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At least 1,387 records · Page 77
All sourcesNASA NTRSDOE OSTI
NASA NTRS1997

Six Month Report on Tissue Cultured Avian Skeletal Myofibers in the STL/A Module Aboard STS-77

Space travel is know to effect skeletal muscle, causing rapid and pronounced atrophy in humans and animals, even when strenuous exercise is used as a countermeasure. The cellular and molecular bases of this atrophy are unknown. Space travel may cause muscle atrophy by a direct effect on the muscle fibers and/or indirectly by reducing circulating levels of growth factors such as growth hormone. The recent development of a tissue culture incubator system for Shuttle Middeck basic science experiments [Space Tissue Loss (STL) Module] by the Walter Reed Army Institute of Research (WRAIR) allows the study of the effects of space travel directly on isolated skeletal myofibers. Avian bioartificial skeletal muscle 'organoids' containing differentiated skeletal myofibers and connective tissue fibroblasts were flown aboard the Space Shuttle (Space Transportation System, STS) on Flight STS-77, a repeat of a similar experiment flown on STS-66. The results from these two flight experiments show for the first time that space travel has a direct effect on skeletal muscle cells separate from any systemic effects resulting from altered circulating growth factors.

Vandenburgh, Herman H.↗
NASA NTRS1998

Role of Corticosteroids in Bone Loss During Space Flight

The primary objective of this research project is to test the hypothesis that corticosteroids contribute to the adverse skeletal effects of space flight. To achieve this objective, serum corticosteroids, which are known to increase during space flight, must be maintained at normal physiologic levels in flight rats by a combination of adrenalectomy and corticosteroid supplementation via implanted hormone pellets. Bone analyses in these animals will then be compared to those of intact flight rats that, based on past experience, will undergo corticosteroid excess and bone loss during space flight. The results will reveal whether maintaining serum corticosteroids at physiologic levels in flight rats affects the skeletal abnormalities that normally develop during space flight. A positive response to this question would indicate that the bone loss and decreased bone formation associated with space flight are mediated, at least in part, by corticosteroid excess.

Wronski, Thomas J.↗
NASA NTRS1998

Animal Enclosure Module (AEM)

The primary objective of this research project is to test the hypothesis that corticosteroids contribute to the adverse skeletal effects of space flight. To achieve this objective, serum corticosteroids, which are known to increase during space flight, must be maintained at normal physiologic levels in flight rats by a combination of adrenalectomy and corticosteroid supplementation via implanted hormone pellets. Bone analyses in these animals will then be compared to those of intact flight rats that, based on past experience, will undergo corticosteroid excess and bone loss during space flight. The results will reveal whether maintaining serum corticosteroids at physiologic levels in flight rats affects the skeletal abnormalities that normally develop during space flight. A positive response to this question would indicate that the bone loss and decreased bone formation associated with space flight are mediated, at least in part, by corticosteroid excess.

Source record↗
NASA NTRS1990

Fed, but not Fasted, Adrenalectomized Rats Survive the Stress of Hemorrhage and Hypovolemia

We have recently shown that conscious adrenalectomized rats exhibit nearly normal recovery of arterial blood pressure during the 5 h after hemorrhage. In those experiments, it appeared that a previous reduction in food intake might have compromised the recovery of blood pressure and increased mortality. These experiments were designed to test in conscious sham-adrenalectomized (control) and adrenalectomized rats prepared with indwelling arterial and venous cannulae: 1. The effects of a 20- to 24-h fast (compared to rats fed ab libitum) on the mobilization of plasma substrates and recovery of arterial blood pressure after a 15 ml/kg - 5 min hemorrhage, and 2. Vascular responsivity to pressor agents in fed or fasted groups before or 2 h after hemorrhage. In all rats hemorrhage resulted in decreased arterial pressure and heart rate. Arterial pressure recovered to near normal in both fed and fasted control groups and in the led adrenalectomized rats, and all of these rats survived for 24 h after stress. By contrast, in the fasted adrenalectomized rats, arterial pressure recovered only during the first 1.5 - 2 h and then failed, resulting in 100% mortality by 3-5 h. Compared to the other three groups, in which substrate levels either increased or remained fairly stable, plasma glucose and beta-hydoxybutyrate concentrations fell steadily, from 1.5-2 h after hemorrhage until death occurred in the fasted adrenalectomized rats. Basal ACTH concentrations were elevated cormpared to control values in both adrenalectomized groups (fed and fasted). Hemorrhage caused increases in plasma ACTH in all groups; the magnitude of the responses did not differ among the groups. The dilution of Evans' blue dve after hemorrhage (used as an index of fluid movement into the vascular space) was not different in contol and adrenalectomized rats (either fed or fasted). There were no differences in pressor responses to phenylephrine, vasopressin, or angiotensin-II between the fed and fasted condition in the control rats either before or after hemorrhage. There was a fasting-associated decrease in vascular responsivity, to vasopressin, but normal responsivity to phenylephrine and angiotensin-II, in the adrenal-ectomized rats both before and after hemorrhage. We conclude that: (1) since fed adrenalectomized rats all survived the stress, adrenal hormones are not required for survival unless fasting is a prior condition; (2) vascular responsiveness to phenylephrine and angiotensin-II is not altered by fasting and is, therefore, probably not the proximate cause of cardiovascular svstem failure; and (3) from these data we cannot distinguish between a failure in substrate supply and a failure in some component of the cardiovascular svstem, other than vascular responsivity, that results in death after hemorrhage in fasted adrenalectomized rats.

Darlington, Daniel N.↗
NASA NTRS1996

Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy

Genetically modified murine skeletal myoblasts were tissue engineered in vitro into organ-like structures (organoids) containing only postmitotic myofibers secreting pharmacological levels of recombinant human growth hormone (rhGH). Subcutaneous organoid Implantation under tension led to the rapid and stable appearance of physiological sera levels of rhGH for up to 12 weeks, whereas surgical removal led to its rapid disappearance. Reversible delivery of bioactive compounds from postimtotic cells in tissue engineered organs has several advantages over other forms of muscle gene therapy.

Vandenburgh, Herman↗
NASA NTRS1997

Methods for the Organogenesis of Skeletal Muscle in Tissue Culture

Skeletal muscle structure is regulated by many factors, including nutrition, hormones, electrical activity, and tension. The muscle cells are subjected to both passive and active mechanical forces at all stages of development and these forces play important but poorly understood roles in regulating muscle organogenesis and growth. For example, during embryogenesis, the rapidly growing skeleton places large passive mechanical forces on the attached muscle tissue. These forces not only help to organize the proliferating mononucleated myoblasts into the oriented, multinucleated myofibers of a functional muscle but also tightly couple the growth rate of muscle to that of bone. Postnatally, the actively contracting, innervated muscle fibers are subjected to different patterns of active and passive tensions which regulate longitudinal and cross sectional myofiber growth. These mechanically-induced organogenic processes have been difficult to study under normal tissue culture conditions, resulting in the development of numerous methods and specialized equipment to simulate the in vivo mechanical environment.These techniques have led to the "engineering" of bioartificial muscles (organoids) which display many of the characteristics of in vivo muscle including parallel arrays of postmitotic fibers organized into fascicle-like structures with tendon-like ends. They are contractile, express adult isoforms of contractile proteins, perform directed work, and can be maintained in culture for long periods. The in vivo-like characteristics and durability of these muscle organoids make them useful for long term in vitro studies on mechanotransduction mechanisms and on muscle atrophy induced by decreased tension. In this report, we described a simple method for generating muscle organoids from either primary embrionic avain or neonatal rodent myoblasts.

Vandenburgh, Herman↗
NASA NTRS1998

High Salt Diets, Bone Strength and Mineral Content of Mature Femur After Skeletal Unloading

It is known that high salt diets increase urinary calcium (Ca) loss, but it is not known whether this effect weakens bone during space flight. The Bone Hormone Lab has studied the effect of high salt diets on Ca balance and whole body Ca in a space flight model (2,8). Neither the strength nor mineral content of the femurs from these studies has been evaluated. The purpose of this study was to determine the effect of high salt diets (HiNa) and skeletal unloading on femoral bone strength and bone mineral content (BMC) in mature rats.

Liang, Michael T. C.↗
NASA NTRS1998

Insulin and Glucagon Secretion In Vitro

Long-duration space flight is associated with many physiological abnormalities in astronauts. In particular, altered regulation of the hormones insulin and glucagon may contribute to metabolic disturbances such as increased blood sugar levels, which if persistently elevated result in toxic effects. These changes are also observed in the highly prevalent disease diabetes, which affects 16 million Americans and consumes over $100 billion in annual healthcare costs. By mimicking the microgravity environment of space in the research laboratory using a NASA-developed bioreactor, one can study the physiology of insulin and glucagon secretion and determine if there are alterations in these cellular processes. The original specific objectives of the project included: (1) growing ('cell culture') of pancreatic islet beta and alpha cells that secrete insulin and glucagon respectively, in the NASA bioreactor; (2) examination of the effects of microgravity on insulin and glucagon secretion; and (3) study of molecular mechanisms of insulin and glucagon secretion if altered by microgravity.

Rajan, Arun S.↗
NASA NTRS1998

Applications of Anabolic Vitamin D Analogs as Countermeasures to Bone Loss

The experiments in Round 2 were designed to extend the results of our efforts in Round 1 which led us to hypothesize that the seco-steroid, 1,25-dihydroxyvitamin D3[1,25(OH)2D3], acts in synergy with parathyroid hormone (PTH) to regulate bone calcium homeostasis. Our work centered on one particular target of 1,25(OH)2D3 action, the voltage-sensitive calcium channels (VSCC's), which are activated acutely by this steroid within milliseconds of exposure . A second area of research focused on the effects of mechanical strain on VSCC expression in bone. These experiments were performed in collaboration with Dr. Steven Goldstein (Univ. Michigan), who generously provided RNA extracted from dog bones that had been exposed to mechanical strain in vivo. Our results suggest that mechanical loading elevated VSCC expression in the long bones from 3 of the 6 animals tested. A second line of experimentation, carried out in collaboration with Dr. Randall Duncan, a NASA-funded investigator in Indianapolis, centered on RT-PCR analysis of effects of mechanical strain on Ca2(+) channel expression in cultured bone cells. Compared to unstrained controls, the expression of vitamin-D-sensidve Ca2(+) channels is elevated 3- to 5-fold over a 24 hr period.

Karin, Norman J.↗
NASA NTRS1976

Effect of Propranolol on Thyroxine-Induced Changes in Body Temperature and Metabolism During Exercise in Dogs

Effects of thyroxine on temperature and metabolism during exercise were studied in dogs after beta-adrenergic blockade. Dogs performed 60 min treadmill exercise of moderate intensity 5 and 72 h following thyroxine injected s. c. in a single dose of 0.1 mg/kg b.w. Thyroxine increased significantly the lipolytic response to exercise as well as blood lactate (LA) concentrations and rectal temperature (T(sub re)) during exercise as early as 5 h following the hormone administration. The changes became more pronounced 72 h after the injection. At rest T(sub re), blood FFA (free fatty acid) and LA levels in the thyroxine-treated dogs did not differ from the control values, and blood glucose was slightly, but significantly higher. Propranolol given intravenously in a dose of 0.25 mg/kg at 30 min of the exercise performed 72 h following thyroxine injection abolished the plasma FFA rise, and inhibited to a certain extent increases in T(sub re) and blood LA concentrations during the next 30 min of exercise.

Kaciuba-Uscilko, Hanna↗
NASA NTRS1994

Growth Factors and Tension-Induced Skeletal Muscle Growth

The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we have performed experiments to determine whether mechanical stimulation of cultured avian muscle cells alters their response to anabolic steroids or glucocorticoids. In static cultures, testosterone had no effect on muscle cell growth, but 5alpha-dihydrotestosterone and the synthetic steroid stanozolol increased cell growth by up to 18% and 30%, respectively, after a three day exposure. We completed development of a new IBM-based mechanical cell stimulator system to provide greater flexibility in operating and monitoring our experiments. Our previous long term studies on myofiber growth were designed around a perfusion system of our own design. We have recently changed to performing these studies using a modified CELLCO cartridge bioreactor system Z since it has been certified as the ground-based model for the Shuttle's Space Tissue Loss (STL) F= Cell Culture Module. The current goals of this aspect of the project are three fold: 1) to design a Z cell culture system for studying avian skeletal myofiber atrophy on the Shuttle and Space Station; 0 2) to expand the use of bioreactors to cells which do not grow in either suspension or attached to the hollow fibers; and 3) to combine the bioreactor system with our computerized mechanical cell stimulator to have a better in vitro model to study tension/gravity/stretch regulation of skeletal muscle size. Preliminary studies also reported on involved : (1) how release of tension can induce rapid atrophy of tissues cultured avian skeletal muscle cells, and (2) a mechanism to transfer and maintain avian skeletal muscle organoids in modified cartridges in the Space Tissue Loss Module.

Vandenburgh, Herman H.↗
NASA NTRS1989

Paraventricular Stimulation with Glutamate Elicits Bradycardia and Pituitary Responses

The excitatory neurotransmitter, L-glutamate (0.5 M, pH 7.4), or the organic acid, acetate (0.5 M, pH 7.4), was microinjected (50 nl over 2 min) directly into the paraventricular nuclei (PVN) of pentobarbital sodium-anesthetized rats while arterial blood pressure and heart rate and plasma adrenocorticotropic hormone (ACTH), vasopressin, and oxytocin were measured. Activation of PVN neurons with L-glutamate led to increases in plasma ACTH, vasopressin, and oxytocin and a profound bradycardia (-80 beats/min) with little change in arterial blood pressure. Microinjection of acetate had no effect on the above variables. The decrease in heart rate was shown to be dependent on the concentration of glutamate injected and the volume of injectate. The bradycardia was mediated through the autonomic nervous system because ganglionic blockade (pentolinium tartrate) eliminated the response; atropine and propranolol severely attenuated the bradycardia. The bradycardia was greatest when L-glutamate was microinjected into the caudal PVN. Injections into the rostral PVN or into nuclei surrounding the PVN led to small or nonsignificant decreases in heart rate. Focal electric stimulation (2-50 pA) of the PVN also led to decreases in heart rate and arterial blood pressure. These data suggest that activation of PVN neurons leads to the release of ACTH, vasopressin, and oxytocin from the pituitary and a bradycardia that is mediated by the autonomic nervous system.

Darlington, Daniel N.↗
NASA NTRS1999

Reactivation of Latent Viruses in Space

Reactivation of latent viruses is an important health risk for people working and living in physically isolated extreme environments such as Antarctica and space. Preflight quarantine does not significantly reduce the risk associated with latent viruses, however, pharmaceutical countermeasures are available for some viruses. The molecular basis of latency is not fully understood, but physical and psychosocial stresses are known to initiate the reactivation of latent viruses. Presumably, stress induced changes in selected hormones lead to alterations in the cell- mediated immune (CMI) response resulting in increased shedding of latent viruses. Limited access to space makes the use of ground-based analogs essential. The Australian Antarctic stations serve as a good stress model and simulate many aspects of space flight. Closed environmental chambers have been used to simulate space flight since the Skylab missions and have also proven to be a valuable analog of selected aspects of space flight.

Pierson, D. L.↗
NASA NTRS1999

Myosin Heavy Chain Gene Expression in Developing Neonatal Skeletal Muscle: Involvement of the Nerve, Gravity, and Thyroid State

The myosin heavy chain (MHC) gene family encodes at least six MHC proteins (herein designated as neonatal, embryonic, slow type I (beta), and fast IIa, IIx, and IIb) that are expressed in skeletal muscle in a muscle-specific and developmentally-regulated fashion. At birth, both antigravity (e.g. soleus) and locomotor (e.g., plantaris) skeletal muscles are undifferentiated relative to the adult MHC phenotype such that the neonatal and embryonic MHC isoforms account for 80 - 90% of the MHC pool in a fast locomotor muscle; whereas, the embryonic and slow, type I isoforms account for approx. 90% of the pool in a typical antigravity muscle. The goal of this study was to investigate the role of an intact nerve, gravity and thyroid hormone (T3), as well as certain interactions of these interventions, on MHC gene expression in developing neonatal skeletal muscles of rodents.

Baldwin, K. M.↗
NASA NTRS1999

Tissue Engineering Organs for Space Biology Research

Long-term manned space flight requires a better understanding of skeletal muscle atrophy resulting from microgravity. Atrophy most likely results from changes at both the systemic level (e.g. decreased circulating growth hormone, increased circulating glucocorticoids) and locally (e.g. decreased myofiber resting tension). Differentiated skeletal myofibers in tissue culture have provided a model system over the last decade for gaining a better understanding of the interactions of exogenous growth factors, endogenous growth factors, and muscle fiber tension in regulating protein turnover rates and muscle cell growth. Tissue engineering these cells into three dimensional bioartificial muscle (BAM) constructs has allowed us to extend their use to Space flight studies for the potential future development of countermeasures.

Vandenburgh, H. H.↗
NASA NTRS1999

Characterization of Treefoil Peptide Genes in Iron-Ion or X-Irradiated Human Cells

The gastrointestinal (GI) tract is especially sensitive to ionizing radiation, probably because of its high rate of cell turn over. Most of the data in the literature concerns the histological/anatomical description of damage rather than functional studies. In fact, previous reports in humans have shown that, at doses of 2 Gy or more, functional abnormalities appear indicating that in radiation sensitive tissues the effects of radiation are not limited to cell death. GI functions are controlled in particular by GI peptides. One hypothesis is that ionizing radiation may modulate the synthesis and release of these peptides and consequently may contribute largely to abnormalities in GI function. However, no previous studies have been concerned with GI-specific gene expression in irradiated GI tissues. The family of human trefoil peptides comprises three members thus far, all of which are expressed in specific regions of the GI tract. In addition, two trefoil peptides, pS2 (TFFI) and HITF (TFF2) are expressed in breast tissue. Their exact function in GI and breast tissues is unclear but mucosal integrity, repair, mucin secretion and responsiveness to hormones have been shown. We recently isolated and characterized pS2 as a novel p53- and estrogen receptor-independent gene whose MRNA expression in several cells lines was found to be delayed 4 to 7 days after irradiation with X-rays, fission neutrons or 1 GeV/n Fe-ions. The aim of the present study was to determine whether pS2 and HITF have a similar induction kinetics in irradiated gastric and breast cell lines, and whether they have the phorbol ester (TPA) responsive element (TRE).

Balcer-Kubiczek, E. K.↗
NASA NTRS1999

Ambient Light Intensity, Actigraphy, Sleep and Respiration, Circadian Temperature and Melatonin Rhythms and Daytime Performance of Crew Members During Space Flight on STS-90 and STS-95 Missions

Sleep disruption and associated waking sleepiness and fatigue are common during space flight. A survey of 58 crew members from nine space shuttle missions revealed that most suffered from sleep disruption, and reportedly slept an average of only 6.1 hours per day of flight as compared to an average of 7.9 hours per day on the ground. Nineteen percent of crewmembers on single shift missions and 50 percent of the crewmembers in dual shift operations reported sleeping pill usage (benzodiazepines) during their missions. Benzodiazepines are effective as hypnotics, however, not without adverse side effects including carryover sedation and performance impairment, anterograde amnesia, and alterations in sleep EEG. Our preliminary ground-based data suggest that pre-sleep administration of 0.3 mg of the pineal hormone melatonin may have the acute hypnotic properties needed for treating the sleep disruption of space flight without producing the adverse side effects associated with benzodiazepines. We hypothesize that pre-sleep administration of melatonin will result in decreased sleep latency, reduced nocturnal sleep disruption, improved sleep efficiency, and enhanced next-day alertness and cognitive performance both in ground-based simulations and during the space shuttle missions. Specifically, we have carried out experiments in which: (1) ambient light intensity aboard the space shuttle is assessed during flight; (2) the impact of space flight on sleep (assessed polysomnographically and actigraphically), respiration during sleep, circadian temperature and melatonin rhythms, waking neurobehavioral alertness and performance is assessed in crew members of the Neurolab and STS-95 missions; (3) the effectiveness of melatonin as a hypnotic is assessed independently of its effects on the phase of the endogenous circadian pacemaker in ground-based studies, using a powerful experimental model of the dyssomnia of space flight; (4) the effectiveness of melatonin as a hypnotic is assessed during the STS-90 (Neurolab) and STS-95 missions in a double-blind placebo-controlled trial. In both flight-based experiments, the effects of melatonin on sleep stages and spectral composition of the EEG during sleep will be determined as well as its effects on daytime alertness and performance; (5) the impact of space flight on sleep and waking neurobehavioral alertness and performance in 30-45-year-old astronauts is compared with its impact in a 77-year-old astronaut. This case study is the first to assess the effects of space flight on an older individual. Because the investigators are still blind to the treatment in this double-blind, placebo-controlled trial, preliminary results will be presented independent of the drug condition.

Czeisler, Charles A.↗