The impact of bed rest on human skeletal muscle metabolism.

Insulin sensitivity and metabolic flexibility decrease in response to bed rest, but the temporal and causal adaptations in human skeletal muscle metabolism are not fully defined. Here, we use an integrative approach to assess human skeletal muscle metabolism during bed rest and provide a multi-system analysis of how skeletal muscle and the circulatory system adapt to short- and long-term bed rest (German Clinical Trials: DRKS00015677). We uncover that intracellular glycogen accumulation after short-term bed rest accompanies a rapid reduction in systemic insulin sensitivity and less GLUT4 localization at the muscle cell membrane, preventing further intracellular glycogen deposition after long-term bed rest. We provide evidence of a temporal link between the accumulation of intracellular triglycerides, lipotoxic ceramides, and sphingomyelins and an altered skeletal muscle mitochondrial structure and function after long-term bed rest. An intracellular nutrient overload therefore represents a crucial determinant for rapid skeletal muscle insulin insensitivity and mitochondrial alterations after prolonged bed rest.

Artificial gravity during a spaceflight analog alters brain sensory connectivity.

Spaceflight has numerous untoward effects on human physiology. Various countermeasures are under investigation including artificial gravity (AG). Here, we investigated whether AG alters resting-state brain functional connectivity changes during head-down tilt bed rest (HDBR), a spaceflight analog. Participants underwent 60 days of HDBR. Two groups received daily AG administered either continuously (cAG) or intermittently (iAG). A control group received no AG. We assessed resting-state functional connectivity before, during, and after HDBR. We also measured balance and mobility changes from pre- to post-HDBR. We examined how functional connectivity changes throughout HDBR and whether AG is associated with differential effects. We found differential connectivity changes by group between posterior parietal cortex and multiple somatosensory regions. The control group exhibited increased functional connectivity between these regions throughout HDBR whereas the cAG group showed decreased functional connectivity. This finding suggests that AG alters somatosensory reweighting during HDBR. We also observed brain-behavioral correlations that differed significantly by group. Control group participants who showed increased connectivity between the putamen and somatosensory cortex exhibited greater mobility declines post-HDBR. For the cAG group, increased connectivity between these regions was associated with little to no mobility declines post-HDBR. This suggests that when somatosensory stimulation is provided via AG, functional connectivity increases between the putamen and somatosensory cortex are compensatory in nature, resulting in reduced mobility declines. Given these findings, AG may be an effective countermeasure for the reduced somatosensory stimulation that occurs in both microgravity and HDBR.

Daily artificial gravity is associated with greater neural efficiency during sensorimotor adaptation.

Altered vestibular signaling and body unloading in microgravity results in sensory reweighting and adaptation. Microgravity effects are well-replicated in head-down tilt bed rest (HDBR). Artificial gravity (AG) is a potential countermeasure to mitigate the effects of microgravity on human physiology and performance. We examined the effectiveness of daily AG for mitigating brain and/or behavioral changes in 60 days of HDBR. One group received AG for 30 minutes daily (AG; n = 16) and a control group spent the same time in HDBR but received no AG (CTRL; n = 8). All participants performed a sensorimotor adaptation task five times during fMRI scanning: twice prior to HDBR, twice during HDBR, and once following HDBR. The AG group showed similar behavioral adaptation effects compared with the CTRLs. We identified decreased brain activation in the AG group from pre to late HDBR in the cerebellum for the task baseline portion and in the thalamus, calcarine, cuneus, premotor cortices, and superior frontal gyrus in the AG group during the early adaptation phase. The two groups also exhibited differential brain-behavior correlations. Together, these results suggest that AG may result in a reduced recruitment of brain activity for basic motor processes and sensorimotor adaptation. These effects may stem from the somatosensory and vestibular stimulation that occur with AG.

Effects of Spaceflight Stressors on Brain Volume, Microstructure, and Intracranial Fluid Distribution.

Astronauts are exposed to elevated CO2 levels onboard the International Space Station. Here, we investigated structural brain changes in 11 participants following 30-days of head-down tilt bed rest (HDBR) combined with 0.5% ambient CO2 (HDBR + CO2) as a spaceflight analog. We contrasted brain changes observed in the HDBR + CO2 group with those of a previous HDBR sample not exposed to elevated CO2. Both groups exhibited a global upward shift of the brain and concomitant intracranial free water (FW) redistribution. Greater gray matter changes were seen in the HDBR + CO2 group in some regions. The HDBR + CO2 group showed significantly greater FW decrements in the posterior cerebellum and the cerebrum than the HDBR group. In comparison to the HDBR group, the HDBR + CO2 group exhibited greater diffusivity increases. In half of the participants, the HDBR + CO2 intervention resulted in signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), a constellation of ocular structural and functional changes seen in astronauts. We therefore conducted an exploratory comparison compared between subjects that did and did not develop SANS and found asymmetric lateral ventricle enlargement in the SANS group. These results enhance our understanding of the underlying mechanisms of spaceflight-induced brain changes, which is critical for promoting astronaut health and performance.

Ophthalmic changes in a spaceflight analog are associated with brain functional reorganization.

Following long-duration spaceflight, some astronauts exhibit ophthalmic structural changes referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). Optic disc edema is a common sign of SANS. The origin and effects of SANS are not understood as signs of SANS have not manifested in previous spaceflight analog studies. In the current spaceflight analog study, 11 subjects underwent 30 days of strict head down-tilt bed rest in elevated ambient carbon dioxide (HDBR+CO2 ). Using functional magnetic resonance imaging (fMRI), we acquired resting-state fMRI data at 6 time points: before (2), during (2), and after (2) the HDBR+CO2 intervention. Five participants developed optic disc edema during the intervention (SANS subgroup) and 6 did not (NoSANS group). This occurrence allowed us to explore whether development of signs of SANS during the spaceflight analog impacted resting-state functional connectivity during HDBR+CO2 . In light of previous work identifying genetic and biochemical predictors of SANS, we further assessed whether the SANS and NoSANS subgroups exhibited differential patterns of resting-state functional connectivity prior to the HDBR+CO2 intervention. We found that the SANS and NoSANS subgroups exhibited distinct patterns of resting-state functional connectivity changes during HDBR+CO2 within visual and vestibular-related brain networks. The SANS and NoSANS subgroups also exhibited different resting-state functional connectivity prior to HDBR+CO2 within a visual cortical network and within a large-scale network of brain areas involved in multisensory integration. We further present associations between functional connectivity within the identified networks and previously identified genetic and biochemical predictors of SANS. Subgroup differences in resting-state functional connectivity changes may reflect differential patterns of visual and vestibular reweighting as optic disc edema develops during the spaceflight analog. This finding suggests that SANS impacts not only neuro-ocular structures, but also functional brain organization. Future prospective investigations incorporating sensory assessments are required to determine the functional significance of the observed connectivity differences.

Altered cerebral perfusion in response to chronic mild hypercapnia and head-down tilt Bed rest as an analog for Spaceflight.

PURPOSE: Following prolonged stays on the International Space Station (ISS), some astronauts exhibit visual acuity changes, ophthalmological findings, and mildly elevated intracranial pressures as part of a novel process called spaceflight-associated neuro-ocular syndrome (SANS). To determine the pathophysiology of SANS, NASA conducted a multi-investigator study in which 11 healthy participants underwent head-down tilt bed rest, mimicking microgravity-induced cephalad fluid shifts, combined with elevated ambient CO2 levels similar to those on the ISS (HDT+CO2). As part of that study, we examined the effects of HDT+CO2 on cerebral perfusion. METHODS: Using arterial spin labeling, we compared cerebral perfusion before, during, and after HDT+CO2 in participants who developed SANS (n = 5) with those who did not (n = 6). RESULTS: All participants demonstrated a decrease in perfusion during HDT+CO2 (mean decrease of 25.1% at HDT7 and 16.2% at HDT29); however, the timing and degree of change varied between the groups. At day 7 of HDT+CO2, the SANS group experienced a greater reduction in perfusion than the non-SANS group (p =.05, 95% CI:-0.19 to 16.11, d=.94, large effect). Conversely, by day 29 of HDT+CO2, the SANS group had significantly higher perfusion (approaching their baseline) than the non-SANS group (p = .04, 95% CI:0.33 to 13.07, d=1.01, large effect). CONCLUSION: Compared with baseline and recovery, HDT+CO2 resulted in reduced cerebral perfusion which varied based on SANS status. Further studies are needed to unravel the relative role of HDT vs hypercapnia, to determine if these perfusion changes are clinically relevant, and whether perfusion changes contribute to the development of SANS during spaceflight.

Brain connectivity and behavioral changes in a spaceflight analog environment with elevated CO2.

Astronauts are exposed to microgravity and elevated CO2 levels onboard the International Space Station. Little is known about how microgravity and elevated CO2 combine to affect the brain and sensorimotor performance during and after spaceflight. Here we examined changes in resting-state functional connectivity (FC) and sensorimotor behavior associated with a spaceflight analog environment. Participants underwent 30 days of strict 6o head-down tilt bed rest with elevated ambient CO2 (HDBR+CO2). Resting-state functional magnetic resonance imaging and sensorimotor assessments were collected 13 and 7 days prior to bed rest, on days 7 and 29 of bed rest, and 0, 5, 12, and 13 days following bed rest. We assessed the time course of FC changes from before, during, to after HDBR+CO2. We then compared the observed connectivity changes with those of a HDBR control group that underwent HDBR in standard ambient air. Moreover, we assessed associations between post-HDBR+CO2 FC changes and alterations in sensorimotor performance. HDBR+CO2 was associated with significant changes in functional connectivity between vestibular, visual, somatosensory and motor brain areas. Several of these sensory and motor regions showed post-HDBR+CO2 FC changes that were significantly associated with alterations in sensorimotor performance. We propose that these FC changes reflect multisensory reweighting associated with adaptation to the HDBR+CO2 microgravity analog environment. This knowledge will further improve HDBR as a model of microgravity exposure and contribute to our knowledge of brain and performance changes during and after spaceflight.

Enhanced physiological tremor deteriorates plantar flexor torque steadiness after bed rest.

This study evaluated the effectiveness of resistance training to preserve submaximal plantar flexor (PF) torque steadiness following 60 days of bed rest (BR). Twenty-two healthy male subjects underwent either BR only (CTR, n=8), or BR plus resistance training (RT, n=14). The magnitude of torque fluctuations during steady submaximal isometric PF contractions (20%, 40%, 60% and 80% of maximum) were assessed before and after BR. Across contraction intensities, torque fluctuations (coefficient of variation, CV) increased more (P<0.05) after BR for CTR (from 0.31±0.10 to 0.92±0.63; P<0.001), than for RT (from 0.30±0.09 to 0.54±0.27; P<0.01). A shift in the spectral content of torque fluctuations towards increased rhythmic activity between 6.5 and 20Hz was observed in CTR only (P<0.05). H-reflex amplitude (H(max)/M(max) ratio) declined across groups from 0.57±0.18 before BR to 0.44±0.14 following BR (P<0.01) without correlation to CV. The present study showed that increased torque fluctuation after BR resulted from enhanced physiological tremor. Resistance training prevented the spectral shift in isometric PF torque fluctuation and offset ∼50% of the decline in performance associated with long-term BR.

Influence of vibration resistance training on knee extensor and plantar flexor size, strength, and contractile speed characteristics after 60 days of bed rest.

Spaceflight and bed rest (BR) result in loss of muscle mass and strength. This study evaluated the effectiveness of resistance training and vibration-augmented resistance training to preserve thigh (quadriceps femoris) and calf (triceps surae) muscle cross-sectional area (CSA), isometric maximal voluntary contraction (MVC), isometric contractile speed, and neural activation (electromyogram) during 60 days of BR. Male subjects participating in the second Berlin Bed Rest Study underwent BR only [control (CTR), n = 9], BR with resistance training (RE; n = 7), or BR with vibration-augmented resistance training (RVE; n = 7). Training was performed three times per week. Thigh CSA and MVC torque decreased by 13.5 and 21.3%, respectively, for CTR (both P < 0.001), but were preserved for RE and RVE. Calf CSA declined for all groups, but more so (P < 0.001) for CTR (23.8%) than for RE (10.7%) and RVE (11.0%). Loss in calf MVC torque was greater (P < 0.05) for CTR (24.9%) than for RVE (12.3%), but not different from RE (14.8%). Neural activation at MVC remained unchanged in all groups. For indexes related to rate of torque development, countermeasure subjects were pooled into one resistance training group (RT, n = 14). Thigh maximal rate of torque development (MRTD) and contractile impulse remained unaltered for CTR, but MRTD decreased 16% for RT. Calf MRTD remained unaltered for both groups, whereas contractile impulse increased across groups (28.8%), despite suppression in peak electromyogram (12.1%). In conclusion, vibration exposure did not enhance the efficacy of resistance training to preserve thigh and calf neuromuscular function during BR, although sample size issues may have played a role. The exercise regimen maintained thigh size and MVC strength, but promoted a loss in contractile speed. Whereas contractile speed improved for the calf, the exercise regimen only partially preserved calf size and MVC strength. Modification of the exercise regimen seems warranted.

Knee extensor fatigability after bedrest for 8 weeks with and without countermeasure.

We analyzed the effects of gravitational unloading on muscular fatigability and the effectiveness of resistive vibration exercise to counteract these changes. Changes in knee extensor fatigability as a consequence of 8 weeks of horizontal bedrest with or without daily resistive vibration exercise were evaluated in 17 healthy male volunteers. Bedrest increased fatigability (% decrease in maximal voluntary isometric torque per minute exercise) from -7.2 +/- 0.5 to -10.2 +/- 1.0%/min (P < 0.05), which was accompanied by a decline (of 52.0 +/- 3.7%, P < 0.05) in muscle blood flow. Daily resistive vibration exercise training during bedrest prevented increases in fatigability (from -10.8 +/- 1.8 to -8.4 +/- 1.6%/min, P < 0.05), and mitigated the reduction in blood flow (decline of 26.1 +/- 5.1%, P < 0.05). Daily resistive exercise may thus be suggested as an effective countermeasure during spaceflight and illness-related prolonged bedrest to combat the detrimental changes in muscle endurance that result from gravitational unloading.

Training with the International Space Station interim resistive exercise device.

UNLABELLED: A unique, interim elastomer-based resistive exercise device (iRED) is being used on the International Space Station. PURPOSE: This study characterized iRED training responses in a 1-g environment by: 1) determining whether 16 wk of high-intensity training with iRED produces increases in muscle strength and volume and bone mineral density (BMD), 2) comparing training responses with iRED to free weights, and 3) comparing iRED training responses at two training volumes. METHODS: Twenty-eight untrained men were assigned to four groups of seven subjects each: a no exercise control group (CON), an iRED group who trained with three sets/exercise (iRED3), a free-weight group (FW) who trained with three sets/exercise, and an iRED group who trained with six sets/exercise (iRED6). Training exercises included squat (SQ), heel raise (HR), and dead lift (DL) exercises, 3 d.wk(-1) for 16 wk. RESULTS: For CON, no changes occurred pre- to posttraining. For iRED3, increases (P< or =0.05) in one-repetition maximum (1-RM) strength (SQ 21 +/- 4%, HR 17 +/- 4%, DL 29 +/- 5%), leg lean mass (3.1 +/- 0.5%) by dual energy x-ray absorptiometry (DXA), and thigh (4.5 +/- 0.9%) and calf (5.9 +/- 0.7%) muscle volume (by magnetic resonance imaging) occurred after training with no changes in BMD (DXA). For FW, increases in 1-RM strength (SQ 22 +/- 5%, HR 24 +/- 3%, DL 41 +/- 7%), whole body (3.0 +/- 1.1%) and leg lean mass (5.4 +/- 1.2%), thigh (9.2 +/- 1.3%) and calf (4.2 +/- 1.0%) muscle volumes, and lumbar BMD (4.2 +/- 0.7%) occurred after training. For iRED6, all responses were similar to iRED3. CONCLUSION: High-intensity training with the iRED produced muscle responses similar to FW but was not effective in stimulating bone. Bed rest and spaceflight studies are needed to evaluate the effectiveness of the iRED to prevent microgravity deconditioning.