° deeper knee-flexion angle than squat (p = 0.01). Quadriceps muscle activity was similar in squat and leg press. Both exercise modalities showed slightly to moderately greater force in the vastii muscles during the eccentric than concentric phase of a repetition (p ≤ 0.05), indicating eccentric overload. That the quadriceps muscle activity was similar in squat and leg press, while rGRF and NJM about the knee were greater in squat than leg press, may, together with the finding of a propensity to perform leg press at deeper knee angle than squat, suggest that leg press is the preferable leg-extension resistance exercise, both from a training efficacy and injury risk perspective.

Finger constrictor and thermoperceptual responsiveness to localised cooling following 5 weeks of intermittent regional exposures to moderately augmented transmural vascular pressure.

PURPOSE: To examine the effects of prolonged intermittent exposures to moderately increased transmural pressure on finger vasoreactivity and thermoperception to localised cooling. METHODS: Eleven men completed a 5-week regimen (3 sessions·week-1; 55 min·session-1), during which the vasculature in one arm (EXP) was exposed intermittently (10-min exposure: 5-min pause) to increased transmural pressure (from +65 mmHg week-1 to +105 mmHg week-5). Before and after the regimen, finger cutaneous vascular conductance (CVC), temperature (Tavg), and thermoperception (thermal sensation, discomfort and pain) were monitored during a 30-min hand cold (8 °C water) provocation trial. The responses of the non-trained hand were examined during an additional cold trial. RESULTS: After the regimen, baseline finger CVC and Tavg were higher in both hands (p ≤ 0.01). During cooling, neither finger CVC nor Tavg were modified (p > 0.05). Yet the magnitude of the cold-induced drop of CVC was augmented in both hands, and to a similar extent (p ≤ 0.02). The regimen alleviated thermal pain in both hands (p ≤ 0.02); the sensation of coldness and thermal discomfort were attenuated mainly in the EXP hand (p = 0.02). CONCLUSIONS: Present findings indicate that iterative local exposures to augmented intravascular pressure do not alter finger vasoreactivity to localised cooling. The pressure training, however, might impair finger basal vasomotor tone, and aggravate the magnitude of constrictor responsiveness to cooling. The pressure training also elicits thermoperceptual desensitisation to noxious thermal stimulus. To large extent, these vascular and perceptual adjustments seem to be transferred to the cutaneous vasculature of the non-trained limb.

Interval-induced metabolic perturbation determines tissue fluid shifts into skeletal muscle.

Intense interval exercise has proven to be as effective as traditional endurance exercise in improving maximal oxygen uptake. Shared by these two exercise regimes is an acute reduction in plasma volume, which is a suggested stimulus behind exercise-induced increases in blood volume and maximal oxygen uptake. This study aimed to link exercise-induced metabolic perturbation with volume shifts into skeletal muscle tissue. Ten healthy subjects (mean age 33 ± 8 years, 5 males and 5 females) performed three 30 s all-out sprints on a cycle ergometer. Upon cessation of exercise magnetic resonance imaging, 31 Phosphorus magnetic resonance spectroscopy and blood samples were used to measure changes in muscle volume, intramuscular energy metabolites and plasma volume. Compared to pre-exercise, muscle volume increased from 1147.1 ± 35.6 ml to 1283.3 ± 11.0 ml 8 min post-exercise. At 30 min post-exercise, muscle volume was still higher than pre-exercise (1147.1 ± 35.6 vs. 1222.2 ± 6.8 ml). Plasma volume decreased by 16 ± 3% immediately post-exercise and recovered back to - 5 ± 6% after 30 min. Principal component analysis of exercise performance, muscle and plasma volume changes as well as changes in intramuscular energy metabolites showed generally strong correlations between metabolic and physiological variables. The strongest predictor for the volume shifts of muscle and plasma was the magnitude of glucose-6-phosphate accumulation post-exercise. Interval training leads to large metabolic and hemodynamic perturbations with accumulation of glucose-6-phosphate as a possible key event in the fluid flux between the vascular compartment and muscle tissue.

Effects of training with flow restriction on the exercise pressor reflex.

PURPOSE: We hypothesized that 5 weeks of endurance training with blood flow restriction (R-training), providing relative ischemia and stimulation of the muscle chemoreflex, would decrease the exercise pressor reflex (EPR) when compared to training with the same workload in a free-flow condition (NR-training). METHODS: 10 subjects performed one-leg knee-extension training four times a week during a 5-week period. Both legs were trained with identical workload, with one leg being trained during flow-restriction induced by lower body positive pressure. The EPR was assessed by measuring the increase in heart rate (HR) and mean arterial pressure (MAP) during an isometric knee extension of 35% of max torque for 90 s, this was done before (C), and after training in each leg (R and NR, respectively). RESULTS: At the end of isometric contraction, the increase in mean AP (MAP) in the NR-trained leg and in the control condition were 41 ± 4 and 38 ± 4 mmHg, respectively, whereas the increase in the R-trained leg was 30 ± 4 mmHg (p < 0.05 R vs C and NR), corresponding to a decrease of about 25%. A similar patter was observed with respect to responses in HR, where the increase was 28 ± 3 and 28 ± 3 bpm in the NR and C, and 22 ± 4 in the R condition (p < 0.05 R vs C and NR). CONCLUSIONS: Peripheral metabolic changes induced by relative ischemia are important in modifying the EPR in response to exercise training.

The arterial baroreflex and inherent G tolerance.

PURPOSE: High G tolerance is based on the capacity to maintain a sufficient level of arterial pressure (AP) during G load; therefore, we hypothesized that subjects with high G tolerance (H group) would have stronger arterial baroreflex responses compared to subjects with low G tolerance (L group). The carotid baroreflex was evaluated using the neck pressure method (NP), which assesses open-loop responses. METHODS: The carotid baroreflex was tested in 16 subjects, n = 8 in the H and L group, respectively, in the supine and upright posture. Heart rate and AP were measured. RESULTS: There were no differences between groups in the maximum slopes of the carotid baroreflex curves. However, the H group had a larger systolic and mean AP (SAP, MAP) increase to the initial hypotensive stimuli of the NP sequence in the upright position compared to the L group, 7.5 ± 6.6 vs 2.0 ± 2.4 and 4.1 ± 3.4 vs 1.1 ± 1.1 mmHg for SAP and MAP, respectively. Furthermore, the L group exhibited an increased latency between stimuli and response in AP in the upright compared to supine position, 4.1 ± 1.0 vs 3.1 ± 0.9 and 4.7 ± 1.1 vs 3.6 ± 0.9 s, for SAP and MAP. No differences in chronotropic responses were observed between the groups. CONCLUSIONS: It is concluded that the capacity for reflexive vasoconstriction and maintained speed of the vascular baroreflex during orthostatic stress are coupled to a higher relaxed GOR tolerance.

Measuring Uptake and Elimination of Nitrogen in Humans at Different Ambient Pressures.

BACKGROUND: To measure nitrogen (N2) wash-out and uptake requires elaborate set-ups, especially when doing the measurements at increased or decreased ambient pressure. Here we present a transportable device for quantifying N2 turnover in humans which can be used at different ambient pressures. METHODS: A modified close-circuit electronic rebreather was used to assess N2 turnover. Changes in N2 volume within the rebreathing circuit, reflecting N2 uptake or washout, were derived from the continuously monitored total system volume and the calculated volumes of oxygen and water vapor. The calculation of continuous N2 volume curves was performed off-line using dedicated computer software. RESULTS: Four subjects participated in the proof-of-concept tests. At steady state, the drift in calculated N2 volume in the rebreathing circuit over a 1-h duration was minimal. Three of the subjects participated in additional N2 steady-state measurements where 1019 mL (BTPD) of N2 was injected into the rebreathing circuit over 20 min and the measured volume increase was 1006 ± 32 mL. Lastly, N2 elimination was assessed during decompression to 0.5 atm and while breathing hyperoxic gas. N2 uptake was measured during compression to 1.8 atm. The elimination and uptake curves were deemed to be realistic. DISCUSSION: A method for assessing N2 turnover in humans has been developed and a first evaluation has been performed. It is easy to work with operationally and can be used at different ambient pressures. More research is needed in order to further validate it as a method for assessing N2 turnover in humans.Sundblad P, Frånberg O, Siebenmann C, Gennser M. Measuring uptake and elimination of nitrogen in humans at different ambient pressures. Aerosp Med Hum Perform. 2016; 87(12):1045-1050.

G tolerance and the vasoconstrictor reserve.

PURPOSE: Because leg arterial stiffness is higher in subjects with high G tolerance, we hypothesized that subjects with high G tolerance would have larger capacity for vasoconstriction. METHODS: Sixteen subjects, eight with high and eight with low G tolerance (H and L group, respectively), were exposed to a cold pressor test (CPT) in supine and upright posture. Heart rate (HR), mean arterial pressure (MAP) and cardiac output (CO) were measured, and total peripheral resistance (TPR) and stroke volume (SV) were calculated. RESULTS: In the supine position, CPT increased TPR more in the H group; 31 ± 18% than in the L group; 11 ± 7% (p < 0.05). The L group had larger increases in CO than the H group; 17 ± 16 vs. 3.4 ± 7% (p = 0.06). In the upright position, the H group had a larger MAP response to CPT than the L group; 26 ± 14 vs. 14 ± 7% (p = 0.06). The H group, but not the L group, had significant increases in TPR whereas the L group had significant increases in CO and SV. CONCLUSIONS: In response to CPT, the high G tolerance group elevated MAP by increasing TPR, whereas the low G tolerance group showed a dependency on increased CO. The H group seemed to have a larger vasoconstrictor reserve. The results further suggest that vasoconstrictor reserve capacity could constitute the link between the recent finding that indicates a relationship between G tolerance and arterial distensibility in the legs.

Time courses of central hemodynamics during rapid changes in posture.

Changes in posture cause blood volume redistribution, affecting cardiac filling and stroke volume (SV). We hypothesized that the time courses of ventricular filling would differ between the right and left ventricle during a rapid (2 s) tilt and that changes in right ventricular filling pressure would be more swift because of the direct coupling to the systemic circulation. We further hypothesized that the transient imbalance between right and left ventricular filling pressure would influence left ventricular SV changes. Right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), left ventricular stroke volume, heart rate, and arterial pressure were recorded beat-by-beat during rapid tilts from supine to upright positions and back again, during rest and dynamic 100-W leg exercise. RAP changes had a faster time course than PCWP during down-tilts, both during rest and exercise (1 ± 1 vs. 6 ± 2 s and 2 ± 2 vs. 6 ± 2 s, respectively; P < 0.05). This discrepancy caused a transient decrease in the end-diastolic pressure difference between the right and left ventricle. The decreased pressure difference in diastole impeded left ventricular filling because of ventricular interdependence, causing SV to fall transiently. The mechanisms of ventricular interdependence were also involved in reverse during up-tilt, where SV was maintained for 2-3 s despite falling PCWP. Furthermore, the decrease in RAP during up-tilt in the resting condition was biphasic with an initial fast and a second slower component, which might suggest the effect of venous valves. This was not seen during dynamic leg exercise where blood pooling is prevented by the venous muscle pump.

G tolerance vis-à-vis pressure-distension and pressure-flow relationships of leg arteries.

During increased gravitoinertial (G) load in the head-to-foot direction, pressures in dependent vascular beds are commonly raised to levels capable of distending precapillary vessels, which, in turn, may reduce arterial pressure, and hence compromise the capacity to withstand G load (G tolerance). We hypothesized that distensibility in precapillary leg vessels would be lower in a group of subjects possessing high G tolerance (H; n = 7; relaxed G tolerance = 6.6 ± 0.8 G) than in a group with low G tolerance (L; n = 8; G tolerance = 3.9 ± 0.3 G). The groups were matched with regard to gender, age, weight, height, and resting arterial pressure. Arterial pressure-distension and pressure-flow experiments were performed with the subject supine in a pressure chamber with a lower leg protruding to the outside. Increased intravascular pressure in the blood vessels of the outside leg was accomplished by stepwise increasing chamber pressure to 240 mmHg. Diameter and flow in the posterior tibial artery were measured by ultrasonographic/Doppler techniques. Pressure-induced increments in arterial diameter and flow were more pronounced (p < 0.03) in the L (14.1 ± 4.2% and 32 ± 21 ml/min respectively) than in the H (1.7 ± 5.0% and 1.6 ± 25 ml/min) group, and the pressure thresholds at which these increments commenced were lower (by 52 and 48 mmHg, respectively) in the L than in the H group (p < 0.04). Negative correlations were observed between G tolerance and the increments in diameter and flow (p < 0.02). Thus, the wall stiffness of precapillary leg vessels is greater in individuals with high relaxed G tolerance; whether a causal relationship exists remains to be established.

Activation of the erythropoietin receptor in human skeletal muscle.

OBJECTIVE: Erythropoietin receptor (EPOR) expression in non-hematological tissues has been shown to be activated by locally produced and/or systemically delivered EPO. Improved oxygen homeostasis, a well-established consequence of EPOR activation, is very important for human skeletal muscle performance. In the present study we investigate whether human skeletal muscle fibers and satellite cells express EPOR and if it is activated by exercise. DESIGN AND METHODS: Ten healthy males performed 65 min of cycle exercise. Biopsies were obtained from the vastus lateralis muscle and femoral arterio-venous differences in EPO concentrations were estimated. RESULTS: The EPOR protein was localized in areas corresponding to the sarcolemma and capillaries. Laser dissection identified EPOR mRNA expression in muscle fibers. Also, EPOR mRNA and protein were both detected in human skeletal muscle satellite cells. In the initial part of the exercise bout there was a release of EPO from the exercising leg to the circulation, possibly corresponding to an increased bioavailability of EPO. After exercise, EPOR mRNA and EPOR-associated JAK2 phosphorylation were increased. CONCLUSIONS: Interaction with JAK2 is required for EPOR signaling and the increase found in phosphorylation is therefore closely linked to the activation of EPOR. The receptor activation by acute exercise suggests that signaling through EPOR is involved in exercise-induced skeletal muscle adaptation, thus extending the biological role of EPO into the skeletal muscle.