J Appl Physiol
89: 1224–1231, 2000.
highlighted topics
Physiology of a Microgravity Environment
Invited Review: Gravitational biology of the neuromotor
systems: a perspective to the next era
V. REGGIE EDGERTON1,2,3 AND ROLAND R. ROY1
Brain Research Institute, 2Department of Physiological Science and 3Department of Neurobiology,
University of California, Los Angeles, California 90095
1
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Edgerton, V. Reggie, and Roland R. Roy. Invited Review: Gravitational biology of the neuromotor systems: a perspective to the next era.
J Appl Physiol 89: 1224–1231, 2000.—Earth’s gravity has had a significant impact on the designs of the neuromotor systems that have evolved.
Early indications are that gravity also plays a key role in the ontogenesis of
some of these design features. The purpose of the present review is not to
assess and interpret a body of knowledge in the usual sense of a review but
to look ahead, given some of the general concepts that have evolved and
observations made to date, which can guide our future approach to gravitational biology. We are now approaching an era in gravitational biology
during which well-controlled experiments can be conducted for sustained
periods in a microgravity environment. Thus it is now possible to study in
greater detail the role of gravity in phylogenesis and ontogenesis. Experiments can range from those conducted on the simplest levels of organization
of the components that comprise the neuromotor system to those conducted
on the whole organism. Generally, the impact of Earth’s gravitational
environment on living systems becomes more complex as the level of
integration of the biological phenomenon of interest increases. Studies of
the effects of gravitational vectors on neuromotor systems have and should
continue to provide unique insight into these mechanisms that control and
maintain neural control systems designed to function in Earth’s gravitational environment. A number of examples are given of how a gravitational
biology perspective can lead to a clearer understanding of neuromotor
disorders. Furthermore, the technologies developed for spaceflight studies
have contributed and should continue to contribute to studies of motor
dysfunctions, such as spinal cord injury and stroke. Disorders associated
with energy support and delivery systems and how these functions are
altered by sedentary life styles at 1 G and by space travel in a microgravity
environment are also discussed.
space biology; ontogenesis; phylogenesis; motor control
WITH MINIMAL ACCESS TO MICROGRAVITY,
considerable insight has been gained about how gravitational environments can affect biological systems (e.g., Refs. 9, 10, 13,
15, 16, 21, 38, and 51). During the previous four decades, numerous observations have directed which
gravitational biology questions should, and now can, be
Address for reprint requests and other correspondence: V. R.
Edgerton, Univ. of California, Los Angeles, Dept. of Physiological
Science, 1804 Life Sciences, 621 Charles E. Young Drive South, Los
Angeles, CA 90095–1527 (E-mail: [email protected]).
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studied carefully. The purpose of this “review” is to give
a perspective on future opportunities to explore the
role of Earth’s gravitational environment in shaping
biological systems, given the history of access and
opportunities for scientists to study these issues to
date. Can we use our past experiences effectively to
look to the future? Although the opportunities for
studying basic gravitational biology questions within
the next decade will continue to be limited to lower
orbits of Earth and to those models of simulated microgravity that we can generate on Earth, we should
8750-7587/00 $5.00 Copyright © 2000 the American Physiological Society
http://www.jap.org
INVITED REVIEW
WHAT ARE THE GRAVITY-SENSING MECHANISMS AND
HOW ARE THESE SENSING MECHANISMS USED TO
CONTROL BASIC PHYSIOLOGICAL SYSTEMS?
Are there neural receptors that have evolved that
specifically detect gravity-related events? Perhaps
there are no gravity receptors per se. Gravity is detected via many types of sensory receptors that project
a sense of acceleration and/or gravitational loading (14,
28, 32, 43–45). In many cases, it seems likely that this
sensation of a gravitational force or load is derived
from multiple receptors. The presence of different combinations and types of input from different combinations of receptors enables motor control systems to
accommodate and to readily respond to gravitational
forces. We propose that ensembles of multiple modes
and sources of sensory information generate the per-
ceptions associated with gravitational forces, i.e., loading on the body. We also suggest that many of these
ensembles are “perceived” and responded to by neurons
located in the spinal cord, which can, in turn, execute
fine and detailed adjustments in posture and locomotion. There are many examples of the highly integrated
sensorimotor responses that accommodate gravitational forces, many of which are “automatic” (14, 17,
19, 20). In a sense, this means that the solution to
many of the details of basic motor responses that sustain upright posture and locomotion have been resolved in the process of “natural selection” of neural
networks designed to function in a 1-G environment.
The extent to which gravitational vectors have shaped
these biological systems can be quantitatively assessed
at levels ranging from gene selection to the behavior of
an organism, given a permanence to microgravity accessibility and that some clever animal models can
lend themselves to this type of experimentation.
The magnitude and kind of impact that gravitational
forces have on a biological system are dependent, in
part, on the level of physiological integration of the
phenomenon being studied. There is little reason to
believe that there would be a direct effect of gravity on
the myosin molecule, but there are clear effects of
gravity on the myosin molecule, presumably because of
its effects on the whole organism and its neuromotor
and endocrine systems (16, 48, 47). For example, the
direct mechanical effect of gravity on eye position is
minimal. However, the neural control of eye position is
highly sensitive to the removal of gravitational loads
on the whole body (12, 13). The disruption of eye
control after exposure to microgravity is not surprising, given that the neural control of the eyes evolved in
a 1-G environment and the coordination of the eyes
must be synchronized with the sensory and motor
commands of the whole body. The eyes cannot be controlled effectively independently of head and body position, and the neural control of the head and body
position must be and is highly dependent on gravity.
This high level of interdependence of control among all
motor systems has evolved with a neural control system designed to function with the gravitational force
vectors on Earth’s surface.
HOW HAS GRAVITY BEEN ACCOMMODATED IN THE
EVOLUTION OF THE PHYSIOLOGY AND ANATOMY
OF MOTOR SYSTEMS?
Our ability to understand how Earth’s gravitational
environment has shaped the evolution of neuromotor
systems can give us a clearer understanding of the
fundamental mechanisms of the control of movement.
The ventral-dorsal asymmetry of the neural, muscular,
and skeletal systems and the orientation of this asymmetry with respect to Earth’s gravitational vectors are
evident throughout the animal kingdom. This gravityassociated asymmetry is evident in the biochemistry as
well as the anatomy and physiology of these systems.
Axonal guidance mechanisms have had to take into
account these gravitational vectors. How has gravity
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consider the next phase of exploration as being preparatory for interplanetary exploration. Access only to
lower-Earth orbit at this stage in our understanding of
the role of gravity in shaping the biology of animals,
however, should not limit the fundamental questions
that can be addressed.
In this brief review, we will present some questions
related to neuromotor systems that we consider to be
among the highest priority in gravitational biology
during this early transitional stage to a more permanent presence in space. We consider this transitional
stage, when more complete and sustained experiments
can be performed, as a new era in gravitational biology.
Although there have been numerous scientists for
many centuries that have conducted experiments in
gravitational biology, it has been only within the last
40 years that we have been able to study the responses
of neuromotor systems to relatively short periods of low
gravitational forces. There have been a few exceptions,
however, with the most notable being the presence of
humans for as long as 14 mo on the Mir space station.
These experiments during the era of the Russian space
stations have provided clear evidence of the capability
of humans to perform in a microgravity environment
for prolonged periods (22, 33–35, 40, 41). The almost
continuous presence of humans in microgravity using
biosatellites and space stations since the 1970s has
provided the confidence and the basic scientific groundwork related to the tolerance of the human body to the
space environment for a new generation of experiments. To date, several hundred humans have traveled
in the space environment. Despite this access and test
of tolerance of humans in space, however, these spacecrafts have limited experimentation to only a few species. Although a wide range of plant and animal species
have been exposed to microgravity, almost all of these
exposures have been for periods of less than 3 wk. In
addition, in all spacecrafts, there have been limited
opportunities to perform well-controlled experiments.
Basically, our experiences in space to date have whetted our scientific appetite for studying gravitational
biology and determining its importance in understanding the fundamentals of biological systems on Earth.
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INVITED REVIEW
clearly designed to function in a 1-G environment.
Thus one means of understanding how these control
mechanisms function can be to define how the gravitational environment has affected their evolution, their
ontogenetic development, and the routine accommodations of daily function when the acceleration vectors
are changing continuously.
TO WHAT EXTENT IS THE ONTOGENESIS OF THE
NEUROMOTOR SYSTEMS DEPENDENT ON A 1-G
ENVIRONMENT?
Studying the control of homeobox genes in the fruit
fly in response to various gravitational environments
could provide considerable insight into the role that
gravity plays in shaping the neuromotor systems during ontogenesis and in the adult (11). Studying the role
of gravitational forces on gene expression during development would seem to have many advantages,
given the extensive amount of information available on
the genome of the fruit fly. Experiments could be performed on the space station on fruit flies to determine
levels and patterns of imposed gravitational forces
during development and the consequential changes in
gene expression over a large number of generations,
thus providing opportunities for observing the selection of specific phenotypes.
Many studies in the biological literature address the
issue of whether there are critical periods for exposure
to a given type of sensory input for normal development to occur. Is there a critical period for the neuromotor system, or some component of the system, to be
exposed to gravitational loading as has been suggested
(42, 50)? If this is the case, what are the physiological
and biochemical mechanisms by which gravitational
factors influence a particular gene and which gene is
involved and in which cell, tissue, or organ? In the
upcoming era during which sustained presence in
space will be likely, facilities that can accommodate a
variety of animals, including humans, would be invaluable for studying the effects of gravitational factors on
development. Centrifuges, which can generate a range
of gravitational forces for weeks or even months, combined with the ability to control breeding cycles allow
us to define critical periods for a given level of gravity.
Understanding the role of gravitational factors during
ontogenesis and phylogenesis will help us to understand how to design solutions to accommodate the
detrimental effects of a range of neural degenerative
diseases on posture and locomotion.
TO WHAT EXTENT ARE THE PROBLEMS OF MANY
DEGENERATIVE DISEASES, ASSOCIATED WITH THE
SEDENTARY NATURE OF MOST OF OUR POPULATION,
A PRODUCT OF THE DESIGN OF OUR SYSTEMS TO
ACCOMMODATE A 1-G ENVIRONMENT?
At 0 G, it seems apparent that the metabolic demands associated with neuromuscular work are less
than those for which the neuromotor systems were
designed. It is obvious that many disease processes are
likely to emerge as a result of malfunctions of the
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biased the evolution of these directional cues? How
does the ontogenetic development of the neural control
of the motor systems depend on Earth’s gravitational
vector?
The morphology and physiology of all motor systems
have evolved such that the repertoire of movement
paradigms enabled survival by accommodating gravity. For examples, the neuromotor systems of birds are
designed to accommodate flight, whereas those of amphibians are designed to accommodate both terrestrial
and aquatic environments (26).
Gravity has played a fundamental role in defining
the biological properties of the organism in large part
based on the physical properties of the environment.
This was clearly illustrated when Japanese quails attempted to fly without Earth’s gravitational forces in
the Mir space station but were unable to control their
direction of flight. Among the many animal species on
Earth, there are numerous examples of the asymmetry
within the muscular system with respect to the direction and level of forces that must be accommodated to
maintain mobility and for adequate escape and reproductive movement repertoires.
It also is important to understand how the energysupporting systems are designed to sustain motor performance in a 1-G environment compared with a microgravity environment (7, 8). The intricate regulation
and integration of the neural control of the muscles
that perform the work must also be effective so that
adequate metabolic substrates and oxygen are distributed to the most active muscle fibers, which rely primarily on oxidative metabolism. Blood distribution
must be controlled with respect to gravity during motor
and postural tasks. Muscle fibers that are recruited
most often and that work directly against gravitational
forces must have a high capacity for sustaining oxidative phosphorylation so that high-energy phosphates
can be generated. The type and availability of substrates must be matched with the organism’s physiology, which, in turn, must be compatible with the organism’s behavior.
Therefore, neural control of the distribution of blood
in varying gravitational environments must be correlated with neural control of skeletal muscles. A classic
example of this coordination is the orthostatic response
to standing from a supine position. It is well documented that, even after short periods of microgravity
or bed rest, a sudden rise to an upright position can
result in an episode of orthostatic intolerance, i.e.,
fainting (10, 51). This could be viewed as a functional
deficiency following spaceflight. However, one can argue that this response helps to maintain adequate
blood flow to the head by assuring that the person does
not remain in an upright position when there is a
critical cardiovascular challenge that limits blood flow
to the brain. In this case, neural mechanisms of the
cardiovascular system take complete control of the
motor systems by rapidly inhibiting those skeletal
muscles that maintain an individual in an upright
position. There are numerous examples of these kinds
of highly integrated control mechanisms that are
INVITED REVIEW
USING MICROGRAVITY AS A TEST BED FOR
DEVELOPING TECHNOLOGIES NEEDED TO STUDY
INTEGRATED PHYSIOLOGICAL SYSTEMS
History has told us repeatedly that incremental advances in technology lead the way to incremental advances in biology. As devices are developed that enable
us to assess smaller and smaller components of a
biological system, to manage more massive amounts of
data within acceptable time periods, and to measure
many physiological properties without interfering with
the basic physiology of the system, our understanding
of basic biological processes will continue to improve.
There are likely to be many examples, as has occurred
in the past, of technological developments that could
considerably improve the kind of experiments that
could be performed in laboratories on Earth (18). There
is little question that technologies developed to perform sound, thorough, and comprehensive experiments
in space will also have considerable use in similar
studies performed on Earth. For example, satellite
technology gives us the ability to continuously track
the location of animals during migration and can help
us understand how to manage our biological resources.
A biological device implanted in muscles and tendons
was developed for recording electrical and mechanical
events for months (46). This device was developed by a
joint effort among National Aeronautics and Space
Administration (NASA), the Russian Space Agency,
and private industry. Presently, it is being used to
develop clinical strategies to improve the recovery of
locomotion following spinal cord injury. There are
many examples of such spin-offs from the spaceflight
programs; the general public and the scientific community are unaware of many of these. However, these
developments, which are designed to study the responses of the physiology of normal systems to gravity,
provide a test bed for technologies for studying normal
and diseased systems on Earth. There are some obvious areas of technical development that could benefit
from gravitational biology and also have immediate
effects on clinical science.
To conduct many of the experiments that are likely
to be selected for the space station, techniques for
handling extremely large and complex sets of data will
be needed. These larger than usual data sets are a
reflection of the integrative nature of many of the
experiments. To perform the highly integrative experiments, the ability to measure multiple physiological
responses is required, often at a high rate of data
sampling. Also, many of the experiments are likely to
require that multiple physiological measurements be
recorded when subjects are largely unencumbered, i.e.,
not attached to large recording devices or otherwise
restricted in their normal functions. Some of these
recording devices, such as telemetered signal recorders, are being developed or are at least on the “drawing
board” for future spaceflight experiments. Although,
theoretically, there is the technical capability of recording complex databases under some restricted conditions, this capability has not developed adequately so
that reliable experiments can be performed in space
with a reasonable probability of success. Further development is needed in miniaturizing sensors and recording devices, in transmitting the data via telemetry,
and in storing massive amounts of data on the miniaturized devices. In addition, it will be important to
develop data analysis techniques that will enable investigators to select and easily retrieve those segments
of the data that will be most informative.
One of the most challenging problems is how to
record from organisms in vivo without interrupting the
normal function of the tissues, organ systems, or organisms. In addition, devices, in many cases, for this
purpose need to be durable for prolonged periods,
sometimes for at least months, and during activities
that can be rather robust mechanically. At the same
time, the advantage of these sensing and transmitting
devices being placed subcutaneously and without
transcutaneous connectivity between implants and recording devices will greatly improve the likelihood of
success of the experiment from all perspectives. For
example, electromyographic activity could be recorded
from multiple muscle groups in multiple limbs while
the subject performs a motor task. In animal experi-
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support systems essential for maintaining homeostasis, e.g., the cardiovascular and metabolic support systems. These systems were designed by evolutionary
processes to accommodate organisms within a range of
neuromuscular activities, many of which are atypical
of those occurring in our highly developed and physically inactive societies. The human genome evolved in
a 1-G environment, which imposes a remarkably predictable amount of muscular work and includes a strategy to replace the amount and kind of substrates used
in the cells that do the work. We seem to have failed to
recognize the importance that the 1-G environment
has had in shaping the integrative functions of the
genome (4). Understanding the responses of the normal biological systems to microgravity may help considerably in developing strategies to overcome the
plethora of biological disorders associated with extremely sedentary lifestyles.
It will also be important to understand these adaptive strategies to microgravity in preparation for long
interplanetary voyages. Almost all biological disorders
in humans quickly become complicated by their subsequent effects on neuromuscular activity levels and mobility. Spaceflight provides an excellent environment to
study how all physiological systems accommodate the
reduced muscular demands. For example, arthritisinduced pain leads to a reduced motivation to move,
which leads to reduced muscle function, which leads to
disrupted metabolic priorities, which can lead to diabetic and cardiovascular dysfunction. This same chain
of events can be associated with many neuromotor
disorders, such as spinal cord injury and stroke. As
suggested by Booth et al. (4), there seems to be a high
incidence of this scenario, which is initiated by a conscious choice for a sedentary lifestyle rather than some
disease process.
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A PERSPECTIVE OF GRAVITATIONAL BIOLOGY ISSUES
IN MOTOR CONTROL SYSTEMS
Microgravity can and should be used as a test bed for
understanding the normal physiology of highly integrated physiological systems. There are many advantages to studying some physiological processes from
the perspective of a gravitational biologist. Although
the fundamental concept that all organisms on Earth
evolved in a 1-G environment is self-evident, awareness of the importance of this concept remains obscure
at best. In a recent review by Booth et al. (4), an
insightful case was made for the fact that our society
has an epidemic of diseases associated with lack of
physical activity. Human biology and its genome have
evolved in environments in which physical activity has
been an integral component. The environment has and
will continue to play a role in selecting those gene pools
that characterize humans. It is generally recognized
that some physical activity is necessary to maintain
normal homeostatic mechanisms. Associated with this
physical activity is the performance of work, much of
which is performed against gravitational loads. In fact,
a means of characterizing a type of physical activity is
often considered to be its rate of work.
In the muscular system, the intensity of the exercise
is defined by the proportion of muscle fibers activated
in a muscle and by the number of muscles that contribute to the exercise. A resistive exercise paradigm often
involves the movement of a mass against gravity. More
muscle fibers must be activated (recruited) to move a
larger mass against gravity. The metabolic consequence of the work is defined largely by the evolutionary-driven design features of the neuromotor system.
The types of muscle fibers and the number of muscle
fibers that must be activated to accomplish the work
define the metabolic impact of the work. In turn, the
types and number of muscle fibers that are recruited is
defined largely by how the motoneurons within the
spinal cord are connected to the muscle fibers. When
one begins a movement, those motor units that are
most likely to be recruited are those that innervate
muscle fibers that have slow myosin, a high oxidative
capacity, relatively little glycogen, and high vascularity. Consequently, these fibers can perform work at a
relatively continuous but slow rate for long periods
without undue fatigue. In addition, these fibers can
perform continuous work with relatively little disruption of the metabolic homeostatic state. In contrast,
when high work rates are necessary for a short period,
the nervous system is designed to recruit more motor
units. The metabolic impact of recruiting more motor
units is not simply linear. The muscle fibers innervated
by motoneurons activated at high work loads have a
relatively low capacity to generate ATP via oxidative
phosphorylation. They also have a high capacity to
generate ATP via glycolysis (but only for brief periods)
and have a relatively low vascularity. Therefore, when
these fibers are recruited, the metabolic impact is substantial because the rate of ATP utilization is much
more rapid than the ability of those muscle fibers to
replace ATP. As a result, a high level of acidosis can be
reached very quickly when performing at 1 G. On the
other hand, the ability to drive the neuromotor system
to the point of severe disruption of metabolic homeostasis has an important survival function. The ability to
perform powerful, and metabolically demanding,
movements enables an animal to escape rapidly, but
these movements are not for long periods.
The highly integrative aspects of the nervous system, the muscles that perform the work, and the supportive cardiovascular and metabolic systems reflect
biological features that can accommodate gravitational
loads. This accommodation is evident in the motor unit
and muscle fiber type composition of muscles that
function principally in an antigravity mode, i.e., support the body against gravity (5). For example, a high
proportion of slow-twitch muscle fibers having a high
oxidative capacity as noted above is found in primary
extensor muscles of almost all mammals, including
humans. These muscle fibers seem to be specifically
designed to maintain an upright posture throughout
the day while imposing minimal metabolic stress. In
contrast, muscles that perform primarily flexor functions have a relatively high proportion of fast and more
fatigable fibers, reflecting the non-antigravity functions of these muscles. Let us suppose that our motor,
and the necessary support, systems evolved in a microgravity environment. It seems highly unlikely that the
asymmetry in the types of muscle fibers observed
among muscles evolved at 1 G would exist in biological
systems evolved in a microgravity environment. It is
interesting to hypothesize how the neuromotor systems of terrestrial animals would evolve in a gravitational environment equivalent to that of the moon.
The contrasting activation patterns of flexor and
extensor muscles in response to gravitational vectors
are as striking as the intricate design of the recruit-
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ments, it also could include the recording of forces and
displacements generated by and within multiple muscles as well as the kinematic events associated with the
limb segments. Other types of experiments involving
performance of some motor task also could require
simultaneous recordings of combinations of cardiovascular and pulmonary functions. On another scale,
there are remarkable advances in “nano” technology,
which could provide a way of measuring intercellular
and intracellular mechanical and chemical events in
vivo. These types of devices, if developed for biological
applications, would enable scientists to ask new questions related to biological mechanisms of control at the
subcellular level.
In general, many biological experiments would be
greatly improved in microgravity as well as on Earth if
more details about the physiological and environmental milieux were known. As noted above, there is considerable technical capability that would allow one to
perform the experiments as thoroughly as needed;
however, this technology may not be ready to be applied reliably in in vivo experiments performed in
space.
INVITED REVIEW
SIGNALING PATHWAYS
In a recent review, Baldwin (2) discussed research
issues in muscles and the importance of identifying
signaling pathways. However, in that case, the signaling is at the molecular not the systems level. Although
the level and pattern of neuromuscular activity determines either directly or indirectly many of the properties of all organ systems, the details of these activity
patterns have been largely undefined. To determine
the mechanisms of gravity-induced adaptations, it will
be imperative to determine with considerable precision
the properties of the activation processes themselves.
We must carefully characterize and quantify which
and how often individual muscles or muscle groups are
activated and at what level of intensity these muscles
must be activated to perform a given type of movement
in a given gravitational environment. It is remarkable
that we have such a vague understanding of what the
neuromuscular systems actually do during routine
daily activities. Not knowing these normal baseline
activity levels precludes us from making any clear
conclusions regarding the role of neuromuscular activity in maintaining homeostasis in an animal in which
the activity levels have been perturbed, for example,
during spaceflight. Unfortunately, in almost all studies
related to how biological systems respond to changes in
activity-associated events, the control condition itself
is poorly defined (4). For example, what are the normal
and/or optimal activity patterns during the course of a
day and night? Clearly, the level of activity varies
widely across muscles, some being orders of magnitude
higher than others (1, 31). To what extent does the
pattern and amount of activity define the properties of
a cell, an organ system, and an organism itself? What
are the dose-response features at each of these levels of
integration?
It would be extremely helpful to understand these
system-level neuromuscular activity patterns (loading
and activation), which are essentially the initiation of
all of the signaling pathways that control the expression levels of each protein. Efforts to identify those
system-level signaling pathways for the induction of
muscle fiber atrophy or hypertrophy must be accompanied by a similar level of detailed understanding of the
molecular events in muscles as noted in recent reviews
by Baldwin (2) and Carson and Wei (6). Are there
unique neuromuscular activity patterns of muscle fibers of extensor compared with flexor muscles that can
explain their greater sensitivity to microgravity, particularly of the extensors comprised predominantly of
slow-twitch muscle fibers (16, 47, 48)? Or are these
different responses to some combination of cellular
events because of a difference in the sensitivity of a
given gene in the muscle fibers of the extensor compared with flexor muscles? Is the response actually due
to the mechanical events (loading) imposed by the
activation or some combination of these factors? What
roles do nerve growth factors play in shaping the responses of genes in the myonuclei of specific types of
muscle fibers? To what extent does the responsiveness
of a combination of genes reflect the “state dependence”
relative to the normal neuromuscular activity patterns
of the muscle fibers?
Let us take this last question as an example. We will
describe a series of experiments that demonstrate a
state dependence of a complex neural pathway that can
regulate the release of a growth factor from the pituitary gland. In collaboration with Dr. Richard Grindeland at NASA Ames Research Center, we have performed a series of experiments that demonstrate that
the release of a growth factor from the pituitary can be
regulated by afferent input from the skeletal musculature. This growth factor is identified by its growthenhancing effect on the epiphyseal growth plate of the
tibial bone of hypophysectomized rats (25). We have
found that short bouts of treadmill exercise in rats or in
humans will induce the release of this growth factor,
which we call bioassayable growth hormone or BGH
(unpublished observations; Ref. 3). We also have found
that stimulation of low-threshold afferents from predominantly fast-twitch skeletal muscles in rats can
excite the release of BGH from the pituitary (24). In
fact, it appears that these afferents are from muscle
spindles that project to the spinal cord (23). Does this
regulatory mechanism assume some background level
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ment of motor units and their metabolic properties. In
an animal that has no supraspinal control of the lower
limbs, exertion of pressure on the bottom of the foot
induces an extensor thrust sufficient to support the
weight of the body at 1 G (27). To support the body
against gravity, there is a predominant activation of
extensors, whereas the flexors are inhibited. This response is obviously built into the neural networks
within the spinal cord, and this design clearly accommodates the level and direction of gravity that has
been present throughout evolution. This response reflects a highly integrated circuit of multiple sensors
located throughout the muscles, tendons, and joints,
with the activation of these receptors projected to specific combinations of flexor and extensor motor pools
and those interneurons that control these motor pools.
Many neuromotor behaviors reflect the detailed
properties of neuromotor pathways that are designed
with gravity dependence. The legs of a complete, lowthoracic spinal animal, when observed stepping on a
treadmill belt, can respond to a disruption (“tripping”)
in the forward swing by lifting the “tripped” ipsilateral
leg and enhancing extensor activation contralaterally,
thus enabling the animal to continue stepping uninterrupted (20, 30, 39). This type of functional capability
must reflect a gravity-dependent strategy; this “automatic” response to anticipated loads would have little
utility in a microgravity environment. Changes in the
relative activation of flexor and extensor motor pools
during normal treadmill stepping occurs in the rhesus
monkey after 2 wk of spaceflight compared with preflight (29, 46, 49). These data indicate that the relative
bias in the recruitment of extensor vs. flexor motor
pools is shaped to some degree by the continuous effect
of gravity.
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of neuromuscular activity to function normally and in
effect define its “state dependence”? We have found
that the release of BGH depends on sustaining at least
an ambulatory level of neuromuscular activity. For
example, the same amount of exercise that induces a
robust release of BGH when the subject is in an ambulatory state will have no effect when the subject has
been confined to bed or has been in a microgravity
environment for more than a few days (36, 37). When
normal ambulatory activity is initiated and maintained for a few days after bed rest or spaceflight, the
normal exercise-induced release of BGH occurs. This is
a remarkably clear example of how our physiology has
a shifting dose-response curve that is affected by the
level of activation and/or loading pattern.
POLICY ISSUES THAT MUST BE ADDRESSED TO
SUSTAIN A PRODUCTIVE RESEARCH PROGRAM
IN GRAVITATIONAL BIOLOGY
We express our sincere thanks to Inessa Koslovskaya from the
Institute of Biomedical Problems in Moscow for insight into the
function of the neuromotor systems in microgravity. We also thank
all of our collaborators on these multiple projects.
These studies were supported, in part, by National Institute of
Neurological Disorders and Stroke Grant NS-16333; NASA Grants
NAG-2–717, NAG-2–438 and NAG-9–970; the Christopher Reeves
Paralysis Foundation; and the Kent Waldrep National Paralysis
Foundation.
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To be successful in this next generation of studies,
sustained access to microgravity must be provided. In
the near future, it appears that a facility will be available for the first time to conduct carefully designed
studies using a variety of biological systems under far
more controllable conditions than previously possible.
Up to now, we have had to rely predominantly on
launching experiments for short periods of time and on
performing them in compromised conditions imposed
by limitations in resources. The resource limitation has
often been the availability of time for the crew members to train for and conduct experiments and the
necessity of sharing equipment and facilities, which
often compromises the integrity of the individual experiments. Given the limited resources for studying
biological systems in space over the last four decades, it
is apparent that clear scientific objectives need to be
formulated and followed in the next era. Furthermore,
the experiments must be supported at a level that will
permit their execution with the care and thoroughness
necessary to answer the questions of the highest priority by experts in the field.
Only under these conditions can there be a robust
and sequential experimental approach during the next
era of the International Space Station. In using this
international facility, there must be an effective and
clear mechanism for selecting the most important experiments proposed by scientists throughout the world.
This will be a very difficult, but essential, task.
Given the level of funding that is likely to be available, it is unlikely that a rigorous research objective
can be mounted in more than a few areas at best. Given
the likelihood that there will continue to be limited
funding, it will be necessary for visible progress to
occur in any given area. Without some focus of resources, any sense of progress and maintenance of a
productive research program will not be evident, even
if the science is of the highest quality. Evidence of
significant scientific progress from the public’s or scientific community’s perspective will be necessary to
sustain support. History indicates, however, that it is
not really a question of whether humans have the
resolve to explore space. The question is which generation will be able to take advantage of this resolve.
INVITED REVIEW
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