T2-relaxation time increases in lumbar intervertebral discs after 21d head-down tilt bed-rest.

OBJECTIVES: Spaceflight back pain and intervertebral disc (IVD) herniations cause problems in astronauts. Purpose of this study was to assess changes in T2-relaxation-time through MRI measurements before and after head-down tilt bed-rest, a spaceflight analog. METHODS: 8 men participated in the bed-rest study. Subjects remained in 6° head down tilt bed-rest in two campaigns of 21 days, and received a nutritional intervention (potassium bicarbonate 90 mmol/d) in a cross-over design. MRI measurements were performed 2 days before bed-rest, as well as one and five days after getting up. Image segmentation and data analysis were conducted for the IVDs Th12/L1 to L5/S1. RESULTS: 7 subjects, average age of 27.6 (SD 3.3) years, completed the study. Results showed a significant increase in T2-time in all IVDs (p⟨0.001), more pronounced in the nucleus pulposus than in the annulus fibrosus (p⟨0.001). Oral potassium bicarbonate did not show an effect (p=0.443). Pfirrmann-grade correlated with the T2-time (p⟨0.001). CONCLUSIONS: 6° head-down tilt bed-rest leads to a T2-time increase in lumbar IVDs. Oral potassium bicarbonate supplementation does not have an effect on IVD T2-time.

Changes in muscle cross-sectional area, muscle force, and jump performance during 6 weeks of progressive whole-body vibration combined with progressive, high intensity resistance training.

OBJECTIVES: We hypothesized that progressive whole-body vibration (WBV) superimposed to progressive high intensity resistance training has greater effects on muscle cross-sectional area (CSA), muscle force of leg muscles, and jump performance than progressive high intensity resistance training alone. METHODS: Two groups of healthy male subjects performed either 6 weeks of Resistive Vibration Exercise (RVE, squats and heel raises with WBV, n=13) or Resistive Exercise (RE, squats and heel raises without WBV, n=13). Squats under RVE required indispensable weight loading on the forefoot to damp harmful vibrations to the head. Time, intervention, and interaction effects were analyzed. RESULTS: After 6 weeks of training, knee extensor CSA, isometric knee extension force, and counter movement jump height increased equally in both groups (time effect, P⟨0.001, P≤0.02, and P≤0.03, respectively), whereas only in RVE ankle plantar flexor CSA and isometric ankle plantar flexion force reached significance or a tendency, respectively, (time effect, P=0.015 and P=0.069, respectively; intervention effect also for the latter, P=0.006). Drop jump contact time did significantly more improve in RVE (interaction effect, P=0.042). CONCLUSIONS: RVE showed better training effects than RE only in plantar flexor muscles. RVE seems to be suitable in professional sports with a special focus on calf muscles.

Atrophy of calf muscles by unloading results in an increase of tissue sodium concentration and fat fraction decrease: a 23Na MRI physiology study.

PURPOSE: 23Na MRI demonstrated increased tissue sodium concentrations in a number of pathologies. Acute atrophy results in muscle fibre volume shrinking that may result in a relative increase of extracellular volume and might affect sodium concentration. Thus, we hypothesized that local unloading of the calf muscles would lead to a decrease in muscle volume and an increase in muscle tissue sodium concentration. METHOD: One lower leg of 12 healthy male subjects was submitted to a 60 day long period of unloading using the Hephaistos orthosis, while the other leg served as control. 23Na MRI and 2D PD-weighted Dixon turbo spin echo were obtained from the control and orthosis leg using a 3T scanner. For quantification, a sodium reference phantom was used with 10, 20, 30, and 40 mmol/L NaCl solution. RESULT: Tissue sodium concentration (TSC) increased as an effect of unloading in the orthosis leg. Relative increases were 17.4 ± 16.8% (P = 0.005) in gastrocnemius medialis muscle, 11.1 ± 12.5 (P = 0.037) in gastrocnemius lateralis muscle, 16.2 ± 4.7% (P < 0.001) in soleus muscle, 10.0 ± 10.5% (P = 0.009) in the ventral muscle group, and 10.7 ± 10.0% (P = 0.003) in the central muscle group, respectively. TSC in the control leg did not significantly change. In the orthosis leg, muscle volume decreased as follows: medial gastrocnemius muscle: -5.4 ± 8.3% (P = 0.043) and soleus muscle: -7.8 ± 15.0% (P = 0.043). CONCLUSION: Unloading atrophy is associated with an increase in muscle sodium concentration. 23Na MRI is capable of detecting these rather small changes.

Centrifugation as a countermeasure during bed rest and dry immersion: What has been learned?

OBJECTIVES: We review the studies that have evaluated intermittent short-radius centrifugation as a potential countermeasure for cardiovascular, musculoskeletal, and sensorimotor deconditioning in simulated weightlessness. METHODS: The findings from 18 experimental protocols that have used bed rest and dry immersion for comparing the protective effects of centrifugation versus standing upright or walking, and the effects of continuous vs. periodic exposure to centrifugation are discussed. RESULTS: Centrifugation for as little as 30 min per day was found to be effective in mitigating orthostatic intolerance and strength in postural muscle after 5 days of bed rest, but it was not effective in mitigating plasma volume loss. CONCLUSION: To determine the optimal prescription for centrifugation as a countermeasure, we recommend further studies using (a) bed rest of longer duration, (b) individualized prescriptions of centrifugation combined with exercise, and

Effects of five days of bed rest with intermittent centrifugation on neurovestibular function.

OBJECTIVES: We tested whether intermittent short-radius centrifugation was effective for mitigating alteration in balance and gait following bed rest. METHODS: Ten male subjects were exposed to 5 days of 6° head-down tilt bed rest with: (a) no countermeasure; (b) daily 1-g centrifugation for a continuous 30-min period; and (c) daily 1-g centrifugation for six periods of 5 min. During and after the bed rest, subjects were asked to scale the severity of neurovestibular symptoms that followed centrifugation or 80° head-up tilt. Following the bed rest, equilibrium scores were derived from anterior-posterior sway while standing on a foam pad with the eyes open or closed while making pitch head movements, and gait was evaluated by grading subjects' performance during various locomotion tasks. RESULTS: At the beginning of bed rest, one single 30-min period of centrifugation induced more severe neurovestibular symptoms than six periods of 5-min centrifugation. After bed rest, although equilibrium scores and gait performance were not significantly altered, subjects felt less neurovestibular dysfunction with orthostatic stress when centrifugation was used. CONCLUSION: Centrifugation was effective at reducing the severity of neurovestibular symptoms after bed rest, but this decrease was not different between one or multiple daily sessions.

Musculoskeletal effects of 5 days of bed rest with and without locomotion replacement training.

OBJECTIVES: The present study evaluated the effectiveness of a short and versatile daily exercise regime, named locomotion replacement training (LRT), to maintain muscle size, isometric strength, power, and endurance capacity of the leg muscles following 5 days of head-down tilt (HDT) bed rest. METHODS: 10 male subjects (age 29.4 ± 5.9 years; height 178.8 ± 3.7 cm; body mass 77.7 ± 4.1 kg) performed, in random order, 5 days of 6° head-down tilt bed rest (BR) with no exercise (CON), or BR with daily 25 min of upright standing (STA) or LRT. RESULTS: Knee extensor and plantar flexor cross-sectional area (CSA) were reduced by 2-3 % following bed rest (P < 0.01) for CON and STA, yet maintained for LRT. Knee extensor isometric strength (MVC) decreased by 8 % for CON (P < 0.05), was maintained for STA, and increased with 12 % for LRT (P < 0.05). Plantar flexor MVC remained unaltered during the study. Maximum jump height declined (~1.5 cm) for all conditions (P < 0.001). Neural activation and knee extensor fatigability did not change with bed rest. Bone resorption increased during BR and neither LRT nor STA was able to prevent or attenuate this increase. CONCLUSION: LRT was adequate to maintain muscle size and to even increase knee extensor MVC, but not muscle power and bone integrity, which likely requires more intense and/or longer exercise regimes. However, with only some variables showing significant changes, we conclude that 5 days of BR is an inadequate approach for countermeasure assessments.

Effects of five days of bed rest with and without exercise countermeasure on postural stability and gait.

OBJECTIVES: We tested whether intermittent standing or a combination of heel raising, squatting and hopping exercises was sufficient to prevent alteration in balance and gait following a 5-day bed rest. METHODS: This cross-over design study was performed with 10 male subjects during 6° head down tilt: (a) with no countermeasure; (b) while standing 25 min per day; (c) during locomotion-like activities 25 min per day. Gait was evaluated by grading subjects' performance during various locomotion tasks. Equilibrium scores were derived from peak-to-peak anterior-posterior sway while standing on a foam pad with the eyes open or closed or while making pitch head movements. RESULTS: When no countermeasure was used, head movements led to decreased postural stability and increased incidence of falls immediately after bed rest compared to before. When upright standing or locomotion-like exercises were used, postural stability and the incidence of falls were not significantly different after the bed rest from the baseline. CONCLUSION: These results indicate that daily 25-min of standing or locomotion-like exercise proves useful against postural instability following a 5-day bed rest. The efficacy of these countermeasures on locomotion could not be evaluated, however, because gait was not found to be altered after a 5-day bed rest.

Study protocol, implementation, and verification of a short versatile upright exercise regime during 5 days of bed rest.

OBJECTIVES: This work provides a reference for future papers originating from this study by providing basic results on body mass, urine volume, and hemodynamic changes to 5 days of bed rest (BR) and by describing acute cardio-respiratory/mechanographic responses to a short versatile upright exercise battery. METHODS: Ten male subjects (mean ± SEM age: 29.4 ± 1.5 years; height: 178.8 ± 1.5 cm; body mass: 77.7 ± 1.5 kg) performed, in random order, 5 days of 6° head-down tilt (HDT) BR with no exercise (CON), or BR with daily 25 minutes of quiet upright standing (STA) or upright locomotion replacement training (LRT). RESULTS: Plasma volume, exercise capacity and orthostatic tolerance decreased similarly between interventions following 5 days of BR. Upright heart rate during LRT and STA increased throughout BR; from 137 ± 4 bpm to 146 ± 4 bpm for LRT (P<0.01); and from 90 ± 3 bpm to 102 ± 6 bpm (P<0.001) for STA. CONCLUSION: the overall similarity in the response to BR, and increase in upright heart rate during the LRT sessions suggest early and advancing cardiovascular deconditioning during 5 days of BR bed rest, which was not prevented by the versatile exercise regime.

Elevated serum soluble CD200 and CD200R as surrogate markers of bone loss under bed rest conditions.

CD200 is a transmembrane protein that belongs to the immunoglobulin family of proteins and is ubiquitously expressed on a variety of cell types. Upon interaction with its receptors (CD200Rs) expressed on myeloid-derived cells and T lymphocytes, an immunoregulatory signal is delivered to receptor-expressing cells. Previous studies have implicated a role for CD200:CD200R in the regulation of the expression of mRNA markers of osteoclastogenesis/osteoblastogenesis, following interaction of CD200 (on osteoblast precursors) with CD200R1 (on osteoclast precursors). Signaling of CD200R1 is hypothesized to attenuate osteoclastogenesis. We have investigated whether levels of soluble forms of CD200 and/or CD200R1 (sCD200, sCD200R1) are altered in volunteers undergoing 6° head down tilt bed rest to mimic conditions of microgravity known to be associated with preferential osteoclastogenesis and whether countermeasures, reported to be beneficial in attenuation of bone loss under microgravity conditions, would lead to altered sCD200 and sCD200R1 levels. Our data suggest that, as predicted, sCD200 levels fall under bed rest conditions while sCD200R1 levels rise. In subjects undergoing 30-minute per day continuous centrifugation protocols, as a countermeasure to attenuate changes which may lead to bone loss, these alterations in sCD200 and sCD200R1 levels seen under conditions of bed rest were abolished or attenuated. Our results suggest that measurement of sCD200 and/or sCD200R1 may prove a useful and rapid means of monitoring subjects at risk of bone loss and/or accessing the efficacy of treatment regimes designed to counter bone loss.

Changes in phosphocreatine concentration of skeletal muscle during high-intensity intermittent exercise in children and adults.

PURPOSE: The aim of the present study was to test the hypotheses that a greater oxidative capacity in children results in a lower phosphocreatine (PCr) depletion, a faster PCr resynthesis and a lower muscle acidification during high-intensity intermittent exercise compared to adults. METHODS: Sixteen children (9.4 ± 0.5 years) and 16 adults (26.1 ± 0.3 years) completed a protocol consisting of a dynamic plantar flexion (10 bouts of 30-s exercise at 25 % of one repetition maximum separated by 20-s recovery), followed by 10 min of passive recovery. Changes of PCr, ATP, inorganic phosphate, and phosphomonoesters were measured by means of (31)Phosphorous-magnetic resonance spectroscopy during and post-exercise. RESULTS: Average PCr (percentage of [PCr] at initial rest (%[PCr]i)) at the end of the exercise (adults 17 ± 12 %[PCr]i, children 38 ± 17 %[PCr]i, P < 0.01) and recovery periods (adults 37 ± 14 %[PCr]i, children 57 ± 17 %[PCr]i, P < 0.01) was significantly lower in adults compared to children, induced by a stronger PCr decrease during the first exercise interval (adults -73 ± 10 %[PCr]i, children -55 ± 15 %[PCr]i, P < 0.01). End-exercise pH was significantly higher in children compared to adults (children 6.90 + 0.20, -0.14; adults 6.67 + 0.23, -0.15, P < 0.05). CONCLUSIONS: From our results we suggest relatively higher rates of oxidative ATP formation in children's muscle for covering the ATP demand of high-intensity intermittent exercise compared to adults, enabling children to begin each exercise interval with significantly higher PCr concentrations and leading to an overall lower muscle acidification.

Randomized controlled study on resistive vibration exercise (EVE study): protocol, implementation and feasibility.

OBJECTIVES: A training intervention comparing resistance exercise with or without whole-body vibration (WBV) was conducted to compare acute and chronic effects on functional and molecular parameters. METHODS: A six-week training intervention was performed including 26 healthy males (26 years, SD=4). Two groups were analyzed in a parallel design performing either resistive exercise (RE, n=13) or resistive vibration exercise (RVE, n=13) training with weekly increasing vibration frequencies (20-40Hz). Resting and exercising blood pressure and heart rate were measured before and after the 6-week intervention. RESULTS: Both training interventions decreased resting systolic blood pressure (P=0.003). Resting diastolic blood pressure was significantly decreased only in the RVE group (P=0.01). Exercising diastolic blood pressure was significantly decreased during the final training (P<0.001) with no additional effect of superimposed vibrations. Resistance exercise with superimposed vibrations evoked back pain to a higher degree than resistance exercise alone when training at frequencies above 30Hz (P<0.01). CONCLUSIONS: These data suggest positive effects of resistance exercise upon cardiovascular health and vascular responsiveness and a further beneficial effect of superimposed vibrations in decreasing resting diastolic blood pressure. Finally, development of back pain may be fostered by superimposed vibrations to high training loads, particularly at higher frequencies.

Vibration training intervention to maintain cartilage thickness and serum concentrations of cartilage oligometric matrix protein (COMP) during immobilization.

OBJECTIVE: To test the hypotheses that 1) 14-days of immobilization of young healthy subjects using a 6 degrees -"head-down-tilt-bed-rest"-model (6 degrees -HDT) would reduce cartilage thickness in the knee and serum Cartilage oligometric matrix protein (COMP) concentration and 2) isolated whole body vibration training would counteract the bed rest effects. METHOD: The study was performed and designed in compliance with the Declaration of Helsinki and is registered as trial DRKS00000140 in the German Clinical Trial Register (register.germanctr.de). Eight male healthy subjects (78.0+/-9.5kg; 179+/-0.96cm, 26+/-5 years) performed 14 days of 6 degrees -HDT. The study was designed as a cross-over-design with two study phases: a training and a control intervention. During the training intervention, subjects underwent 2x5-min whole body vibration training/day (Frequency: 20Hz; amplitude: 2-4mm). Magnetic resonance (MR) images (slice thickness: 2mm; in-plane resolution: 0.35x0.35mm; pixels: 448x512) were taken before and after the 6 degrees -HDT periods. Average cartilage thicknesses were calculated for the load bearing regions on the medial and lateral articulating surfaces in the femur and tibia. RESULTS: While the control intervention resulted in an overall loss in average cartilage thickness of -8% (pre: 3.08mm+/-0.6mm post: 2.82mm+/-0.6mm) in the weight-bearing regions of the tibia, average cartilage thickness increased by 21.9% (pre: 2.66mm+/-0.45mm post: 3.24mm+/-0.63mm) with the vibration intervention. No significant differences were found in the weight-bearing regions of the femur. During both interventions, reduced serum COMP concentrations were observed (control intervention: -13.6+/-8.4%; vibration intervention: -9.9+/-3.3%). CONCLUSION: The results of this study suggest that articular cartilage thickness is sensitive to unloading and that vibration training may be a potent countermeasure against these effects. The sensitivity of cartilage to physical training is of high relevance for training methods in space flight, elite and sport and rehabilitation after illness or injury.

Treatment of glycogenosys type V (McArdle disease) with creatine and ketogenic diet with clinical scores and with 31P-MRS on working leg muscle.

McArdle's disease is caused by genetic defects of the muscle-specific isozyme of glycogen phosphorylase, which block ATP formation from glycogen in skeletal muscle. Creatine supplementation and ketogenic diet have been tested as potential supplements for muscle energy metabolism which may improve muscle symptomatic. Outcome measures were clinical scores describing muscle symptomatic and parameters derived from 31P-MRS examinations on working muscle. In two placebo controlled cross-over studies low dose creatine showed beneficial effects on muscle symptoms and performance whereas high dose creatine distinctly worsened muscle symptomatic in patients. In both studies, however, the absence of an elevation in phosphocreatine indicated the absence of a creatine uptake by the muscle fibre. The effects of creatine on muscle symptomatic may be independent from energy metabolism in muscle. In a case study, ketogenic diet improved muscle symptomatic and performance. However, these effects again did not result in 31P-MRS visible changes in muscle energy metabolism.

Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MRS crossover study.

The purpose of our randomized, double-blind, placebo-controlled crossover study in 15 patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) because of single large-scale mitochondrial (mt) DNA deletions was to determine whether oral creatine (Cr) monohydrate can improve skeletal muscle energy metabolism in vivo. Each treatment phase with Cr in a dosage of 150 mg/kg body weight/day or placebo lasted 6 weeks. The effect of Cr was estimated by phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS), clinical and laboratory tests. (31)P-MRS analysis prior to treatment showed clear evidence of severe mitochondrial dysfunction. However, there were no relevant changes in (31)P-MRS parameters under Cr. In particular, phosphocreatine (PCr)/ATP at rest did not increase, and there was no facilitation of post-exercise PCr recovery. Clinical scores and laboratory tests did not alter significantly under Cr, which was tolerated without major side-effects in all patients. Cr supplementation did not improve skeletal muscle oxidative phosphorylation in our series of patients. However, one explanation for our negative findings may be the short study duration or the limited number of patients included.

L-carnitine and creatine in Friedreich's ataxia. A randomized, placebo-controlled crossover trial.

Impaired oxidative phosphorylation is a crucial factor in the pathogenesis of Friedreich's ataxia (FA). L-carnitine and creatine are natural compounds that can enhance cellular energy transduction. We performed a placebo-controlled triple-phase crossover trial of L-carnitine (3 g/d) and creatine (6.75 g/d) in 16 patients with genetically confirmed FA. Primary outcome measures were mitochondrial ATP production measured as phosphocreatine recovery by 31Phosphorus magnetic resonance spectroscopy, neurological deficits assessed by the international co-operative ataxia rating scale and cardiac hypertrophy in echocardiography. After 4 months on L-carnitine phosphocreatine recovery was improved compared to baseline (p<0.03, t-test) but comparison to placebo and creatine effects did not reach significance (p=0.06, F-test). Ataxia rating scale and echocardiographic parameters remained unchanged. Creatine had no effect in FA patients. L-carnitine is a promising substance for the treatment of FA patients, and larger trials are warranted.

Hypoxia modulates rapid effects of aldosterone on oxidative metabolism in human calf muscle.

Non-genomic effects of aldosterone on oxidative metabolism of skeletal muscle have been shown, recently. To further characterize these rapid effects on the increase of phosphocreatine (PCr) in the recovery period after isometric exercise, a randomized cross-over placebo-controlled study was conducted on 9 healthy volunteers. Hypoxia was chosen to test the dependence of the effect on oxygen supply and thus its relation to oxidative vs non-oxidative metabolism. Parameters related to the energy metabolism of calf muscles were measured by 31P magnetic resonance spectroscopy during four repetitive contractions in four different tests (hypoxia [FiO2=0.13] vs normoxia [FiO2=0.21], +/- 0.5 mg aldosterone). The area-under-curves of post-exercise PCr levels after the 4th contraction were significantly increased by aldosterone vs placebo during normoxia (875.5 +/- 5.1 vs 857.2 +/- 8.3%-min; p=0.02). In addition, aldosterone induced an undershoot of inorganic phosphate (Pi) in the recovery after isometric exercise (77.5 +/- 5.4 vs 88.9 +/- 5.1 mmol/l x min; p=0.05). Hypoxia blocked effects of aldosterone on PCr overshoot and Pi undershoot. Concentrations of ATP, ADP, phosphomonoesters, and intracellular pH were not affected by those interventions. In conclusion, these data demonstrate rapid actions of aldosterone on post-excercise PCr and Pi levels in human calf muscle, which are blocked by hypoxia. We hypothesize that aldosterone rapidly interferes with oxidative metabolism probably by direct modulation of ATP-turnover, which is induced by an oxygen-dependent imbalance of the ATP-synthesis and utilization rate.

Idebenone in patients with Friedreich ataxia.

Friedreich ataxia (FA), the most common form of degenerative ataxia, is thought to be caused by respiratory deficiency due to mitochondrial iron accumulation and oxidative stress. Idebenone, a free-radical scavenger, protects mitochondrial function in in vitro models of FA. In a placebo-controlled crossover trial we studied the effect of idebenone on respiratory function in nine ambulant FA patients. (31)P magnetic resonance spectroscopy demonstrated mitochondrial impairment in vivo in skeletal muscle of all FA patients, but no recovery with idebenone. No effects were seen in clinical scores. Echocardiography did not confirm a preliminary study reporting improvement of FA-associated cardiomyopathy with idebenone.