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At least 199 records · Page 11

Changes in markers of bone formation and resorption in a bed rest model of weightlessness

To study the mechanism of bone loss in physical unloading, we examined indices of bone formation and bone resorption in the serum and urine of eight healthy men during a 7 day -6 degrees head-down tilt bed rest. Prompt increases in markers of resorption--pyridinoline (PD), deoxypyridinoline (DPD), and hydroxyproline (Hyp)/g creatinine--during the first few days of inactivity were paralleled by tartrate-resistant acid phosphatase (TRAP) with significant increases in all these markers by day 4 of bed rest. An index of formation, skeletal alkaline phosphatase (SALP), did not change during bed rest and showed a moderate 15% increase 1 week after reambulation. In contrast to SALP, serum osteocalcin (OC) began increasing the day preceding the increase in Hyp, remained elevated for the duration of the bed rest, and returned to pre-bed rest values within 5 days of reambulation. Similarly, DPD increased significantly at the onset of bed rest, remained elevated for the duration of bed rest, and returned to pre-bed rest levels upon reambulation. On the other hand, the other three indices of resorption, Hyp, PD, and TRAP, remained elevated for 2 weeks after reambulation. The most sensitive indices of the levels of physical activity proved to be the noncollagenous protein, OC, and the collagen crosslinker, DPD. The bed rest values of both these markers were significantly elevated compared to both the pre-bed rest values and the post-bed rest values. The sequence of changes in the circulating markers of bone metabolism indicated that increases in serum OC are the earliest responses of bone to head-down tilt bed rest.

NASA Discipline Number 26-10↗

Effect of spaceflight on the maximal shortening velocity, morphology, and enzyme profile of fast- and slow-twitch skeletal muscle fibers in rhesus monkeys

Weightlessness has been shown to cause limb muscle wasting and a reduced peak force and power in the antigravity soleus muscle. Despite a reduced peak power, Caiozzo et al. observed an increased maximal shortening velocity in the rat soleus muscle following a 14-day space flight. The major purpose of the present investigation was to determine if weightlessness induced an elevated velocity in the antigravity slow type I fibers of the rhesus monkey (Macaca mulatta), as well as to establish a cellular mechanism for the effect. Spaceflight or models of weightlessness have been shown to increase glucose uptake, elevate muscle glycogen content, and increase fatigability of the soleus muscle. The latter appears to be in part caused by a reduced ability of the slow oxidative fibers to oxidize fats. A second goal of this study was to establish the extent to which weightlessness altered the substrate profile and glycolytic and oxidative enzyme capacity of individual slow- and fast-twitch fibers.

Bion 11 Project↗

Spaceflight on STS-48 and earth-based unweighting produce similar effects on skeletal muscle of young rats

Eight female albino rats were exposed to 5.4 days of weightlessness aboard the Space Shuttle mission STS-48 in 1991. An asynchronous ground control experiment mimicked the flight cage conditions and mission duration of the STS-48 rats, and a third group of animals underwent limb suspension for 5.4 days. The flight animals gained a greater percentage of body mass per day despite similar rates of food consumption in the three groups. The results obtained on insulin response and muscle size show that a tail-cast hindlimb-suspension model is suitable for mimicking the effects of weightlessness on rapidly growing juvenile rat muscles.

Tischler, Marc E.↗

Directed Research in Bone Discipline: Refining Previous Research Observations for Space Medicine

Dual-energy X-ray absorptiometry bone mass density, as a sole index, is an insufficient surrogate for fracture; Clinical Practice Guidelines using bone mass density (both World Health Organization and FRAX) are not specific for complicated subjects such as young, healthy persons following prolonged exposure to skeletal unloading (i.e. an attribute of spaceflight); Research data suggest that spaceflight induces changes to astronaut bones that could be profound, possibly irreversible and unlike age-related bone loss on Earth.; There is a need to objectively assess factors across human physiology that are also influenced by spaceflight (e.g., muscle) that contribute to fracture risk. Some of these objective assessments may require innovative technologies, analyses and modeling.; Astronauts are also exposed to novel situations that may overload their bones highlighting a need integrate biomechanics of physical activities into risk assessments.; As we accumulate data, which reflects the biomechanical competence of bone under specific mechanically-loaded scenarios (even activities of daily living), BONE expects Bone Fracture Module to be more sensitive and/or have less uncertainty in its assessments of fracture probability.; Fracture probability drives the requirement for countermeasures. Level of evidence will unlikely be obtained; hence, the Bone Research and Clinical Advisory Panel (like a Data Safety Monitoring Board) will provide the recommendations.

Sibonga, Jean D.↗

In vitro modeling of human tibial strains during exercise in micro-gravity

Prolonged exposure to micro-gravity causes substantial bone loss (Leblanc et al., Journal of Bone Mineral Research 11 (1996) S323) and treadmill exercise under gravity replacement loads (GRLs) has been advocated as a countermeasure. To date, the magnitudes of GRLs employed for locomotion in space have been substantially less than the loads imposed in the earthbound 1G environment, which may account for the poor performance of locomotion as an intervention. The success of future treadmill interventions will likely require GRLs of greater magnitude. It is widely held that mechanical tissue strain is an important intermediary signal in the transduction pathway linking the external loading environment to bone maintenance and functional adaptation; yet, to our knowledge, no data exist linking alterations in external skeletal loading to alterations in bone strain. In this preliminary study, we used unique cadaver simulations of micro-gravity locomotion to determine relationships between localized tibial bone strains and external loading as a means to better predict the efficacy of future exercise interventions proposed for bone maintenance on orbit. Bone strain magnitudes in the distal tibia were found to be linearly related to ground reaction force magnitude (R(2)>0.7). Strain distributions indicated that the primary mode of tibial loading was in bending, with little variation in the neutral axis over the stance phase of gait. The greatest strains, as well as the greatest strain sensitivity to altered external loading, occurred within the anterior crest and posterior aspect of the tibia, the sites furthest removed from the neutral axis of bending. We established a technique for estimating local strain magnitudes from external loads, and equations for predicting strain during simulated micro-gravity walking are presented.

NASA Discipline Musculoskeletal↗

Improving Bone-Health Monitoring in Astronauts: Recommended Use of Quantitative Computed Tomography [QCT] for Clinical and Operational Decisions by NASA

DXA measurement of areal bone mineral density [aBMD,g/cm2] is required by NASA for assessing skeletal integrity in astronauts. Due to the abundance of population-based data that correlate hip and spine BMDs to fragility fractures, BMD is widely applied as a predictor of fractures in the general aging population. In contrast, QCT is primarily a research technology that measures three-dimensional , volumetric BMD (vBMD,mg/cm3) of bone and is therefore capable of differentiating between cortical and trabecular components. Additionally, when combined with Finite Element Modeling [FEM], a computational tool, QCT data can be used to estimate the whole bone strength of the hip [FE strength] for a specific load vector. A recent report demonstrated that aBMD failed to correlate with incurred changes in FE strength (for fall and stance loading) by astronauts over typical 180-day ISS (International Space Station) missions. While there are no current guidelines for using QCT data in clinical practice, QCT increases the understanding of how bone structure and mineral content are affected by spaceflight and recovery on Earth. In order to understand/promote/consider the use of QCT, NASA convened a panel of clinicians specializing in osteoporosis. After reviewing the available, albeit limited, medical and research information from long-duration astronauts (e.g., data from DXA, QCT, FEM, biochemistry analyses, medical records and in-flight exercise performance) the panelists were charged with recommending how current and future research data and analyses could inform clinical and operational decisions. The Panel recommended that clinical bone tests on astronauts should include QCT (hip and lumbar spine) for occupational risk surveillance and for the estimation of whole hip bone strength as derived by FEM. FE strength will provide an improved index that NASA could use to select astronauts of optimal bone health for extended duration missions, for repeat missions or for specific mission operations.

Sibonga, J. D.↗

Acute Effects of Simulated Space Radiation and Micro-Gravity on Cancellous Bone Loss in Mice Tibiae

Space radiation and micro-gravity are the two major obstacles impeding human exploration of Mars and beyond. Long-duration space flights expose astronauts to high doses of high linear energy transfer (LET) radiation as well as prolonged periods of skeletal disuse due to weightlessness. One important consequence of both radiation exposure and micro-gravity is acute bone loss. However, biological responses to different radiation types and combined radiation and micro-gravity environments remain unknown. Thus, the purpose of this study is to compare the acute effects of different radiation species and simulated weightlessness on bone degeneration for the purpose of developing accurate risk assessments of prolonged space flight. Mouse models were used to simulate space flight-relevant doses of different radiation types as well as weightlessness via hind-limb unloading. Three groups of mice (n 9) were irradiated with 1 Gy (Gray) H+, 1 Gy 56Fe, and 1 Gy combined H+ and 56Fe (dual ion) respectively and compared to sham irradiated (n 9) and 2 Gy 56Fe irradiated positive controls (n 6). Two groups of mice (n 9) were hind-limb unloaded for three days and then either sham irradiated or dual ion irradiated respectively, followed by subsequent hind-limb unloading for 11 days. Cancellous tissue from tibiae metaphyses were harvested 11 days post-irradiation for ex vivo micro-computed tomography analysis. Microarchitecture parameters including bone volume to total volume ratio (BVTV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular spacing (Tb.S), and connectivity density (Conn.D) will be quantified using a novel automated segmentation procedure developed in our lab. The anticipated results will be instrumental in developing counter-measures against micro-gravity and radiation-induced bone loss. Moreover, possible synergistic effects may provide insight into underlying mechanisms mediating biological response.

Micro-Gravity↗

Differential skeletal responses of hindlimb unloaded rats on a vitamin D-deficient diet to 1,25-dihydroxyvitamin D3 and its analog, seocalcitol (EB1089)

Conditions of disuse in bed rest patients, as well as microgravity experienced by astronauts are accompanied by reduced mechanical loading, reduced calcium absorption, and lower serum levels of 1,25(OH)2D3 (1,25-D), the active metabolite of vitamin D, all contributing to bone loss. To determine whether 1,25-D or a less calcemic analog, Seocalcitol or EB1089 (1 alpha,25-dihydroxy-22,24-diene-24,26,27-trihomovitamin D3) can alleviate bone loss in a rat hindlimb unloading model of disuse osteopenia, mature male rats originally on a vitamin D replete diet containing 1.01% calcium were transferred to a vitamin D-deficient diet containing 0.48% calcium and then tail suspended and treated for 28 days with vehicle, 0.05 microg/kg 1,25-D, or 0.05 microg/kg EB1089. The vitamin D-deficient diet caused a substantial decrease in bone mineral density (-8%), which may be compounded by hindlimb unloading (-10%). Exogenous 1,25-D not only prevented the bone loss but also increased the bone mineral density to greater than the baseline level (+7%). EB1089 was less effective in preventing bone loss. Analysis of site and cell-specific effects of 1,25-D and EB1089 revealed that 1,25-D was more active than EB1089 in the intestine, the site of calcium absorption, and in inducing osteoclastogenesis and bone resorption whereas EB1089 was more effective in inducing osteoblast differentiation. These studies suggest that elevating circulating 1,25-D levels presumably increasing calcium absorption can counteract bone loss induced by disuse or microgravity with its associated reductions in circulating 1,25-D and decreased calcium absorption.

Non-NASA Center↗

Further observations on the relationship of EMG and muscle force

Human skeletal muscle may be regarded as an electro-mechanical transducer. Its physiological input is a neural signal originating at the alpha motoneurons in the spinal cord and its output is force and muscle contraction, these both being dependent on the external load. Some experimental data taken during voluntary efforts around the ankle joint and by direct electrical stimulation of the nerve are described. Some of these experiments are simulated by an analog model, the input of which is recorded physiological soleus muscle EMG. The output is simulated foot torque. Limitations of a linear model and effect of some nonlinearities are discussed.

Agarwal, G. C.↗

Vitamin E provides protection for bone in mature hindlimb unloaded male rats

The deleterious effects of skeletal unloading on bone mass and strength may, in part, result from increased production of oxygen-derived free radicals and proinflammatory cytokines. This study was designed to evaluate the ability of vitamin E (alpha-tocopherol), a free-radical scavenger with antiinflammatory properties, to protect against bone loss caused by skeletal unloading in mature male Sprague-Dawley rats. A 2 x 3 factorial design was used with either hindlimb unloading (HU) or normal loading (ambulatory; AMB), and low-dose (LD; 15 IU/kg diet), adequate-dose (AD; 75 IU/kg diet), or high-dose (HD; 500 IU/kg diet) vitamin E (DL-alpha-tocopherol acetate). To optimize the effects of vitamin E on bone, dietary treatments were initiated 9 weeks prior to unloading and continued during the 4-week unloading period, at which time animals were euthanized and blood and tissue samples were collected. Serum vitamin E was dose-dependently increased, confirming the vitamin E status of animals. The HD treatment improved oxidation parameters, as indicated by elevated serum ferric-reducing ability and a trend toward reducing tissue lipid peroxidation. Histomorphometric analysis of the distal femur revealed significant reductions in trabecular thickness (TbTh), double-labeled surface (dLS/BS), and rate of bone formation to bone volume (BFR/BV) due by HU. AMB animals on the HD diet and HU animals on the LD diet had reduced bone surface normalized to tissue volume (BS/TV) and trabecular number (TbN); however, the HD vitamin E protected against these changes in the HU animals. Our findings suggest that vitamin E supplementation provides modest bone protective effects during skeletal unloading.

NASA Discipline Musculoskeletal↗

What do we really know about the ubiquitin-proteasome pathway in muscle atrophy?

Studies of many different rodent models of muscle wasting have indicated that accelerated proteolysis via the ubiquitin-proteasome pathway is the principal cause of muscle atrophy induced by fasting, cancer cachexia, metabolic acidosis, denervation, disuse, diabetes, sepsis, burns, hyperthyroidism and excess glucocorticoids. However, our understanding about how muscle proteins are degraded, and how the ubiquitin-proteasome pathway is activated in muscle under these conditions, is still very limited. The identities of the important ubiquitin-protein ligases in skeletal muscle, and the ways in which they recognize substrates are still largely unknown. Recent in-vitro studies have suggested that one set of ubquitination enzymes, E2(14K) and E3(alpha), which are responsible for the 'N-end rule' system of ubiquitination, plays an important role in muscle, especially in catabolic states. However, their functional significance in degrading different muscle proteins is still unclear. This review focuses on the many gaps in our understanding of the functioning of the ubiquitin-proteasome pathway in muscle atrophy, and highlights the strengths and limitations of the different experimental approaches used in such studies.

Review↗

Gravity, Calcium, and Bone: Update, 1989

Some of the results of recent short-term flights and ground-based experiments that have contributed new insights into skeletal adaptation, calcium metabolism, and growth processes in 0 g, are highlighted. After 6 months in space, bone demineralization, invariably involving the os calcis, was found not to extend to the lumbar spine in 4 exercising cosmonauts. A flight experiment in the Space Shuttle crew has documented the early events in the calcium endocrine system during spaceflight. On the ground, brief and long-term bed rest studies of healthy volunteers in the head-down tile (HDT) model of weightlessness were completed. The skeleton of the adult male responds more rapidly to unloading than previously recognized. Regional changes in bone density can be quantified in only 30 days, are highly individual, and follow the direction of gravitational forces in the HDT model during inactivity. Bone biopsy results in healthy volunteers after bed rest differ from results in paraplegics from the same sampling site. Flight experiments in growing rats reveal changes in the composition of bone mineral and matrix in the femur postflight that were found to be highly regional and suggestive of an effect of gravity on mineral distribution. These observations may be relevant to the results from an earlier Cosmos flight where artificial gravity in space was found to maintain bone strength, but not to correct the radial growth deficit.

Arnaud, Sara B.↗

Skeletal muscle metabolism in hypokinetic rats

This grant focused on the mechanisms of metabolic changes associated with unweighting atrophy and reduced growth of hind limb muscles of juvenile rats. Metabolic studies included a number of different areas. Amino acid metabolic studies placed particular emphasis on glutamine and branched-chain amino acid metabolism. These studies were an outgrowth of understanding stress effects and the role of glucocorticoids in these animals. Investigations on protein metabolism were largely concerned with selective loss of myofibrillar proteins and the role of muscle proteolysis. These investigations lead to finding important differences from denervation and atrophy and to define the roles of cytosolic versus lysosomal proteolysis in these atrophy models. A major outgrowth of these studies was demonstrating an ability to prevent atrophy of the unweighted muscle for at least 24 hours. A large amount of work concentrated on carbohydrate metabolism and its regulation by insulin and catecholamines. Measurements focused on glucose transport, glycogen metabolism, and glucose oxidation. The grant was used to develop an important new in situ approach for studying protein metabolism, glucose transport, and hormonal effects which involves intramuscular injection of various agents for up to 24 hours. Another important consequence of this project was the development and flight of Physiological-Anatomical Rodent Experiment-1 (PARE-1), which was launched aboard Space Shuttle Discovery in September 1991. Detailed descriptions of these studies can be found in the 30 peer-reviewed publications, 15 non-reviewed publications, 4 reviews and 33 abstracts (total 82 publications) which were or are scheduled to be published as a result of this project. A listing of these publications grouped by area (i.e. amino acid metabolism, protein metabolism, carbohydrate metabolism, and space flight studies) are included.

Tischler, Marc E.↗

Solar Cruiser TRAC Boom Development

The TRAC boom studied is a 30 meter, high-aspect ratio and highly nonlinear structural element planned for the NASA Solar Cruiser spacecraft where it would serve as the solar sail’s skeletal system designed to deploy the packaged reflective sail membrane as well as support operational sail tension loads for flight. Key design drivers for this boom are understanding and characterizing load-deformation behavior and quantifying buckling performance–under flight conditions (zero gravity). Knowing that the full-scale solar sail system cannot be feasibly tested for flight conditions under Earth’s gravity, a building block approach is methodically followed to verify finite element analysis (FEA) predictions and to evolve the finite element model (FEM) accordingly, beginning with the lowest level complexity to match global elastic behavior to the highest level complexity to bound theoretical responses under conservative expected flight conditions. Although the testing campaign for the TRAC boom has not developed yet to produce a full-scale test data point that loads the boom to failure, the fidelity of simulations have evolved with success and warrant further interest and work on this high-aspect ratio, but highly stable, deployable structural boom.

Lee Nguyen↗

Crosslinking Amine-Modified Silica Aerogels with Epoxies: Mechanically Strong Lightweight Porous Materials

The mesoporous surfaces of TMOS-derived silica aerogels have been modified with amines by co-polymerization of TMOS with APTES. The amine sites have become anchors for crosslinking the nanoparticles of the skeletal backbone of the aerogel by attachment of di-, tri and tetra-functional epoxies. The resulting conformal coatings increase the density of the native aerogels by a factor of 2-3 but the strength of the resulting materials may increase by more than two orders of magnitude. Processing variables such as amount of APTES used to make the gels, the epoxy type and concentration used for crosslinking, as well as the crosslinking temperature and time were varied according to a multivariable design-of-experiments (DOE) model. It was found that while elastic modulus follows a similar trend with density, maximum strength is attained neither at the maximum density nor at the highest concentration of -NH2 groups, suggesting surface saturation effects. Aerogels crosslinked with the tri-functional epoxide always show improved strength compared with aerogels crosslinked with the other two epoxides under identical conditions. Solid C-13 NMR studies show residual unreacted epoxides, which condense with ne another by heating crosslinked aerogels at 150 C.

Meador, Mary Ann B.↗

Experiment K-6-07. Metabolic and morphologic properties of muscle fibers after spaceflight

The present study demonstrates that the general capability of skeletal muscle to maintain its proteins decreases rapidly in response to space flight. The present findings suggest further that the magnitude of enzymatic and cell volumes changes in response to space flight depend on several factors including the muscle and its fiber type composition. It appears that in order to associate physiological relevance to the observed enzymatic changes, cell volume should be considered also. Although it remains unclear as to the stimulus, or lack of stimulus, that triggers the rapid changes in muscle proteins in response to space flight, ground-based models of muscle atrophy suggest that the reduction in mechanical loading of muscle may be more important than the total amount of activation over a 24-hr period.

Edgerton, R.↗

The Implications of Reduced Ground Reaction Forces During Space Flight for Bone Strains

The specific mechanisms regulating bone mass are not known, but most investigators agree that bone maintenance is largely dependent upon mechanical demand and the resultant local bone strains. During space flight, bone loss such as that reported by LeBlanc et al. may result from failure to effectively load the skeleton and generate sufficient localized bone strains. In microgravity, a gravity replacement system can be used to tether an exercising subject to a treadmill. It follows that the ability to prevent bone loss is critically dependent upon the external ground reaction forces (GRFs) and skeletal loads imparted by the tethering system. To our knowledge, the loads during orbital flight have been measured only once (on STS 81). Based on these data and data from ground based experiments, it appears likely that interventions designed to prevent bone loss in micro-gravity generate GRFs substantially less than body weight. It is unknown to what degree reductions in external GRFs will affect internal bone strain and thus the bone maintenance response. To better predict the efficacy of treadmill exercise in micro-gravity we used a unique cadaver model to measure localized bone strains under conditions representative of those that might be produced by a gravity replacement system in space.

Peterman, Marc M.↗

Differentiation of mammalian skeletal muscle cells cultured on microcarrier beads in a rotating cell culture system

The growth and repair of adult skeletal muscle are due in part to activation of muscle precursor cells, commonly known as satellite cells or myoblasts. These cells are responsive to a variety of environmental cues, including mechanical stimuli. The overall goal of the research is to examine the role of mechanical signalling mechanisms in muscle growth and plasticity through utilisation of cell culture systems where other potential signalling pathways (i.e. chemical and electrical stimuli) are controlled. To explore the effects of decreased mechanical loading on muscle differentiation, mammalian myoblasts are cultured in a bioreactor (rotating cell culture system), a model that has been utilised to simulate microgravity. C2C12 murine myoblasts are cultured on microcarrier beads in a bioreactor and followed throughout differentiation as they form a network of multinucleated myotubes. In comparison with three-dimensional control cultures that consist of myoblasts cultured on microcarrier beads in teflon bags, myoblasts cultured in the bioreactor exhibit an attenuation in differentiation. This is demonstrated by reduced immunohistochemical staining for myogenin and alpha-actinin. Western analysis shows a decrease, in bioreactor cultures compared with control cultures, in levels of the contractile proteins myosin (47% decrease, p < 0.01) and tropomyosin (63% decrease, p < 0.01). Hydrodynamic measurements indicate that the decrease in differentiation may be due, at least in part, to fluid stresses acting on the myotubes. In addition, constraints on aggregate size imposed by the action of fluid forces in the bioreactor affect differentiation. These results may have implications for muscle growth and repair during spaceflight.

Non-NASA Center↗