Baroreflex impairment during rapid posture changes at rest and exercise after 120 days of bed rest

Orthostatic intolerance is common after space flight and head-down tilt (HDT) bed rest. We hypothesized that HDT-induced impairments of arterial blood pressure (AP) control would be more marked during exercise and that recovery of baroreflex function after very long-term HDT would be delayed. Six subjects were studied before (BDC) during (day 60, D60; D113) and after (recovery day 0, R0; R3; R15) 120 days of HDT. Supine resting subjects were exposed to repeated 1 min passive tilts to upright at 3-min interval. During 50 W steady-state exercise corresponding tilt had a 2-min duration at 4-min interval. The amplitudes of the tilt-induced transient beat-by-beat deviations in AP and rate (HR) were determined during the gravity transients. At rest these deviations did not change over time, but during exercise the total peak-to-nadir range of deviations in systolic AP (SAP) at up-tilt and down-tilt increased to 168±16% (mean±SEM) of BDC at D113 with no clear recovery upto and including R15. Counter-regulatory HR responses were not increased proportionally and especially not tachycardic responses to up-tilt, resulting in a reduction of baroreflex sensitivity (ΔRR-interval/ΔSAP) by 55±9% of BDC at D113 with no recovery upto and including R15. We conclude that prolonged bed rest cause long-lasting impairments in AP control and baroreflex function in exercising humans.     

Human thermoregulatory function during exercise and immersion after 35 days of horizontal bed-rest and recovery

The present study evaluated the effect of 35 days of experimental horizontal bed-rest on exercise and immersion thermoregulatory function. Fifteen healthy male volunteers were assigned to either a Control (n=5) or Bed-rest (n=10) group. Thermoregulatory function was evaluated during a 30-min bout of submaximal exercise on a cycle ergometer, followed immediately by a 100-min immersion in 28°C water. For the Bed-rest group, exercise and immersion thermoregulatory responses observed post-bed-rest were compared with those after a 5 week supervised active recovery period. In both trials, the absolute work load during the exercise portion of the test was identical. During the exercise and immersion, we recorded skin temperature, rectal temperature, the difference in temperature between the forearm and third digit of the right hand (T_{forearm-fingertip})— an index of skin blood flow, sweating rate from the forehead, oxygen uptake and heart rate at minute intervals. Subjects provided ratings of temperature perception and thermal comfort at 5-min intervals. Exercise thermoregulatory responses after bed-rest and recovery were similar. Subjective ratings of temperature perception and thermal comfort during immersion indicated that subjects perceived similar combinations of Tsk and Tre to be warmer and thermally less uncomfortable after bed-rest. The average (SD) exercise-induced increase in Tre relative to resting values was not significantly different between the Post-bed-rest (0.4 (0.2)°C) and Recovery (0.5 (0.2)°C) trials. During the post-exercise immersion, the decrease in Tre, relative to resting values, was significantly (P<0.05) greater in the Post-bed-rest trial (0.9 (0.5)°C) than after recovery (0.4 (0.3)°C). T_{forearm-fingertip} was 5.2 (0.9)°C and 5.8 (1.0)°C at the end of the post-bed-rest and recovery immersions, respectively. The gain of the shivering response (increase in O₂ relative to the decrease in Tre; O₂/Tre) was 1.19 l min^–1°C^–1 in the Recovery trial, and was significantly attenuated to 0.51 l min^–1°C^–1 in the Post-bed-rest trial. The greater cooling rate observed in the post-bed-rest trial is attributed to the greater heat loss and reduced heat production. The former is the result of attenuated cold-induced vasoconstriction and enhanced sweating rate, and the latter a result of a lower shivering O₂ response.     

Metabolic and cardiovascular responses during sub-maximal exercise in humans after 14 days of head-down tilt bed rest and inactivity

f _H, SV, [Hb], C_aO₂, O₂, MAP and R _P were measured in 10 young subjects at rest and during exercise at 50, 100 and 150 W before and after 14 days of head-down tilt bed rest (HDTBR) and of ambulatory (AMB) control period. f _H was 18 and 8% higher after HDTBR and AMB, respectively. SV dropped by 15% both after HDTBR and AMB, whereas did not change. After HDTBR, C_aO₂ decreased at rest (−8%) and at 50 W (−5%), whereas O₂ did not change; MAP was 14 and 6% lower at rest and at 100 W and R _P decreased by 23% only at rest. Changes in f _H and SV were larger after HDTBR than after AMB. These results show that, notwhistanding the drop of SV, moderate-intensity dynamic exercise elicited a normal pressure response after 14 days of HDTBR.     

Changes in muscle size, architecture, and neural activation after 20 days of bed rest with and without resistance exercise

Nine healthy men carried out head-down bed rest (BR) for 20 days. Five subjects (TR) performed isometric, bilateral leg extension exercise every day, while the other four (NT) did not. Before and after BR, maximal isometric knee extension force was measured. Neural activation was assessed using a supramaximal twitch interpolated over voluntary contraction. From a series cross-sectional magnetic resonance imaging scans of the thigh, physiological cross-sectional areas (PCSA) of the quadriceps muscles were estimated (uncorrected PCSA, volume/estimated fibre length). Decrease in mean muscle force after BR was greater in NT [−10.9 (SD 6.9)%, P < 0.05] than in TR [0.5 (SD 7.9)%, not significant]. Neural activation did not differ between the two groups before BR, but after BR NT showed smaller activation levels. Pennation angles of the vastus lateralis muscle, determined by ultrasonography, showed no significant changes in either group. The PCSA decreased in NT by −7.8 (SD 0.8)% (P < 0.05) while in TR PCSA showed only an insignificant tendency to decrease [−3.8 (SD 3.8)%]. Changes in force were related more to changes in neural activation levels than to those in PCSA. The results suggest that reduction of muscle strength by BR is affected by a decreased ability to activate motor units, and that the exercise used in the present experiment is effective as a countermeasure. Accepted: 18 September 2000     

Effect of 21 days of horizontal bed rest on behavioural thermoregulation

The present study investigated the effect of 21 days of horizontal bed rest on cutaneous cold and warm sensitivity, and on behavioural temperature regulation. Healthy male subjects (N = 10) were accommodated in a hospital ward for the duration of the study and were under 24-h medical care. All activities (eating, drinking, hygiene, etc.) were conducted in the horizontal position. On the 1st and 22nd day of bed rest, cutaneous temperature sensitivity was tested by applying cold and warm stimuli of different magnitudes to the volar region of the forearm via a Peltier element thermode. Behavioural thermoregulation was assessed by having the subjects regulate the temperature of the water within a water-perfused suit (T _wps) they were wearing. A control unit established a sinusoidal change in T _wps, such that it varied from 27 to 42°C. The subjects could alter the direction of the change of T _wps, when they perceived it as thermally uncomfortable. The magnitude of the oscillations towards the end of the trial was assumed to represent the upper and lower boundaries of the thermal comfort zone. The cutaneous threshold for detecting cold stimulus decreased (P < 0.05) from 1.6 (1.0)°C on day 1 to 1.0 (0.3)°C on day 22. No effect was observed on the ability to detect warm stimuli or on the regulated T _wps. We conclude that although cold sensitivity increased after bed rest, it was not of sufficient magnitude to cause any alteration in behavioural thermoregulatory responses.     

Characteristics of fast voluntary and electrically evoked isometric knee extensions during 56 days of bed rest with and without exercise countermeasure

The contractile characteristics of fast voluntary and electrically evoked unilateral isometric knee extensions were followed in 16 healthy men during 56 days of horizontal bed rest and assessed at bed rest days 4, 7, 10, 17, 24, 38 and 56. Subjects were randomized to either an inactive control group (Ctrl, n = 8) or a resistive vibration exercise countermeasure group (RVE, n = 8). No changes were observed in neural activation, indicated by the amplitude of the surface electromyogram, or the initial rate of voluntary torque development in either group during bed rest. In contrast, for Ctrl, the force oscillation amplitude at 10 Hz stimulation increased by 48% (P < 0.01), the time to reach peak torque at 300 Hz stimulation decreased by 7% (P < 0.01), and the half relaxation time at 150 Hz stimulation tended to be slightly reduced by 3% (P = 0.056) after 56 days of bed rest. No changes were observed for RVE. Torque production at 10 Hz stimulation relative to maximal (150 Hz) stimulation was increased after bed rest for both Ctrl (15%; P < 0.05) and RVE (41%; P < 0.05). In conclusion, bed rest without exercise countermeasure resulted in intrinsic speed properties of a faster knee extensor group, which may have partly contributed to the preserved ability to perform fast voluntary contractions. The changes in intrinsic contractile properties were prevented by resistive vibration exercise, and voluntary motor performance remained unaltered for RVE subjects as well.     

20-Hz whole body vibration training fails to counteract the decrease in leg muscle volume caused by 14 days of 6° head down tilt bed rest

A 6° head down tilt bed rest (HDT) was used to simulate the effects of muscle unloading in space. We tested whether vibration training (VT) reduces the decrease in leg muscle volume induced by 14 days HDT. In two study phases eight healthy male subjects received both (1) HDT and VT or (2) HDT and a control intervention. Twice daily five intervals of 1 min VT were performed (20 Hz, 2–4 mm) in upright standing position followed by 1 min breaks in seated position. The control intervention included identical procedures except the vibration plate was off. Before and the day after HDT volumes of upper and lower leg muscles were measured using magnetic resonance imaging. HDT combined with control intervention caused a significant (P < 0.05) decrease in the volumes of muscles by −4 to −6.5%. VT failed to counteract the decrease in leg muscle volume induced by HDT.     

Functional changes in autonomic nervous system and baroreceptor reflex induced by 14 days of 6° head-down bed rest

We studied the effects of 14 days of 6° head-down bed rest (HDBR) in 16 healthy male subjects to examine the functional changes in the autonomic nervous system and cardiac baroreceptor reflex response with an emphasis on dynamic changes during HDBR. Beat-by-beat RR intervals (RRIs) and systolic arterial pressures (SAPs) were measured non-invasively from simultaneous, continuous recordings of ECG and arterial pressure waves in supine resting postures. A power spectrum analysis by the fast Fourier transform was applied to a data set composed of interpolated 512 RRIs and 512 SAPs (256 s in duration). Three indices of cardiac baroreceptor reflex sensitivity (BRS) were obtained by applying a sequence technique and a cross-spectrum analysis technique to the spontaneous RRIs and SAPs. The high-frequency band power of RRI variability (HF_RRI) decreased significantly in the latter part of HDBR and persisted until the initial stage of the post-HDBR period (POST). The low-frequency band power of SAP variability decreased significantly only during the mid-part of HDBR. The BRS_sequence obtained by the sequence technique showed a significant increase temporarily on the initial day of HDBR. The BRS_sequence and the estimate of BRS obtained by the cross-spectrum analysis handling the high-frequency band were both significantly decreased on the initial day of POST. Each of the BRS estimates correlated negatively with heart rate and positively with HF_RRI during HDBR and POST. These results suggest the following: (1) cardiac spontaneous baroreceptor reflex sensitivity might be transiently increased at the initial stage of HDBR, (2) the reduction in vagal modulation on the sinus node occurs from the latter part of HDBR to the initial stage of POST, (3) sympathetic vasomotor control is probably slightly inhibited during the mid-part of HDBR, and (4) the enhancement in cardiac sympathetic modulation and the impairment in cardiac spontaneous baroreceptor reflex sensitivity may occur in the initial stage of POST.     

Leg-press resistance training during 20 days of 6° head-down-tilt bed rest prevents muscle deconditioning

The purpose of this study was to investigate the effects of resistance training on the morphological and functional properties of human lower limb muscles during 20 days of 6° head-down-tilt bed rest. Nine men were randomly assigned to the resistance training group (BR-Tr, n=5) or the non-training, control group (BR-Cont, n=4). Isometric leg-press exercises were performed: 3 s × 30 repetitions (30 s rest between repetitions) daily for 20 days during the bed-rest period. Serial axial magnetic resonance images were taken from the right thigh and leg muscles, and muscle volume, muscle length, and fibre length were estimated. The physiological cross-sectional areas (PCSAs) of the knee extensor, knee flexor, ankle plantarflexor, and ankle dorsiflexor (tibialis anterior) muscle groups were determined as muscle volume multiplied by the cosine of the angle of fibre pennation divided by fibre length. Maximum voluntary contraction (MVC) during knee extension was measured. No significant changes were observed in the PCSA of the knee extensor muscles in BR-Tr group, whereas the PCSA in the BR-Cont group decreased by 7.8%. The PCSA of the knee flexor and plantarflexor muscles in the BR-Tr group and BR-Cont group significantly decreased after bed rest (knee flexors, 10.2% and 11.5%; plantarflexors, 13.0% and 12.8%, respectively). However, in both groups bed rest had no effect on the muscle volume and PCSA of the tibialis anterior. MVC was maintained by resistance training in the BR-Tr group (decreased by 1%). In contrast, a decline of strength was observed in the BR-Cont group (−16%), but this result was not statistically significant. These results suggest that isometric leg-press training prevents the deconditioning (i.e. atrophy and decline of strength) of the knee extensor muscle group. Accepted: 23 December 1999     

Effect of 5 weeks horizontal bed rest on human muscle thickness and architecture of weight bearing and non-weight bearing muscles

The aim of the present study was to investigate the changes in thickness, fascicle length (L (f)) and pennation angle (theta) of the antigravity gastrocnemius medialis (GM) and vastus lateralis (VL) muscles, and the non-antigravity tibialis anterior (TA) and biceps brachii (BB) muscles measured by ultrasonography in ten healthy males (aged 22.3 +/- 2.2 years) in response to 5 weeks of horizontal bed rest (BR). After BR, muscle thickness decreased by 12.2 +/- 8.8% (P < 0.05) and 8.0 +/- 9.1% (P < 0.005) in the GM and VL, respectively. No changes were observed in the TA and BB muscles. L (f) and theta decreased by 4.8 +/- 5.0% (P < 0.05) and 14.3 +/- 6.8% (P < 0.005) in the GM and by 5.9 +/- 5.3% (P < 0.05) and 13.5 +/- 16.2% (P < 0.005) in the VL, again without any changes in the TA and BB muscles. The finding that amongst the antigravity muscles of the lower limbs, the GM deteriorated to a greater extent than the VL is possibly related to the differences in relative load that this muscle normally experiences during daily loading. The dissimilar response in antigravity and non-antigravity muscles to unloading likely reflects differences in loading under normal conditions. The significant structural alterations of the GM and VL muscles highlight the rapid remodelling of muscle architecture occurring with disuse.     

Changes in muscle contractile characteristics and jump height following 24 days of unilateral lower limb suspension

We measured changes in maximal voluntary and electrically evoked torque and rate of torque development because of limb unloading. We investigated whether these changes during single joint isometric muscle contractions were related to changes in jump performance involving dynamic muscle contractions and several joints. Six healthy male subjects (21 ± 1 years) underwent 3 weeks of unilateral lower limb suspension (ULLS) of the right limb. Plantar flexor and knee extensor maximal voluntary contraction (MVC) torque and maximal rate of torque development (MRTD), voluntary activation, and maximal triplet torque (thigh; 3 pulses at 300 Hz) were measured next to squat jump height before and after ULLS. MVC of plantar flexors and knee extensors (MVCke) and triplet torque decreased by 12% (P = 0.012), 21% (P = 0.001) and 11% (P = 0.016), respectively. Voluntary activation did not change (P = 0.192). Absolute MRTD during voluntary contractions decreased for plantar flexors (by 17%, P = 0.027) but not for knee extensors (P = 0.154). Absolute triplet MRTD decreased by 17% (P = 0.048). The reduction in MRTD disappeared following normalization to MVC. Jump height with the previously unloaded leg decreased significantly by 28%. No significant relationships were found between any muscle variable and jump height (r < 0.48), but decreases in torque were (triplet, r = 0.83, P = 0.04) or tended to be (MVCke r = 0.71, P = 0.11) related to decreases in jump height. Thus, reductions in isometric muscle torque following 3 weeks of limb unloading were significantly related to decreases in the more complex jump task, although torque in itself (without intervention) was not related to jump performance.     

Oxygen deficits and oxygen delivery kinetics during submaximal intensity exercise in humans after 14 days of head-down tilt-bed rest

The effect of two running sessions completed within a 12-h period on hemolysis, inflammation, and hepcidin activity in endurance athletes was investigated. Ten males completed two experimental trials in a randomized, counterbalanced order. The two trials included (a) a one-running-session trial (T1) including 10 × 1 km interval repeats (90% peak velocity), and (b) a two-running-session trial (T2), comprising a continuous 10-km run (70% peak velocity), and a 10 × 1 km interval run (90% peak velocity) completed 12 h later. Interleukin-6 (IL-6), free hemoglobin (Hb), haptoglobin (Hp), iron, ferritin, and hepcidin were assessed post-exercise. After the T1 and T2 interval runs, free Hb was significantly increased and Hp significantly decreased (p ≤ 0.05), with a cumulative effect shown in T2 after the second run (p ≤ 0.05). The IL-6, serum iron, ferritin, and hepcidin activity were increased after each running session (p ≤ 0.05), with no cumulative effect in T2. In conclusion, a cumulative effect of two running sessions on hemolysis was shown, but no similar effect with inflammation and hepcidin activity was evident.     

Effects of concentric and repeated eccentric exercise on muscle damage and calpain–calpastatin gene expression in human skeletal muscle

The purpose of this study was to compare the responsiveness of changes in Ca²⁺-content and calpain–calpastatin gene expression to concentric and eccentric single-bout and repeated exercise. An exercise group (n = 14) performed two bouts of bench-stepping exercise with 8 weeks between exercise bouts, and was compared to a control-group (n = 6). Muscle strength and soreness and plasma creatine kinase and myoglobin were measured before and during 7 days following exercise bouts. Muscle biopsies were collected from m. vastus lateralis of both legs prior to and at 3, 24 h and 7 days after exercise and quantified for muscle Ca²⁺-content and mRNA levels for calpain isoforms and calpastatin. Exercise reduced muscle strength and increased muscle soreness predominantly in the eccentric leg (P < 0.05). These responses as well as plasma levels of creatine kinase and myoglobin were all attenuated after the repeated eccentric exercise bout (P < 0.05). Total muscle Ca²⁺-content did not differ between interventions. mRNA levels for calpain 2 and calpastatin were upregulated exclusively by eccentric exercise 24 h post-exercise (P < 0.05), with no alteration in expression between bouts. Calpain 1 and calpain 3 mRNA did not change at any specific time point post-exercise for either intervention. Our mRNA results suggest a regulation on the calpain–calpastatin expression response to muscle damaging eccentric exercise, but not concentric exercise. Although a repeated bout effect was demonstrated in terms of muscle function, no immediate support was provided to suggest that regulation of expression of specific system components is involved in the repeated bout adaptation. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration

Erythropoietin (Epo) has neuroprotective and neurotrophic effects and improves cognitive function in animal models of neurodegenerative and neuropsychiatric illness. In humans, weekly Epo administration over 3 months improves cognitive function in schizophrenia. The neural underpinnings and time-course of this effect of Epo are currently unknown. It is also unclear whether the cognitive improvement reflects direct neurobiological actions or is secondary to hematological effects. We therefore assessed the actions of single administration of Epo (40,000 IU) vs. saline to healthy volunteers on cognitive and neural measures of executive function using a verbal fluency task and N-back working memory (WM) paradigm during functional magnetic resonance imaging (fMRI) on day 3 and 7 after administration in two separate cohorts of subjects. Epo modulated neuronal response in a fronto-parietal network during WM performance at both time points; on day 3 after administration, activation was increased in left-hemisphere frontal and cingulate cortex and reduced in the right parietal cortex; in contrast, neural response was enhanced in a right-lateralized fronto-parietal network and reduced in left-side regions 1 week post-administration. In addition, Epo-treated volunteers displayed improved verbal fluency performance 1 week post-administration. These effects occurred in the absence of changes in hematological measures suggesting that they reflect direct neurobiological actions of Epo. The findings are co nsistent with enduring effects of Epo on neurotrophic signaling and induction of neurochemical changes over time in neural networks typically affected in neuropsychiatric illness. The present study supports the notion that Epo may have clinical applications in the treatment of psychiatric disorder characterized by cognitive dysfunction.     

Cytosolic pH buffering during exercise and recovery in skeletal muscle of patients with McArdle’s disease

Cellular pH control is important in muscle physiology, and for interpretation of ³¹P magnetic resonance spectroscopy (MRS) data. Cellular acidification in exercise results from coupled glycolytic ATP production mitigated by cytosolic buffering, ‘consumption’ of H⁺ by phosphocreatine (PCr) breakdown, and membrane transport processes. Ex vivo methods for cytosolic buffer capacity are vulnerable to artefact, and MRS methods often require assumptions. ³¹P MRS of early exercise, when pH increases unopposed by glycolysis, is conceptually simple, but limited in normal muscle by time resolution and signal-to-noise. A therapeutic trial (Martinuzzi A et al. Musc Nerve 37: 350–357, 2007) in McArdle’s disease (glycogen phosphorylase deficiency), where pH does not decrease with exercise, offered the opportunity to test ³¹P MRS data obtained throughout incremental plantar flexion exercise and recovery in ten McArdle’s patients against the simple model of cellular pH control. Changes in pH, [Pi] and [PCr] throughout exercise and recovery were quantitatively consistent with mean ± SEM buffer capacity of 10 ± 1 mM/(pH unit), which was not significantly different from the control subjects under the initial-exercise conditions where the comparison could be made. The simple model of cellular acid–base balance therefore gives an adequate account of cellular pH changes during both exercise and recovery in McArdle’s disease.     

Strength, size and activation of knee extensors followed during 8 weeks of horizontal bed rest and the influence of a countermeasure

Changes in the quadriceps femoris muscle with respect to anatomical cross sectional area (CSA), neural activation level and muscle strength were determined in 18 healthy men subjected to 8 weeks of horizontal bed rest (BR) with (n = 9) and without (n = 9) resistive vibration exercise (RVE). CSA of the knee extensor muscle group was measured with magnetic resonance imaging every 2 weeks during bed rest. In the control subjects (Ctrl), quadriceps femoris CSA decreased linearly over the 8 weeks of bed rest to −14.1 ± 5.2% (P < 0.05). This reduction was significantly (P < 0.001) mitigated by the exercise paradigm (−3.5 ± 4.2%; P < 0.05). Prior to and seven times during bed rest, maximal unilateral voluntary torque (MVT) values of the right leg were measured together with neural activation levels by means of a superimposed stimulation technique. For Ctrl, MVT decreased also linearly over time to −16.8 ± 7.4% after 8 weeks of bed rest (P < 0.01), whereas the exercise paradigm fully maintained MVT during bed rest. In contrast to previous reports, the maximal voluntary activation remained unaltered for both groups throughout the study. For Ctrl, the absence of deterioration of the activation level might have been related to the repeated testing of muscle function during the bed rest. This notion was supported by the observation that for a subset of Ctrl subjects (n = 5) the MVT of the left leg, which was not tested during BR, was reduced by 20.5 ± 10.1%, (P < 0.01) which was for those five subjects significantly (P < 0.05) more than the 11.1 ± 9.2% (P < 0.01) reduction for the right, regularly tested leg.Grants The BBR study was supported by grant 14431/02/NL/SH2 from the European Space Agency. The study was further sponsored by Charité—University Medicine Berlin (Campus Benjamin Franklin), DLR (German AeroSpace), MSD Sharp & Dohme, Lilly Germany, Servier Germany, Hoffmann-LaRoche, Siemens, Novartis, and Seca.