The effects of spaceflight microgravity on the musculoskeletal system of humans and animals, with an emphasis on exercise as a countermeasure: a systematic scoping review.

The purpose of this systematic review is twofold: 1) to identify, evaluate, and synthesize the heretofore disparate scientific literatures regarding the effects of direct exposure to microgravity on the musculoskeletal system, taking into account for the first time both bone and muscle systems of both humans and animals; and 2) to investigate the efficacy and limitations of exercise countermeasures on the musculoskeletal system under microgravity in humans.The Framework for Scoping Studies (Arksey and O'Malley 2005) and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins JPT 2011) were used to guide this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was utilized in obtaining the combined results (Moher, Liberati et al. 2009). Data sources, PubMed, Embase, Scopus, and Web of Science were searched for published articles through October 2019 using the Mesh terms of microgravity, musculoskeletal system, and exercise countermeasures. A total of 84 references were selected, including 40 animal studies and 44 studies with human participants. The heterogeneity in the study designs, methodologies, and outcomes deemed this review unsuitable for a meta-analysis. Thus, we present a narrative synthesis of the results for the key domains under five categories: 1) Skeletal muscle responses to microgravity in humans 2) Skeletal muscle responses to microgravity in animals 3) Adaptation of the skeletal system to microgravity in humans 4) Adaptation of the skeletal system to microgravity in animals 5) Effectiveness of exercise countermeasures on the human musculoskeletal system in microgravity. Existing studies have produced only limited data on the combined effects on bone and muscle of human spaceflight, despite the likelihood that the effects on these two systems are complicated due to the components of the musculoskeletal system being anatomically and functionally interconnected. Bone is directly affected by muscle atrophy as well as by changes in muscle strength, notably at muscle attachments. Given this interplay, the most effective exercise countermeasure is likely to be robust, individualized, resistive exercise, primarily targeting muscle mass and strength.

Space Flight Diet-Induced Deficiency and Response to Gravity-Free Resistive Exercise.

Immune system dysregulation is among the many adverse effects incurred by astronauts during space flights. Omega-3 fatty acids, ß-alanine, and carnosine are among the many nutrients that contribute to immune system health. For space flight, crewmembers are prescribed a diet with a macronutrient composition of 55% carbohydrate, 30% fat, and 15% protein. To quantify omega-3 fatty acid, ß-alanine and carnosine intakes from such a diet, and to examine each nutrient's impact on exercise performance, 21 participants adhered to the aforementioned macronutrient ratio for 14 days which was immediately followed by a workout performed on gravity-independent resistive exercise hardware. Results included daily omega-3 fatty acid intakes below the suggested dietary intake. Daily omega-3 fatty acid, ß-alanine and carnosine intakes each correlated with non-significant amounts of variance from the workout's volume of work. Given the nutritional requirements to maintain immune system function and the demands of in-flight exercise countermeasures for missions of increasingly longer durations current results, in combination with previously published works, imply in-flight supplementation may be a prudent approach to help address the physiological and mental challenges incurred by astronauts on future space flights.

Motion sickness symptoms during jumping exercise on a short-arm centrifuge.

Artificial gravity elicited through short-arm human centrifugation combined with physical exercise, such as jumping, is promising in maintaining health and performance during space travel. However, motion sickness symptoms could limit the tolerability of the approach. Therefore, we determined the feasibility and tolerability, particularly occurrence of motion sickness symptoms, during reactive jumping exercises on a short-arm centrifuge. In 15 healthy men, we assessed motion sickness induced by jumping exercises during short-arm centrifugation at constant +1Gz or randomized variable +0.5, +0.75, +1, +1.25 and +1.5 Gz along the body axis referenced to center of mass. Jumping in the upright position served as control intervention. Test sessions were conducted on separate days in a randomized and cross-over fashion. All participants tolerated jumping exercises against terrestrial gravity and on the short-arm centrifuge during 1 Gz or variable Gz at the center of mass without disabling motion sickness symptoms. While head movements markedly differed, motion sickness scores were only modestly increased with jumping on the short-arm centrifuge compared with vertical jumps. Our study demonstrates that repetitive jumping exercises are feasible and tolerable during short-arm centrifugation. Since jumping exercises maintain muscle and bone mass, our study enables further development of exercise countermeasures in artificial gravity.

Analysis of changes in cardiac circadian rhythms of RR and QT induced by a 60-day head-down bed rest with and without nutritional countermeasure.

PURPOSE: Prolonged weightlessness exposure generates cardiovascular deconditioning, with potential implications on ECG circadian rhythms. Head-down (- 6°) tilt (HDT) bed rest is a ground-based analogue model for simulating the effects of reduced motor activity and fluids redistribution occurring during spaceflight. Our aim was to evaluate the impact of 60-day HDT on the circadianity of RR and ventricular repolarization (QTend) intervals extracted from 24-h Holter ECG recordings, scheduled 9 days before HDT (BDC-9), the 5th (HDT5), 21st (HDT21) and 58th (HDT58) day of HDT, the 1st (R + 0) and 8th (R + 7) day after HDT. Also, the effectiveness of a nutritional countermeasure (CM) in mitigating the HDT-related changes was tested. METHODS: RR and QTend circadian rhythms were evaluated by Cosinor analysis, resulting in maximum and minimum values, MESOR (a rhythm-adjusted mean), oscillation amplitude (OA, half variation within a night-day cycle), and acrophase (φ, the time at which the fitting sinusoid's amplitude is maximal) values. RESULTS: RR and QTend MESOR increased at HDT5, and the OA was reduced along the HDT period, mainly due to the increase of the minima. At R + 0, QTend OA increased, particularly in the control group. The φ slightly anticipated during HDT and was delayed at R + 0. CONCLUSION: 60-Day HDT affects the characteristics of cardiac circadian rhythm by altering the physiological daily cycle of RR and QTend intervals. Scheduled day-night cycle and feeding time were maintained during the experiment, thus inferring the role of changes in the gravitational stimulus to determine these variations. The applied nutritional countermeasure did not show effectiveness in preventing such changes.

Effects of exercise countermeasure on myocardial contractility measured by 4D speckle tracking during a 21-day head-down bed rest.

OBJECTIVE: To evaluate functional myocardial contractility after 21 days of head-down bed rest (HDBR) in sedentary control (CON) or with a resistive vibration exercise (RVE) countermeasure (CM) applied, by using 4D echocardiographic (4D echo) imaging and speckle tracking strain quantification. METHODS: Twelve volunteers were enrolled in a crossover HDBR design, and 4D echo was performed in supine position (REST) at BDC-2 and at R + 2, and in - 6° HDT at day 18, and during the first and the last minute of the 80° head-up step of tilt test performed at both BDC-2 and R + 2. Radial (Rad-Str), longitudinal (Lg-Str) and twist (Tw-Str) strains were measured by 4D speckle tracking, as well as left ventricle diastolic volume (LVDV) and mass (LVmass). RESULTS: On HDT 18: in the CON group, LVDV and LVmass were reduced (p < 0.05), the Rad-Str decreased (p < 0.05) and Tw-Str showed a tendency to increase (p < 0.11), with no changes in Lg-Str. In RVE group, LVDV and LV mass, as well as all the strain parameters remained unchanged. On R + 2: in the CON group, LVDV and LVmass were not recovered in all subjects compared to pre-HDBR (p < 0.08) and Rad-Str was still decreased (p < 0.05), while Tw-Str tended to increase (p < 0.09). These parameters remained unchanged in the RVE group. Tilt 80°: Rad-Str and Lg-Str values at 80° tilt were similar post-HDT in both groups. CONCLUSION: The 4D echo and speckle tracking analysis showed that in the CON group, Rad-Str decreased concomitant with LVmass and LVDV with HDBR, but this observation did not allow concluding if HDBR induced a real remodeling or a muscle atrophy. RVE was able to preserve LVmass, LVDV and contractility during HDBR, thus proving its effectiveness to this aim. Nevertheless, the significant HDBR-induced changes observed in the CON group had only a limited effect on the cardiac contractile response as observed during post-HDBR tilt test. The level of contractility at 80° Tilt position was not affected either by HDBR or by RVE CM.

rTMS pre-treatment effectively protects against cognitive and synaptic plasticity impairments induced by simulated microgravity in mice.

During space flight, microgravity has several negative effects on cognitive functions and learning and memory abilities. However, there are few effectively preventive methods that have been developed yet. Previous studies showed that repetitive transcranial magnetic stimulation (rTMS), as a novel non-invasive technique, alleviated cognitive dysfunctions and facilitated synaptic plasticity. In the present study, we used a hindlimb unloading (Hu) mouse model to simulate microgravity conditions. And then, we investigated whether rTMS played a neuroprotective role in a Hu mouse model. Behavioral experiments including Open field test and Novel object recognition test were performed. These results showed that spontaneous activity and recognition memory were reduced by Hu, while rTMS significantly protected against the harmful effect. Furthermore, electrophysiological recordings were performed to examine the level of synaptic plasticity including paired-pulse facilitation (PPF) and long-term potentiation (LTP). In the hippocampus DG and CA1 regions, dendritic spine density was measured using Golgi-Cox staining. Our data showed that rTMS effectively impeded the impairment of PPF and LTP, as well as the decrease of spine density induced by Hu. Subsequently, Western blot assay showed that rTMS inhibited the downregulation of CREB/BDNF signaling network associated proteins in Hu mice. It suggests that rTMS pre-treatment plays a neuroprotective role in protecting against cognitive impairments and synaptic plasticity deficits induced by microgravity stimulation.

Effect of Constraint Loading on the Lower Limb Muscle Forces in Weightless Treadmill Exercise.

Long exposure to the microgravity will lead to muscle atrophy and bone loss. Treadmill exercise could mitigate the musculoskeletal decline. But muscle atrophy remains inevitable. The constraint loading applied on astronauts could affect the muscle force and its atrophy severity. However, the quantitative correlation between constraint loading mode and muscle forces remains unclear. This study aimed to characterize the influence of constraint loading mode on the lower limb muscle forces in weightless treadmill exercise. The muscle forces in the full gait cycle were calculated with the inverse dynamic model of human musculoskeletal system. The calculated muscle forces at gravity were validated with the EMG data. Muscle forces increased at weightlessness compared with those at the earth's gravity. The increasing percentage from high to low is as follows: biceps femoris, gastrocnemius, soleus, vastus, and rectus femoris, which was in agreement with the muscle atrophy observed in astronauts. The constraint loading mode had an impact on the muscle forces in treadmill exercise and thus could be manipulated to enhance the effect of the muscle training in spaceflight. The findings could provide biomechanical basis for the optimization of treadmill constraint system and training program and improve the countermeasure efficiency in spaceflight.

Heart in space: effect of the extraterrestrial environment on the cardiovascular system.

National space agencies and private corporations aim at an extended presence of humans in space in the medium to long term. Together with currently suboptimal technology, microgravity and cosmic rays raise health concerns about deep-space exploration missions. Both of these physical factors affect the cardiovascular system, whose gravity-dependence is pronounced. Heart and vascular function are, therefore, susceptible to substantial changes in weightlessness. The altered cardiovascular function in space causes physiological problems in the postflight period. A compromised cardiovascular system can be excessively vulnerable to space radiation, synergistically resulting in increased damage. The space radiation dose is significantly lower than in patients undergoing radiotherapy, in whom cardiac damage is well-documented following cancer therapy in the thoracic region. Nevertheless, epidemiological findings suggest an increased risk of late cardiovascular disease even with low doses of radiation. Moreover, the peculiar biological effectiveness of heavy ions in cosmic rays might increase this risk substantially. However, whether radiation-induced cardiovascular effects have a threshold at low doses is still unclear. The main countermeasures to mitigate the effect of the space environment on cardiac function are physical exercise, antioxidants, nutraceuticals, and radiation shielding.

Parallels between astronauts and terrestrial patients - Taking physiotherapy rehabilitation "To infinity and beyond".

Exposure to the microgravity environment induces physiological changes in the cardiovascular, musculoskeletal and sensorimotor systems in healthy astronauts. As space agencies prepare for extended duration missions, it is difficult to predict the extent of the effects that prolonged exposure to microgravity will have on astronauts. Prolonged bed rest is a model used by space agencies to simulate the effects of spaceflight on the human body, and bed rest studies have provided some insights into the effects of immobilisation and inactivity. Whilst microgravity exposure is confined to a relatively small population, on return to Earth, the physiological changes seen in astronauts parallel many changes routinely seen by physiotherapists on Earth in people with low back pain (LBP), muscle wasting diseases, exposure to prolonged bed rest, elite athletes and critically ill patients in intensive care. The medical operations team at the European Space Agency are currently involved in preparing astronauts for spaceflight, advising on exercises whilst astronauts are on the International Space Station, and reconditioning astronauts following their return. There are a number of parallels between this role and contemporary roles performed by physiotherapists working with elite athletes and muscle wasting conditions. This clinical commentary will draw parallels between changes which occur to the neuromuscular system in the absence of gravity and conditions which occur on Earth. Implications for physiotherapy management of astronauts and terrestrial patients will be discussed.

Astronaut adherence to exercise-based reconditioning: Psychological considerations and future directions.

INTRODUCTION: Exercise-based reconditioning is essential for mitigating the negative physiological and functional effects of spaceflight. Astronaut adherence to prescribed reconditioning programmes is imperative, but there has been limited research in this area. PURPOSE: This commentary discusses adherence predictors in analogous terrestrial populations (sport, clinical rehabilitation, general exercise) that may translate to spaceflight environments. IMPLICATIONS: Reconditioning programmes should foster intrinsic motivation, realistic outcome expectancies, self-regulation skills, and strong therapeutic alliances to promote ongoing exercise adherence. Research is needed to understand spaceflight-specific barriers and facilitators to adherence, and to develop appropriate strategies to promote ongoing exercise behaviours.

The role of physiotherapy in the European Space Agency strategy for preparation and reconditioning of astronauts before and after long duration space flight.

Spaceflight and exposure to microgravity have wide-ranging effects on many systems of the human body. At the European Space Agency (ESA), a physiotherapist plays a key role in the multidisciplinary ESA team responsible for astronaut health, with a focus on the neuro-musculoskeletal system. In conjunction with a sports scientist, the physiotherapist prepares the astronaut for spaceflight, monitors their exercise performance whilst on the International Space Station (ISS), and reconditions the astronaut when they return to Earth. This clinical commentary outlines the physiotherapy programme, which was developed over nine long-duration missions. Principles of physiotherapy assessment, clinical reasoning, treatment programme design (tailored to the individual) and progression of the programme are outlined. Implications for rehabilitation of terrestrial populations are discussed. Evaluation of the reconditioning programme has begun and challenges anticipated after longer missions, e.g. to Mars, are considered.

Postflight reconditioning for European Astronauts - A case report of recovery after six months in space.

BACKGROUND: Postflight reconditioning of astronauts is understudied. Despite a rigorous, daily inflight exercise countermeasures programme during six months in microgravity (µG) on-board the International Space Station (ISS), physiological impairments occur and postflight reconditioning is still required on return to Earth. Such postflight programmes are implemented by space agency reconditioning specialists. Case Description and Assessments: A 38 year old male European Space Agency (ESA) crewmember's pre- and postflight (at six and 21 days after landing) physical performance from a six-month mission to ISS are described. ASSESSMENTS: muscle strength (squat and bench press 1 Repetition Maximum) and power (vertical jump), core muscle endurance and hip flexibility (Sit and Reach, Thomas Test). INTERVENTIONS: In-flight, the astronaut undertook a rigorous daily (2-h) exercise programme. The 21 day postflight reconditioning exercise concept focused on motor control and functional training, and was delivered in close co-ordination by the ESA physiotherapist and exercise specialist to provide the crewmember with comprehensive reconditioning support. OUTCOMES: Despite an intensive inflight exercise programme for this highly motivated crewmember, postflight performance showed impairments at R+6 for most parameters, all of which recovered by R+21 except muscular power (jump tests). CONCLUSIONS: Regardless of intense inflight exercise countermeasures and excellent compliance to postflight reconditioning, postflight performance showed impairments at R+6 for most parameters. Complex powerful performance tasks took longer to return to preflight values. Research is needed to develop optimal inflight and postflight exercise programmes to overcome the negative effects of microgravity and return the astronaut to preflight status as rapidly as possible.

The Effect of the Gravity Loading Countermeasure Skinsuit Upon Movement and Strength.

Carvil, PA, Attias, J, Evetts, SN, Waldie, JM, and Green, DA. The effect of the gravity loading countermeasure skinsuit upon movement and strength. J Strength Cond Res 31(1): 154-161, 2017-Effective countermeasures against musculoskeletal deconditioning induced by microgravity and disuse are required. A simple alternative to provision of artificial gravity by centrifugation is compressive axial loading. The Russian "Pingvin" suit was the first wearable suit to apply this concept using bungee cords tethered around the shoulders and feet. However, poor loading characteristics and severe thermal and movement discomfort were reported. The gravity loading countermeasure skinsuit (GLCS) uses a bidirectional weave to generate staged axial loading from shoulders to feet, better mimicking how Earth's gravity induces progressive loading head to foot. The Mk III GLCS's loading was evaluated and tolerability assessed during maximal joint motion, ambulation, and selected strength exercises. Eight subjects (5 male and 3 female; 28 ± 3 years; 179 ± 0.1 cm and 74.8 ± 2.9 kg), having given written informed consent, had an Mk III GLCS individually tailored. Axial loading imparted, body height, joint range of motion (ROM), ambulation, and strength tests (12 repetition maximum) were performed in the GLCS and gym attire, with subjective (rating of perceived exertion, thermal comfort, movement discomfort and body control) ratings recorded throughout. Gravity loading countermeasure skinsuit provided significant axial loading when standing but significantly reduced knee (-13°), spinal (-28°) and shoulder flexion/extension ROM (-34°/-13°), in addition to Sit and Reach (-12.8 cm). No thermal issues were reported but there was an increase in subjective discomfort. Gravity loading countermeasure skinsuit did not significantly impede strength exercise, with the exception of shoulder press. The GLCS (Mk III) demonstrates potential as a countermeasure by providing tolerable, static axial loading. Furthermore, it may serve as an elasticlike strength exercise adjunct, which may have utility as a rehabilitation modality after further design refinement.

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

WISE 2005: Aerobic and resistive countermeasures prevent paraspinal muscle deconditioning during 60-day bed rest in women.

Microgravity-induced lumbar paraspinal muscle deconditioning may contribute to back pain commonly experienced by astronauts and may increase the risk of postflight injury. We hypothesized that a combined resistive and aerobic exercise countermeasure protocol that included spinal loading would mitigate lumbar paraspinal muscle deconditioning during 60 days of bed rest in women. Sixteen women underwent 60-day, 6° head-down-tilt bed rest (BR) and were randomized into control and exercise groups. During bed rest the control group performed no exercise. The exercise group performed supine treadmill exercise within lower body negative pressure (LBNP) for 3-4 days/wk and flywheel resistive exercise for 2-3 days/wk. Paraspinal muscle cross-sectional area (CSA) was measured using a lumbar spine MRI sequence before and after BR. In addition, isokinetic spinal flexion and extension strengths were measured before and after BR. Data are presented as means ± SD. Total lumbar paraspinal muscle CSA decreased significantly more in controls (10.9 ± 3.4%) than in exercisers (4.3 ± 3.4%; P < 0.05). The erector spinae was the primary contributor (76%) to total lumbar paraspinal muscle loss. Moreover, exercise attenuated isokinetic spinal extension loss (-4.3 ± 4.5%), compared with controls (-16.6 ± 11.2%; P < 0.05). In conclusion, LBNP treadmill and flywheel resistive exercises during simulated microgravity mitigate decrements in lumbar paraspinal muscle structure and spine function. Therefore spaceflight exercise countermeasures that attempt to reproduce spinal loads experienced on Earth may mitigate spinal deconditioning during long-duration space travel.

The First Decade of ISS Exercise: Lessons Learned on Expeditions 1-25.

INTRODUCTION: Long-duration spaceflight results in musculoskeletal, cardiorespiratory, and sensorimotor deconditioning. Historically, exercise has been used as a countermeasure to mitigate these deleterious effects that occur as a consequence of microgravity exposures. The International Space Station (ISS) exercise community describes their approaches, biomedical surveillance, and lessons learned in the development of exercise countermeasure modalities and prescriptions for maintaining health and performance among station crews. This report is focused on the first 10 yr of ISS defined as Expeditions 1-25 and includes only crewmembers with missions > 30 d on ISS for all 5 partner agencies (United States, Russia, Europe, Japan, and Canada). All 72 cosmonauts and astronauts participated in the ISS exercise countermeasures program. This Supplement presents a series of papers that provide an overview of the first decade of ISS exercise from a multidisciplinary, multinational perspective to evaluate the initial countermeasure program and record its operational limitations and challenges. In addition, we provide results from standardized medical evaluations before, during, and after each mission. Information presented in this context is intended to describe baseline conditions of the ISS exercise program. This paper offers an introduction to the subsequent series of manuscripts.

Exercise Countermeasure Hardware Evolution on ISS: The First Decade.

The hardware systems necessary to support exercise countermeasures to the deconditioning associated with microgravity exposure have evolved and improved significantly during the first decade of the International Space Station (ISS), resulting in both new types of hardware and enhanced performance capabilities for initial hardware items. The original suite of countermeasure hardware supported the first crews to arrive on the ISS and the improved countermeasure system delivered in later missions continues to serve the astronauts today with increased efficacy. Due to aggressive hardware development schedules and constrained budgets, the initial approach was to identify existing spaceflight-certified exercise countermeasure equipment, when available, and modify it for use on the ISS. Program management encouraged the use of commercial-off-the-shelf (COTS) hardware, or hardware previously developed (heritage hardware) for the Space Shuttle Program. However, in many cases the resultant hardware did not meet the additional requirements necessary to support crew health maintenance during long-duration missions (3 to 12 mo) and anticipated future utilization activities in support of biomedical research. Hardware development was further complicated by performance requirements that were not fully defined at the outset and tended to evolve over the course of design and fabrication. Modifications, ranging from simple to extensive, were necessary to meet these evolving requirements in each case where heritage hardware was proposed. Heritage hardware was anticipated to be inherently reliable without the need for extensive ground testing, due to its prior positive history during operational spaceflight utilization. As a result, developmental budgets were typically insufficient and schedules were too constrained to permit long-term evaluation of dedicated ground-test units ("fleet leader" type testing) to identify reliability issues when applied to long-duration use. In most cases, the exercise unit with the most operational history was the unit installed on the ISS.

Physical Training for Long-Duration Spaceflight.

INTRODUCTION: Physical training has been conducted on the International Space Station (ISS) for the past 10 yr as a countermeasure to physiological deconditioning during spaceflight. Each member space agency has developed its own approach to creating and implementing physical training protocols for their astronauts. We have divided physical training into three distinct phases (preflight, in-flight, and postflight) and provided a description of each phase with its constraints and limitations. We also discuss how each member agency (NASA, ESA, CSA, and JAXA) prescribed physical training for their crewmembers during the first 10 yr of ISS operations. It is important to understand the operational environment, the agency responsible for the physical training program, and the constraints and limitations associated with spaceflight to accurately design and implement exercise training or interpret the exercise data collected on ISS. As exploration missions move forward, resolving agency differences in physical training programs will become important to maximizing the effectiveness of exercise as a countermeasure and minimizing any mission impacts.