Human Physiology Research and the ISS: Staying Fit Along the Journey

The human body undergoes numerous adaptations when it leaves Earth’s gravity. Researchers are studying how to minimize those physiological changes in astronauts and in people on Earth with similar health conditions. Exercising in space on a cycle ergometer and other suitable equipment can go a long way toward lessening such conditions as muscle atrophy and bone loss, which occur in microgravity.

Imagine the sensations of being an astronaut – the force of rocket thrust pushing you skyward while Earth’s gravity struggles to keep you in its grip; the view from the cockpit as you climb higher and higher; and finally, many minutes later, when the space shuttle has reached its orbit and is in freefall around Earth, the giddy freedom of “floating” through air as you “swim” from spot to spot, tumbling in a slow-motion somer-sault now and then, just because you can.

But there’s more. Now imagine the cold-like sinus and nasal stuffiness you get as fluids shift upward in your body, no longer pulled to your feet by gravity. Though you would not be able to feel it, there is a gradual weakening of your heart and other muscles since they are no longer challenged to resist the pull of gravity. Similarly, there is bone loss as your limbs no longer have to bear the skeletal weight they do every day on Earth. These are a few of the adaptations the body makes when an astronaut travels on the International Space Station (ISS) or on any other orbiting spacecraft.

All these adjustments can make work in space more difficult, and they definitely pose problems when an astronaut re-enters Earth’s gravity at the end of a mission. Upon returning to Earth, the muscles and bones weakened in space need to readjust to gravity’s pull, and fluids that have shifted and been expelled by the body need to be replaced. To minimize the physiological effects of long-term travel in space, scientists supported by NASA’s Office of Biological and Physical Research (OBPR) are conducting research on humans, on other life forms, and even on individual cells. As they find the causes of the physiological effects and devise countermeasures to minimize their impact, scientists are also learning more about how to combat similar health conditions that occur on Earth.

Getting a Workout in Space

Good old-fashioned exercise can reduce some of the physiological deficiencies associated with spaceflight, and getting the right exercise prescription is just what Donald Hagan, exercise lead for the Human Adaptation and Countermeasures Office and director of the Exercise Physiology Laboratory at Johnson Space Center, is looking for. Exercise prescriptions are the individualized exercise plans that astronauts follow to maintain their aerobic capacity, bone density, and muscle mass as much as possible during flight. Hagan’s group works with the astronauts themselves, recommending preflight fitness plans, training the astronauts for in-flight use of the exercise equipment onboard the ISS, and monitoring the health of astronauts after their return to Earth.

The researcher’s studies are related to three different exercise machines, the leg cycle ergometer, the treadmill, and the interim resistance exercise device. The cycle ergometer was the first exercise device to be flown on spacecraft; it flew on Skylab and Russian Space Station Mir, and is now on the ISS. Astronauts can use this versatile piece of exercise equipment to cycle with their legs or their arms to gain aerobic conditioning benefits. Before flight, astronauts complete a baseline test on the equipment to determine their maximum workload.

During flight, all astronauts are required to complete physical fitness tests on the equipment once a month. The workloads for the test are based on the subject’s maximum workload capacity determined before flight. Hagan describes the test protocol: “They have 5 minutes of rest, 5 minutes at 25 percent, 5 minutes at 50 percent, 5 minutes at 75 percent of their capacity, and then they do a 5-minute recovery at a low workload. Each crewmember has his or her own workload protocol.”

The purposes of the test are to determine the relationship between the heart rate and the power output, and to see how much the relationship has changed compared to the preflight test. The goal is for the in-flight relationship to be the same as the preflight relationship.

Hagan illustrates, “For example, let’s say that on the ground their heart rate at the 25-percent workload is 110 beats a minute, at 50 percent workload it’s 140 beats a minute, and at the 75 percent workload, let’s say up to 160.

“Next we take them into flight and we do the same test. At 25 percent, instead of being 110, the heart rate is now 115. Then at 50 percent workload, instead of being 140 it’s 150, and at the 75 percent workload, instead of being 160, it’s 175. So what that tells us is that for any given workload they have a higher heart rate and a decrease in their aerobic capacity.

“When we see that, we’ll write an exercise prescription or change their current exercise prescription in-flight to increase their actual aerobic conditioning and training, so that we can bring that relationship back in line with what it was during preflight.”

The second device used in the exercise plans is the treadmill, which is operated in both motor-driven and self-driven modes. Hagan describes, “The astronaut is held to the treadmill surface using a subject-loading device that consists of two spring-loaded cords that come up from either side of the treadmill and are attached to a harness that fits around the waist of the astronaut. The cords holding the astronaut to the treadmill can be loaded with anywhere from 66 percent to 100 percent of the subject’s body weight.” Optimum loading is usually about 75 percent of the astronaut’s weight on Earth.

According to Hagan, treadmill exercise stresses multiple systems. It not only allows for sustained, rhythmic exercise for 20 to 30 minutes, so astronauts can simulate walking and running on Earth, but it also can be loaded to levels that provide more resistance during a workout. “That added resistance should help to maintain bone density and muscle mass that is so easily lost during spaceflight,” explains Hagan.

The third exercise machine is the interim resistance exercise device, or IRED. Hagan describes the equipment: “The IRED is basically two cylinders, and inside each of these cylinders are 13 disks, or flex packs. The flex packs are connected to a central axle with a series of rubber connections.” The astronaut sets the number of flex packs to be engaged and pulls on a cord tied to the axle. The flex packs create resistance; the greater the number of flex packs, the greater the resistance, up to 300 pounds per cylinder.

The weight-lifting or strength device also can be used for other exercises. “We have a shoulder harness system [that can be attached to the IRED] so astronauts can do deep knee bends, what we call squats,” says Hagan. “They can do back exercises, they can do heel raises. Basically, they’re taxing what we call the antigravity muscles: the calves, the thighs, the buttocks, all the back muscles – all those muscles that are engaged when you stand up.”

With the IRED, as well as the treadmill and the cycle ergometer, astronauts are better equipped to maintain their health while in space. Studies of their physiological systems are also helping scientists learn about what is required to maintain health on Earth. Hagan says, “What we have learned about response to microgravity is profound. When you go to space and spend a lot of time in microgravity without exercising, you basically end up wasting away. When we remove the stimulus of gravity, protein synthesis and calcium deposition in bone all stop, but the degradation processes all continue.

“But by making the muscles and bones work against high resistances, then we can better maintain the protein synthesis and the calcium status quo, and we can maintain stress on the cardiovascular system. Exercise is the single most important health maintenance method we currently have.” He says that it’s important on Earth, too. “Becoming highly sedentary is much like going to space. What we see in the sedentary lifestyle is exactly what happens when people spend a lot of time in flight and don’t exercise. That’s why we all have to exercise.”

But exercise is an inexact science, and researchers still don’t know what magnitude of stimulus is required to maintain bone and muscle at preflight levels. So OBPR researchers are also looking for answers at a more basic level – genes.

Finding a Genetic Light Switch

Kenneth Baldwin, an OBPR principal investigator at the University of California, Irvine, and chair of the OBPR Biological and Physical Research Advisory Committee, is conducting research on how reducing the stimulus of gravity affects production of the RNA that the body uses as a blueprint for making muscle proteins. Muscle proteins are what give muscles their strength, so when the RNA blueprints aren’t available for producing new proteins to replace old ones – a situation that occurs in microgravity – the muscles atrophy. Baldwin, who serves as team leader on muscle research at the National Space Biomedical Research Institute, explains why this information is important to astronauts: “When the skeletal muscle system is exposed to microgravity during spaceflight, the muscles undergo a reduced mass that translates to a reduction in strength.” When this happens, muscle endurance decreases and the muscles are more prone to injury, “so individuals could have problems in performing extravehicular activity [space walks] or emergency egress because their bodies are functionally compromised.”

The stimulus of gravity affects RNA production, which helps maintain the strength of human muscles on Earth (top), as seen in this section of muscle fiber taken from an astronaut before spaceflight. Astronauts in orbit and patients on Earth fighting muscle-wasting diseases need countermeasures to prevent muscle atrophy, indicated here with white lipid droplets (bottom) in the muscle sample taken from the same astronaut after spaceflight.

During spaceflight investigations conducted from 1991 to 1997, Baldwin studied the development of skeletal muscles in rodents during critical developmental periods following birth. He and his research team found that in microgravity, “muscle that would normally be programmed to become antigravity muscles [such as leg and back muscles] was not producing the appropriate type of motor proteins in those fibers that basically are designed for the body to oppose gravity. The specific genes [that trigger slow motor protein production in those muscles] were not activated.” Baldwin suspected that these same genes were being shut down in astronauts while they were in microgravity, reducing the key proteins produced by antigravity muscles and thereby contributing to atrophy.

So Baldwin and his team began studying the effect of microgravity on transcription, translation, and protein degradation. Transcription is the process of using a DNA molecule as a template to construct a messenger RNA molecule that ends up with the same genetic information as the DNA. Translation is the process of then using the genetic information in the messenger RNA (mRNA) to form a protein molecule. Baldwin explains the connection between these two processes and degradation, the decomposing of proteins at the end of their life cycle, and atrophy: “When we talk about the flow of information for any given gene, we have what is called ‘promoter’ activity [such as the presence of gravity], which keeps the gene turned on so it produces more mRNA [transcribes], and then that mRNA now gets translated into the building of a protein. That protein now continues to serve some functional role, and then over time that protein is targeted for degradation through the activation of other important genes.”

Baldwin is looking at the genes connected to a specific motor protein, called a myosin-heavy chain. He explains, “Myosin is the most abundant protein that is expressed in muscle, and it is a structural motor protein that serves as the key regulatory protein for bringing about the process of contraction. It regulates the force that is built up in the muscle when the muscle is induced to contract by the nervous system, and it regulates the intensity of the contraction, and hence the power-generating capability of the muscle.”

Baldwin says that weight bearing, as it occurs normally on Earth, keeps the slow myosin gene active in the antigravity muscle fibers, and when there’s no regular force production, the gene gets shut down. So Baldwin, too, is looking for the amount of force necessary to keep muscles strong. “If I make the muscles contract five times a day with very high amounts of loading on them,” he asks, “is this enough to keep the gene turned on that will keep the protein expressed that will keep the fiber integrity there?”

Baldwin foresees the possibility of using gene therapy as another countermeasure to muscle atrophy: “It may be that we will find certain factors that are pivotal in controlling the gene [connected to the myosin-heavy chain]. If we understood basically how to turn those factors on, you could end up controlling muscle strength through pharmacological intervention rather than using work.

“There’s a practical side to this,” he continues. “We may find, for example, that in order to keep the muscle integrity of individuals in space, they may have to exercise eight hours a day. That’s not cost-effective. So the question is, could astronauts take a pill or some other type of prescription that would enable them to have that factor that acts in concert with exercise, so with 40 minutes of exercise a day, coupled with this ‘magic pill’ they take, they could maintain their homeostasis, or equilibrium?”

OBPR researchers are studying the effects of microgravity on how messenger RNA molecules form protein molecules that maintain muscle strength. Practical applications of his research could lead to finding how gene therapy (through pharmaceuticals) and exercise could work in concert to keep astronauts’ muscles strong.

The answer to Baldwin’s questions could help keep astronauts’ muscles strong during spaceflight to prepare them for returning to Earth’s gravity, maintain terrestrial athletes’ muscles at top performance levels, and preserve the muscles of humans fighting muscle-wasting diseases.

The Bare Bones of Spaceflight

OBPR scientists are also studying how to minimize bone loss, another condition experienced by astronauts. Ted Bateman, a principal investigator and director of biomedical research at BioServe Space Technologies, a NASA-sponsored commercial space center, describes this effect: “When you remove gravitational loading, bones no longer sense the stresses and strains that are normally experienced here on Earth. As a result, astronauts are subjected to an accelerated rate of bone loss, losing between a half of 1 percent and 2 percent of their bone mass per month,” or 6 to 24 percent a year. By contrast, bone loss in women with Type I (hormone-related) osteoporosis, a condition characterized by a decrease in bone density and an increase in porosity and fragility, is 3 to 4 percent a year, and less in men and women with Type II (age-related) osteoporosis.

Bateman, who is based at the University of Colorado, Boulder, has been using mice in ground-based studies to learn what happens to bones in microgravity. He is partnering with Amgen Inc. to examine a potential countermeasure for the related bone loss. The mice are positioned in a ground-based procedure to mimic reduced gravity conditions in space and are treated with osteoprotegerin (OPG), a naturally occurring protein that is a potent regulator of bone metabolism. OPG is being developed by BioServe’s commercial partner, Amgen, as a pharmaceutical drug and is currently undergoing clinical trials with the Food and Drug Administration. In his ground-based studies, Bateman found that OPG maintained the mechanical strength of bones in mice in simulated microgravity when they were treated with levels of OPG equal to that of a mouse in normal gravity.

OPG could be an effective countermeasure to bone loss experienced by astronauts and by patients with osteoporosis.

Now Bateman is examining the osteoporosis that mice experience in actual microgravity and whether OPG can minimize or even prevent this bone loss. In December 2001, the flight-based portion of the BioServe/Amgen research went to orbit as a space shuttle experiment on STS-108. For this experiment, Bateman and Paul Kostenuik, the Amgen principal investigator, injected 12 mice with OPG, and another 12 mice with a placebo. OPG binds with another protein in the body, OPG-ligand. By doing so, OPG prevents osteoclasts (bone absorbing cells) from removing too much of the bone that osteoblasts (bone-forming cells) are producing. A proper balance between osteoclasts and osteoblasts is fundamental to development and maintenance of bone health. Extra osteoblast activity in children allows for bones to grow, while after maturity, approximately equal activity of the two cell types keep bone formation and absorption in balance. Bateman explains the importance of this function: “With astronauts, it is pretty clear that microgravity uncouples bone formation and bone resorption, so there exists an inhibition of bone formation. But most of the loss in bone mass is going to come from an increase in bone resorption.” Finding an effective countermeasure to this increased resorption could help astronauts maintain their bone density and strength while they’re in space.

An OPG treatment also could potentially help people on Earth with osteoporosis. According to the National Osteoporosis Foundation, 10 million people in the United States have been diagnosed with this disease, with another 18 million Americans at risk with low bone density. Eighty percent of patients with osteoporosis are women. Osteoporosis is responsible for more than 1.5 million fractures every year. Bateman describes the seriousness of the condition: “Osteoporosis is a disease without symptoms. You don’t have any indication that you have it until you get a bone density scan or until you get fractures. People in their 60s or 70s could be out playing golf, playing tennis, or walking several miles a day, and suddenly get a hip fracture or a vertebral fracture, and become bedridden.” Bateman hopes the BioServe/Amgen research with mice will lead to an effective treatment for osteoporosis that could impact thousands of lives, both in space and on Earth.

Learning the Basics of “Moon Face”

Another study that could help astronauts is the work of John Tarbell, of Pennsylvania State University. Tarbell is using a cell culture model to find the cause of and countermeasures for “Moon face,” a shift of fluids to the upper body, creating a rounder, fuller face.

Astronauts experience a cold-like sinus and nasal stuffiness and a rounder, fuller face called “Moon face”(right) when the barrier that normally prevents fluids from passing from blood vessels into surrounding tissues on Earth becomes ineffective in microgravity.

Looking to cells for answers to some of the mysteries of how spaceflight affects the bodies is not such an unusual research move. Kathie L. Olsen, OBPR acting associate administrator, explains, “In terms of understanding human physiology, you can look at the human on down [to a subcellular level], but you can also be reductionistic – [start at the smallest level] and come up.” Scientists like Tarbell in the microgravity fluid physics discipline are working at the cellular level. Fluid physics discipline scientist Bhim Singh, of Glenn Research Center, explains the importance of research at this level: “While a great deal of progress has been made in understanding the changes in human physiology caused by microgravity, and some effective countermeasures have been developed, little is really understood about the fundamental mechanisms responsible for the changes. Understanding fluid physics and transport at the cellular level in the microgravity environment will be crucial to identifying the factors responsible for creating adverse physiological problems.”

Tarbell is learning the causes of Moon face by studying the endothelial cell layer, which lines blood vessels from the aorta to the capillaries. These cells provide the principal barrier to transvascular transport, the passing of water and solutes between blood and underlying tissue. On Earth, these cells are continuously exposed to the mechanical shearing force and the pressure imposed by blood flowing over their surfaces, and they are adapted to this environment. When the cardio-vascular system is placed in microgravity, which affects fluid flow, pressure in the blood vessels changes, and the shearing force is eventually reduced, which increases the endothelial cell layer’s hydraulic conductivity, or its ability to transport water and solute, making the layer much less effective as a barrier. Tarbell proposes that this situation allows transvascular transport, causing the fluid shift that occurs in humans in microgravity.

In ground-based research using a tissue culture model of the endothelial transport barrier, he has shown that a sudden increase in vascular pressure, which occurs in the face in microgravity, induces an early adaptive response. The endothelial layer’s resistance to the flow of water from the blood into the tissue space increases for about an hour after the pressure increases. This natural control mechanism tends to limit facial swelling. The ground-based experiments further demonstrate that after an hour of altered pressure, the resistance begins to drop substantially, leading to a condition in which there is excessive leakage of fluid from the blood to the tissue. This loss of control of transvascular transport exacerbates facial swelling.

Tarbell is studying the biomolecular mechanisms that mediate the response of the endothelial transport barrier to changes in pressure. His group has found that the loss of resistance to fluid transport from blood to tissue can be blocked completely by inhibiting the formation of nitric oxide (NO) using pharmacologic agents. Findings in Tarbell’s research related to NO tie in to studies by other OBPR scientists in biomedicine and fundamental space biology who are studying how NO affects other fluid-related conditions experienced by astronauts such as bone blood flow, orthostatic intolerance (lightheadedness upon standing or sitting up), cardiac atrophy, and circadian rhythms (natural sleep patterns).

Tarbell also has found that the loss of resistance can be reversed by elevating intracellular levels of cAMP (cyclic adenosine monophosphate), a signaling molecule that affects the hydraulic conductivity of endothelial cells. As a consequence, fluid volume shifts, affecting astronauts. Tarbell says, “The results suggest a variety of possible approaches for pharmacologic intervention to regulate hydraulic activity of endothelial cells in microgravity,” thereby reducing the degree of “Moon face” and other fluid-related conditions experienced by astronauts.

On Earth, Tarbell’s research findings could provide insight into the importance of maintaining normal tissue homeostasis and knowledge about how its breakdown becomes critical in various diseases. These include atherosclerosis, a degenerative disease of arteries that underlies heart attacks and strokes; diabetic retinopathy, leakage of albumin into the retina; and when tissue is inflamed, the transvascular transport that leads to tissue edema (swelling).

Joint Research in Human Physiology

NASA is not the only federal agency interested in human physiology research, and NASA is benefiting from and contributing to what other organizations are learning. In fact, the space agency has 40 agreements to conduct joint studies regarding various aspects of human health and well-being with other federal agencies and organizations. Here are just a few:

• American College of Sports Medicine: musculoskeletal and exercise physiology research
• American Federation for Aging: the aging process
• Centers for Disease Control and Prevention: remote sensing technology in the areas of infectious disease surveillance, control, and prevention
• Department of Defense: mechanisms associated with blood volume and pressure regulation
• Department of Energy: radiation research
• Food and Drug Administration: diabetes research
• Juvenile Diabetes Foundation: research on the treatment of juvenile diabetes
• National Institutes of Health: a wide range of topics, from sensory motor functions, to application of robotics to neuromuscular adaptations, to spinal cord injury, to laser light scattering for early detection of cataracts; to basic understanding of vestibular functions.
• National Osteoporosis Foundation: educational outreach regarding osteoporosis
• National Science Foundation: basic research on psychological factors linked to spaceflight

Related Reading

For more information on Tarbell’s research, see:

• Tarbell, J. M., Demaio, L., & Zaw, M. M. (1999). Effect of pressure on hydraulic conductivity of endothelial monolayers: The role of endothelial cleft shear stress. Journal of Applied Physiology, 87, 261-268
• Tarbell Faculty Web page: http://fenske.che.psu.edu/Faculty/Tarbell/BTDL/rsch.html

For more information on Bateman’s research, see:

• Bateman, T. A., Dunstan, C. R., Ferguson, V. L., Lacey, D. L., Ayers, R. A., Simske, S. J. (2000). Osteoprotegerin mitigates tail suspension-induced osteopenia. Bone, 26, 443-449
• Bateman, T. A., Dunstan, C. R., Ferguson, V. L., Lacey, D. L., Ayers, R. A., Simske, S. J. (2001). Osteoprotegerin ameliorates sciatic nerve crush induced bone loss. Journal of Orthopaedic Research, 19, 518-523
• BioServe Research, including Bateman’s research on bone growth: http://www.colorado.edu/engineering/BioServe/research.html

For more information on Baldwin’s research, see:

• Adams, G. R., McCue, S. A., Bodell, P. W., Zeng, M., and Baldwin, K. M. (2000). The effects of spaceflight on rat hindlimb development I: Muscle mass and IGF-1 expression. Journal of Applied Physiology, 88, 894-903
• Adams, G., Haddad, F., McCue, S. A., Bodell, P. W., Zeng, M., Qin, L., Qin, A. X., and Baldwin, K. M (2000). The effects of spaceflight and thyroid deficiency on rat hindlimb development II: Expression of myosin heavy chain isoforms. Journal of Applied Physiology, 88, 904-916

For more information on research conducted by Hagan and other scientists at the Exercise Physiology Laboratory at Johnson Space Center, visit the laboratory’s web site:

• http://www.jsc.nasa.gov/sa/sd/sd3/exl/