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Constitutive properties of adult mammalian cardiac muscle cells
BACKGROUND: The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction. METHODS AND RESULTS: Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (sigma), and resultant changes in cell strain (epsilon) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the sigma on the agarose gel at a constant rate to define the cardiocyte sigma-versus-epsilon relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte sigma-versus-epsilon relationship during an increase and then a decrease in sigma. In both protocols, myofilament activation was minimized by a reduction in [Ca2+]i. Myofilament activation effects were assessed in protocol C by defining cardiocyte sigma versus epsilon during an increase in sigma with physiological [Ca2+]i. In protocol A, the cardiocyte sigma-versus-epsilon relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the sigma-versus-epsilon relation in hypertrophied cardiocytes was shifted to the left compared with normal cells. CONCLUSIONS: Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.
Cytoskeletal role in the transition from compensated to decompensated hypertrophy during adult canine left ventricular pressure overloading
Increased microtubule density causes cardiocyte contractile dysfunction in right ventricular (RV) pressure-overload hypertrophy, and these linked phenotypic and contractile abnormalities persist and progress during the transition to failure. Although more severe in cells from failing than hypertrophied RVs, the mechanical defects are normalized in each case by microtubule depolymerization. To define the role of increased microtubule density in left ventricular (LV) pressure-overload hypertrophy and failure, in a given LV we examined ventricular mechanics, sarcomere mechanics, and free tubulin and microtubule levels in control dogs and in dogs with aortic stenosis both with LV hypertrophy alone and with initially compensated hypertrophy that had progressed to LV muscle failure. In comparing initial values with those at study 8 weeks later, dogs with hypertrophy alone had a very substantial increase in LV mass but preservation of a normal ejection fraction and mean systolic wall stress. Dogs with hypertrophy and associated failure had a substantial but lesser increase in LV mass and a reduction in ejection fraction, as well as a marked increase in mean systolic wall stress. Cardiocyte contractile function was equivalent, and unaffected by microtubule depolymerization, in cells from control LVs and those with compensated hypertrophy. In contrast, cardiocyte contractile function in cells from failing LVs was quite depressed but was normalized by microtubule depolymerization. Microtubules were increased only in failing LVs. These contractile and cytoskeletal changes, when assayed longitudinally in a given dog by biopsy, appeared in failing ventricles only when wall stress began to increase and function began to decrease. Thus, the microtubule-based cardiocyte contractile dysfunction characteristic of pressure-hypertrophied myocardium, originally described in the RV, obtains equally in the LV but is shown here to have a specific association with increased wall stress.
Spaceflight effects on adult rat muscle protein, nucleic acids, and amino acids
Exposure to conditions of weightlessness has been associated with decrements in muscle mass and strength. The present studies were undertaken to determine muscle responses at the cellular level. Male Sprague-Dawley rats (360-410 g) were exposed to 7 days of weightlessness during the Spacelab-3 shuttle flight (May 1985). Animals were killed 12 h postflight, and soleus (S), gastrocnemius (G), and extensor digitorum longus (EDL) muscles were excised. Muscle protein, RNA, and DNA were extracted and quantified. Differential muscle atrophy was accompanied by a significant (P less than 0.05) reduction in total protein only in S muscles. There were no significant changes in protein concentration (mg/g) in the muscles examined. In S muscles from flight animals, sarcoplasmic protein accounted for a significantly greater proportion of total protein that in ground controls (37.5 vs. 32.5%). Tissue concentrations (nmol/g) of asparagine-aspartate, glutamine-glutamate, glycine, histidine, and lysine were significantly reduced (from 17 to 63%) in S muscles from flight animals, but only glutamine-glutamate levels were decreased in the G and EDL. Muscle DNA content (microgram) was unchanged in the tissues examined, but S muscle DNA concentration (micrograms/mg) increased 27%. RNA content (micrograms) was significantly (P less than 0.025) reduced in S (-28%) and G(-22%) muscles following spaceflight. These results identify specific alterations in rat skeletal muscle during short term (7-day) exposure to weightlessness and compare favorably with observations previously obtained from ground-based suspension simulations.
Comparison of Bystander Cardiopulmonary Resuscitation (BCPR) Performance in the Absence and Presence of Timing Devices for Coordinating Delivery of Ventilatory Breaths and Cardiac Compressions in a Model of Adult Cardiopulmonary Arrest
Astronaut crew medical officers (CMO) aboard the International Space Station (ISS) receive 40 hours of medical training during the 18 months preceding each mission. Part of this training ilncludes twoperson cardiopulmonary resuscitation (CPR) per training guidelines from the American Heart Association (AHA). Recent studies concluded that the use of metronomic tones improves the coordination of CPR by trained clinicians. Similar data for bystander or "trained lay people" (e.g. CMO) performance of CPR (BCPR) have been limited. The purpose of this study was to evailuate whether use of timing devices, such as audible metronomic tones, would improve BCPR perfomance by trained bystanders. Twenty pairs of bystanders trained in two-person BCPR performled BCPR for 4 minutes on a simulated cardiopulmonary arrest patient using three interventions: 1) BCPR with no timing devices, 2) BCPR plus metronomic tones for coordinating compression rate only, 3) BCPR with a timing device and metronome for coordinating ventilation and compression rates, respectively. Bystanders were evaluated on their ability to meet international and AHA CPR guidelines. Bystanders failed to provide the recommended number of breaths and number of compressions in the absence of a timing device and in the presence of audible metronomic tones for only coordinating compression rate. Bystanders using timing devices to coordinate both components of BCPR provided the reco number of breaths and were closer to providing the recommended number of compressions compared with the other interventions. Survey results indicated that bystanders preferred to use a metronome for delivery of compressions during BCPR. BCPR performance is improved by timing devices that coordinate both compressions and breaths.
Satellite cell proliferation in adult skeletal muscle
Novel methods of retroviral-mediated gene transfer for the in vivo corporation and stable expression of eukaryotic or prokaryotic foreign genes in tissues of living animals is described. More specifically, methods of incorporating foreign genes into mitotically active cells are disclosed. The constitutive and stable expression of E. coli .beta.-galactosidase gene under the promoter control of the Moloney murine leukemia virus long terminal repeat is employed as a particularly preferred embodiment, by way of example, establishes the model upon which the incorporation of a foreign gene into a mitotically-active living eukaryotic tissue is based. Use of the described methods in therapeutic treatments for genetic diseases, such as those muscular degenerative diseases, is also presented. In muscle tissue, the described processes result in genetically-altered satellite cells which proliferate daughter myoblasts which preferentially fuse to form a single undamaged muscle fiber replacing damaged muscle tissue in a treated animal. The retroviral vector, by way of example, includes a dystrophin gene construct for use in treating muscular dystrophy. The present invention also comprises an experimental model utilizable in the study of the physiological regulation of skeletal muscle gene expression in intact animals.
Gait Training Improves Performance in Healthy Adults Exposed to Novel Discordant Conditions
After they return to Earth, astronauts experience sensorimotor disturbances that disrupt their ability to walk. We have previously shown that training with a variety of sensorimotor adaptive challenges enhances the capability of adapting to novel sensorimotor conditions. We are currently developing a sensorimotor adaptability (SA) training program designed to facilitate recovery of function after gravitational transitions. The purpose of this study was to determine whether trained subjects could transfer learned skills from one discordant visuo-proprioceptive environment to another. During three sessions, subjects walked at 2.5 km/h on a treadmill mounted on a motion base platform. Ten subjects trained with a combination of lateral treadmill translation and superimposed sinusoidal lateral optic flow that was presented on a large screen positioned in front of them. Ten controls completed the same training schedule while viewing only the forward optic flow with no visual or physical oscillation. Twenty minutes after the final training session, all subjects completed a 2-minute trial with a novel combination of visual and treadmill roll perturbations not previously experienced during the training (Transfer Test). Compared to the untrained group, participants who received SA training showed faster reaction times and, based on a composite score derived from stride frequency, heart rate, and reaction time, an overall enhanced performance. Our results showed that an SA training program can improve overall walking performance when subjects are exposed to novel incongruent sensory environments. This training has application for both enhancing adaptive responses in astronauts and reducing fall and injury risk in the elderly.
Dietary Supplement Attenuates Radiation-Induced Osteoclastogenic and Oxidative Stress-Related Responses and Protects Adult Mice from Radiation-Induced Bone Loss
Our central hypothesis is that oxidative stress plays a key role in cell dysfunction and progressive bone loss caused by radiation exposure during spaceflight. In animal studies, excess free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. We previously reported that exposure to low or high-LET radiation rapidly increases expression levels of pro-osteoclastogenic and oxidative stress-related genes in bone and marrow, followed by pathological changes in skeletal structure. To screen various antioxidants for radioprotective effects on bone, 4 month old, male C57Bl6/J mice were treated with a dietary antioxidant cocktail, injectable alpha-lipoic acid, or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs total body radiation and one day later marrow cells were collected and the relevant genes analyzed for expression levels. Of the candidates tested, DP was most effective in reducing bone resorption-related gene expression. Microcomputed tomography revealed that DP also prevented the radiation-induced deterioration of skeletal microarchitecture, as indicated by percent bone volume, trabecular spacing and trabecular number. DP had similar protective effects on skeletal structure after sequential exposure to protons (0.5 Gy, 150MeV/n) and 56Fe 0.5Gy, 600 MeV/n). When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerted pro-osteogenic effects apart from previously identified anti-resorptive actions, which may contribute to radioprotection of skeletal tissue. In conclusion, a diet enriched in certain types of antioxidants and polyphenols such as DP may be useful as an intervention to protect tissues from degenerative effects of ionizing radiation.
Simulated Microgravity Affects Behavior and Cytokine Expression in the Hippocampus of Adult Mice: Influence of Mitochondrial Reactive Oxygen Species
The effects of microgravity, and social isolation on the CNS are poorly understood. We hypothesize that mitochondrial reactive oxygen species (ROS) play an important role in this process. Since mice are social animals, our lab developed a novel social model of hindlimb unloading (HU), enabling us to determine the effects of both social isolation and simulated microgravity. Responses to 30d of HU were compared in wildtype or transgenic MCAT mice who over-express human catalase in mitochondria. Abundance of 4-Hydroxynonenal, Park7 (a redox-sensitive chaperone and sensor of oxidative stress) and corticosterone were measured by ELISA. Cytokines related to inflammation in the hippocampus and in plasma were analyzed by a protein array. Behavioral data was collected over a 24-hour period.Socially housed HU mice were more active and conducted at least two times more exploratory activities, compared to normally loaded mice. Correlation analysis revealed that specific brain and plasma cytokines correspond with specific behaviors. Simulated microgravity and/or social isolation caused changes in cytokine patterns in the hippocampus and in plasma, with significant interaction effects of HU and genotype in expression levels of five cytokines (out of 35). Interestingly, elevation of these generally pro-inflammatory cytokines by HU in WT mice was mitigated in MCAT mice, suggesting a role for mitochondrial ROS signaling in inflammatory CNS responses to microgravity. Interestingly, socially housed mice had also lower level of 4HNE and higher level of Park7 in the hippocampus compared to singly housed animals. The cytokine responses to social isolation were more extensive in brain vs plasma. Further, there was no overlap in the cytokine repertoire regulated in response to microgravity versus, isolation suggesting divergent mechanisms or downstream signaling. These findings implicate a potentially important role for mitochondrial ROS in CNS responses to the challenges posed both by prolonged missions in space and bedrest on Earth
A Comparison of Evaluation Techniques for in-School Programs vs. Adult-Oriented Planetarium Programs
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Mitigating Effects of Exercise and Testosterone on Aerobic Fitness in Healthy Adults during 70-days of Head Down Bed Rest
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Sleep movements and respiratory coupling as a biobehavioral metric for early Alzheimer’s disease in independently dwelling adults
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Genetic Markers of Differential Vulnerability to Sleep Loss in Adults
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Segmental Tissue Resistance of Healthy Young Adults during Four Hours of 6-Degree Head-Down-Tilt Positioning
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Chronic Kidney Disease Stage and Cardiovascular and Mortality Events Among Older Adults: The SPRINT Trial
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Revisiting a Model: Continually Reassessing the Computational Role of Adult Neurogenesis.
Abstract not provided.