1 Department of Surgery, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, New Jersey 08084; and 2 Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610
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ABSTRACT |
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Human spaceflight is associated with a chronic
loss of protein from muscle. The objective of this study was to
determine whether changes in urinary hormone excretion could identify a
hormonal role for this loss. Urine samples were collected from the
crews of two Life Sciences Space Shuttle missions before and during spaceflight. Data are means ± SE with the number of subjects in parentheses. The first value is the mean preflight measurement, and the
second value is the mean inflight measurement. Adrenocorticotropic hormone (ACTH) [27.7 ± 4.4 (9) vs. 25.1 ± 3.4 (9)
ng/day], growth hormone [724 ± 251 (9) vs. 710 ± 206 (9) ng/day], insulin-like growth factor I [6.81 ± 0.62 vs. 6.04 ± 0.51 (8) nM/day], and C-peptide [44.9 ± 8.3 (9) vs. 50.7 ± 10.3 (9) µg/day] were unchanged with spaceflight. In contrast, free
3,5,3'-triiodothyronine [791 ± 159 (9) vs.
371 ± 41 (9) pg/day,
P < 0.05], prostaglandin
E2 (PGE2) [1,064 ± 391 (8) vs. 465 ± 146 (8) ng/day,
P < 0.05], and its metabolite
PGE-M [1,015 ± 98 (9) vs. 678 ± 105 (9) ng/day, P < 0.05] were decreased
inflight. The urinary excretion of most hormones returned
to their preflight levels during the postflight period, with the
exception of ACTH [47.5 ± 10.3 (9) ng/day],
PGE2 [1,433 ± 327 (8)
ng/day], PGF2,
[2,786 ± 313 (8) ng/day], and its metabolite PGF-M
[4,814 ± 402 (9) ng/day], which were all increased
compared with the preflight measurement
(P < 0.05). There was a trend for
urinary cortisol to be elevated inflight [55.3 ± 5.9 (9) vs.
72.5 ± 11.1 µg/day, P = 0.27] and postflight [82.7 ± 8.6 (8) µg/day,
P = 0.13]. The inflight human
data support ground-based in vitro work showing that prostaglandins
have a major role in modulating the changes in muscle protein content in response to tension or the lack thereof.
cortisol; shuttle; urinary hormone excretion
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INTRODUCTION |
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MICROGRAVITY PERTURBS the homeostasis of the body because of the loss of hydrostatic pressure, conflicting inputs into the neurovestibular system, and lack of physical tension on the musculoskeletal system. The fluid shifts and the neurovestibular disorientation generally resolve within the first day or two in microgravity, but the effects on the musculoskeletal system are chronic. Specifically, there is a continued loss of protein from muscles and calcium from bones with antigravity functions, particularly in the trunk and legs (12, 22, 37, 48).
In a previous report, we described the metabolic response to spaceflight by humans as consisting of two components, a fixed obligatory component and a variable component, depending on whether the astronauts were in energy balance. The latter is subject and mission dependent; the former is not (37). The obligatory response consists of an initial metabolic stress response combined with the chronic loss of protein from muscle and calcium from bone. The metabolic stress response diminishes within the first few days, whereas the bone and muscle losses continue (37). In this report, we describe the urinary hormone excretion profile during spaceflight on the shuttle. The objective of the study was to determine whether changes in the urinary hormone excretion could be used to identify a hormonal role in the obligatory losses of protein from muscle.
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MATERIALS AND METHODS |
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Informed consent for these studies was obtained in accordance with the procedures of the National Aeronautics and Space Administration and the University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine.
The shuttle data presented here are from two recent Life Sciences Missions (SLS1 and SLS2) that were flown in 1991 and 1993, respectively (36, 37). The SLS1 mission lasted 9.5 days and the SLS2 mission 15 days. Dietary intake and urine output were monitored for 10 days preflight, during the inflight period, and for 7 days postflight. Details of sample collection and nitrogen balance determination have been reported previously (37).
Biochemical analyses. Urine samples
were kept frozen until analyzed. After thawing, 24-h urine pools were
made by the fractional aliquot method. All hormonal analyses were done
in duplicate on the urine samples with commercially available reagents.
Enzyme-linked immunosorbent (ELISA) kits (Quantikine HS) for
interleukin (IL)-6 and IL-10 were obtained from R & D Systems
(Minneapolis, MN); kits for C-peptide, cortisol, adrenocorticotropic
hormone (ACTH), free 3,5,3'-triiodothyronine
(T3), and insulin-like growth
factor I (IGF-I) were purchased from Incstar (Stillwater, MN), and a human growth hormone (GH) Radioimmunoassay kit was purchased from Kallestad Diagnostics (Chaska, MN). The GH assay was specific for total
GH. Enzyme immunoassay (EIA) kits for prostaglandin E2
(PGE2), its metabolite
13,14-dihydro-15-keto-PGE2
(PGE-M), and PGF2 were obtained
from Cayman Chemicals (Ann Arbor MI). The reagents for the EIA assay of
PGF2
metabolite
13,14-dihydro-15-keto-PGF2
(PGF-M) were also purchased from Cayman Chemicals. The
epinephrine and norepinephrine data and some of the cortisol data were
supplied by National Aeronautics and Space Administration (NASA) as
part of the SLS1/2 investigators' data-sharing agreement. The cortisol analyses for the two subjects for whom values were not provided by NASA
were determined with an RIA kit from Incstar.
Statistical analyses. The database was divided into four periods, preflight, flight day 1 (FD1), flight days 2-12 (FD2-FD12), and the 7 postflight days (R0-R7). Because dietary intake was significantly reduced on FD1 (Ref. 37, Table 1), data for FD1 were evaluated separately from the other inflight days. Means were computed for each period, and a repeated-measures analysis of variance (RMANOVA) was performed with the SAS program (SAS Institute, Cary, NC). Significance was accepted at P < 0.05. If significance was found during the inflight period FD2-FD12, the period was further divided into flight days 2-7 (FD2-FD7) and flight days 8-12 (FD8-FD12) with the objective of determining whether the observed difference in the total inflight value was attributable to either the early or late inflight periods or both. Paired t-tests were used and significance was accepted at P < 0.05. Values in the text, tables, and figures are means ± SE, and the number of subjects is in parentheses.
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RESULTS |
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The data are given as the composite means of the SLS1 (n = 3) and SLS2 (n = 6) missions with inflight points beyond flight day 10 being from SLS2 only. The hormonal data have not been normalized to body weight because body weight and composition may change with spaceflight.
Table 1 summarizes the previously reported anthropometric and dietary data for these astronauts (37). On FD1 dietary intake was reduced by ~55% because of space motion sickness. After the first day, however, dietary intake was stable at ~80% of the preflight level for the remainder of the time in orbit (Table 1, Ref. 37). The nitrogen balance values are estimates because they are derived from urinary nitrogen alone and do not include fecal nitrogen losses. Nitrogen retention was decreased during the inflight period and returned to the preflight levels after landing (Table 1).
Table 2 summarizes the urinary excretion measurements, and the figures demonstrate how selected parameters changed with time in space. Entry into microgravity was associated with increases in IL-6 (P < 0.05), IL-10 (P < 0.05), and cortisol excretion (Fig. 1) and decreases in C-peptide (P < 0.05), norepinephrine (P < 0.05), GH (P < 0.05), and ACTH (P < 0.05, Table 2). The RMANOVA for cortisol approached but failed to achieve statistical significance (P = 0.0597). If it is accepted that this overall P value indicates significance, cortisol was increased on FD1 (P < 0.05). Urinary creatinine was reduced on FD1 (Table 1) possibly because of some incomplete collections in the period immediately after launch. Normalizing the FD1 data to creatinine renders the decreases in GH and ACTH no longer significant, but the increase in cortisol becomes significant.
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With the possible exception of cortisol, the urinary excretion of the hormones discussed above returned to preflight values and was unchanged for the remainder of time in orbit. There was a weak trend for cortisol to be elevated for the period FD2-FD12 (P = 0.27, Table 2, Fig. 1). In contrast, T3 (P < 0.05, Fig. 2), norepinephrine (P < 0.05, Table 2) (20), PGE2 (P = 0.05, Fig. 3), and PGE-M excretion (P < 0.05, Fig. 4) were all decreased inflight. The decreases in T3, norepinephrine, PGE2, and PGE-M excretion were statistically significant for both the early (FD2-FD7) and late (FD8-FD12) phases of the mission (Table 2).
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After landing, dietary intake and nitrogen balance returned to
preflight levels (Table 1) as did the urinary excretion of T3 (Fig. 2), norepinephrine,
PGE2 (Fig. 3), and PGE-M (Fig. 4). PGF2 (Fig.
5) and PGF-M (Fig.
6), which showed only weak trends toward
decreases inflight (P = 0.14 and
P = 0.13, respectively), were
significantly increased above their preflight values postflight (P = 0.02 and
P = 0.01).
PGE2
(P < 0.006) but not PGE-M excretion (P = 0.23) was also increased during
the postflight period. The trend for cortisol excretion to be elevated
persisted into the postflight measurement period (Fig. 1,
P = 0.12) and was paralleled by an
increase in ACTH excretion (Table 2,
P < 0.05).
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DISCUSSION |
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As with other spaceflight missions, the astronauts on SLS1 and SLS2 lost body protein (22, 37, 48). Details of the changes in nitrogen balance studies on these astronauts have been discussed in Ref. 37. The observations are in agreement with the report by LeBlanc et al. (22), who used dual-beam X-ray absorptiometry to document the loss of lower body and back muscle protein after shuttle flights. The astronauts on these missions also lost calcium from bone. Urinary calcium and deoxypyridinoline excretion were increased by 19 (P < 0.02) and 23% (P < 0.01), respectively, inflight (1).
The database. The studies reported here have relied on 24-h urinary excretion measurements to document the daily production of several hormones and inflammatory mediators. The use of urine instead of blood to assess total production has both disadvantages and advantages. The two principal disadvantages are as follows. 1) Urine-derived data could be affected by abnormal renal function. This is not a likely possibility because there is no evidence that renal function is generally altered by spaceflight (20). There was an early increase in the glomerular filtration rate on these missions, but these changes did not persist beyond the first week in orbit (20, 33). 2) Urinary measurements are further removed from the sites of synthesis and action of a hormone than plasma. However, neither urine nor plasma actually reflects the situation at the site of tissue production or action.
An advantage of urinary excretion measurements is that changes can sometimes be detected in urine when they cannot be detected in the plasma. This is because plasma samples represent single spot values, and plasma hormone levels can fluctuate very rapidly with time. In contrast, urine measurements give an integrated value over time, depending on the biological half-life of the molecule. This is particularly advantageous in situations where anticipated changes are small, when the hormone is released in a pulsatile manner, and when sampling opportunities are limited.
In analyzing the data, we have made two assumptions. First, as discussed above, urine excretion data are a valid measure of 24-h whole body production.
The second assumption is that the data are not complicated by an
inflight energy deficit. Actual energy balance data are not available
for any of these astronauts, but it is highly likely that they were
either in or close to energy balance. Energy expenditure as measured by
the doubly labeled water method for four subjects on a similar mission,
the 1996 Life and Microgravity Sciences mission (LMS), was 40.8 ± 0.6 kcal · kg1 · day
1
(39). Physical activity was greater on the LMS mission because there
were required exercise regimens. There was no mandatory exercising on
SLS1/2 because of time constraints (37). Energy expenditure on the LMS
mission was greater than the dietary intake of the subjects on SLS1/2
(40.8 ± 0.6 vs. 31.1 ± 1.8 kcal · kg
1 · day
1)
(37). The difference can be explained by the difference in activity
between the two missions.
There is considerable experimental evidence to suggest that energy expenditure is reduced during spaceflight. Energy expenditure was reduced during spaceflight on the LMS mission (39). Energy expenditure was also reduced by chair-adapted Rhesus monkeys flown as part of the U.S.-Russian Bion biosatellite program (37). A reduction in energy expenditure can account for the reduced urinary excretion of T3 found in this study (Fig. 2).
Catecholamines. Decreases in urinary norepinephrine secretion have been consistently documented in many spaceflight and bed rest studies (3, 11, 20, 21), and the same result was found in these two flights (20). The reduction in norepinephrine and the unchanged epinephrine excretion have been attributed to inhibition of sympathoneural outputs secondary to increased cardiac filling from the head-directed fluid shifts (11). Urinary catecholamine excretion was elevated on the day of reentry, and a trend toward an increase persisted for the remainder of the recovery period. The postflight catecholamine data are for the most part uninterpretable because of fluid loading with some of the subjects before landing and electrolyte replacement for other subjects after landing (20).
Insulin. Potentially, alterations in insulin production and responsiveness could be a major factor in the protein loss, because insulin resistance does occur in stress states, and we have previously shown that entry into orbit is associated with a metabolic stress response (37). The current data, however, show that no major changes were found with insulin production. There was a small increase in C-peptide excretion with time in orbit (37), but the changes were modest compared with some of the other hormones.
Cortisol and the hypothalamic-pituitary-adrenal axis. With the exception of cortisol, which was increased on FD1 and marginally increased during spaceflight (P = 0.27), spaceflight had little discernible effect on the urinary excretion of the hypothalamic-pituitary-adrenal (HPA) axis hormones. The urinary GH findings agree with the analyses on blood samples collected during the Skylab missions by Leach et al. (20). On Skylab, GH was unchanged except for a transient increase on flight days 3 and 4 (20). The absence of a decrease in GH inflight is paralleled by the absence of any increase during the postflight period. These findings argue against a primary role for the HPA axis and GH in particular on the regulation of muscle protein content inflight. This conclusion is supported by animal data. Inflight replacement of GH in rats was without any effect on skeletal muscle mass (15). HPA axis hormones act systemically and lack specificity on individual muscle groups. In contrast, spaceflight-induced muscle atrophy is limited primarily to muscles with antigravity functions (12, 40).
There was however a weak trend for cortisol excretion to be increased during (P = 0.27) and after spaceflight (P = 0.12, Fig. 1). Urinary cortisol levels were persistently elevated in six of the nine subjects (178 ± 21% of the mean preflight value). Seven of the nine subjects were the same as studied by Leach et al. (20). For these seven subjects, the increase in urinary cortisol was statistically significant (20). On Skylab, urinary cortisol was elevated for the duration of the mission for all nine subjects (28-84 days). It is therefore reasonable to believe that cortisol production is increased during spaceflight. However, there are a number of arguments against cortisol being a major factor in the muscle loss.
1) On the ground, infusion of cortisol results only in a transient increase in protein degradation, and the increased degradation is primarily seen in myofibrillar proteins as evidenced by increased 3-methylhistidine excretion (4, 16, 27). In contrast, there was no evidence that myofibrillar protein breakdown was increased on these two missions. Urinary 3-methylhistidine excretion was unchanged with spaceflight (38).
2) The spaceflight-induced increase in cortisol excretion differs from that found with a metabolic stress response in which an increase in plasma cortisol is associated with an increase in ACTH. This relationship is not found during human spaceflight, but it was found postflight when both cortisol and ACTH excretion were increased. As with other missions, ACTH excretion was unchanged in these astronauts. Both U.S. and Russian investigators have observed and commented on this apparent anomaly (12, 20, 41). Leach et al. (20) suggested that this was due in some way to cortisol lagging behind ACTH secretion because blood was not sampled until some time after any increase in ACTH secretion may have occurred (20). This explanation is inconsistent with our data because the urine measurements are integrated over time, and the trend for an increase in cortisol persisted for the duration of the mission. An alternate explanation is that the elevated cortisol excretion found after the initial adaptation period is not due to a metabolic stress response but may be a consequence of the emotional stress that is associated with spaceflight (41, 45, 46).
3) Increased cortisol has only been found with some but not all bed rest studies (6, 10, 41, 45, 46), whereas bed rest is invariably associated with muscle atrophy.
4) An increase in cortisol production is a systemic response and so cannot by itself account for the specificity of the load-bearing muscle and bone losses that are found.
5) With spaceflight, slow-twitch fibers (type I) atrophy more rapidly than fast-twitch fibers (type II, Ref. 5), whereas with cortisol the effect is predominantly on fast-twitch fibers (9).
Prostaglandins. Plasma
PGE2 and
PGF2 are unstable and so are
measured as their metabolites PGE-M and PGF-M. PGE-M and PGF-M are the
major metabolites of the E and F prostaglandins, respectively (2, 13,
26). They are excreted unchanged in the urine and are generally taken
to reflect whole body as opposed to renal plus systemic prostaglandin
production (2, 7, 8, 25, 32).
Both PGE-M (P = 0.005, Fig. 4) and PGF-M excretion values (P = 0.13, Fig. 6) were decreased inflight compared with their preflight values, but the decrease in PGE-M was much greater (30%) and statistically significant. Postflight, the pattern of prostaglandin excretion was reversed. There was a ~30% increase in PGF-M (P = 0.001) and a return to the preflight value for PGE-M.
Much of the urinary PGE2 and
PGF2 is renal in origin, and
therefore urinary measurements will reflect an unknown mixture of
systemic and renal prostaglandin metabolism (2, 31). Even so, the
changes in PGE2 and
PGF2
excretion paralleled the PGE-M and PGF-M profiles, suggesting that the changes found with PGE2 and
PGF2
reflected systemic rather
than renal production of PGE2 and
PGF2
.
As with any whole body study, unambiguous assignment of the source of the decreased prostaglandin production cannot be made. It is, however, reasonable to assume that the site(s) is/are ones that is/are known to be affected by spaceflight. In the present case, these are muscle and bone. Both muscle and bone release prostaglandins in response to mechanical stress (17, 24, 34, 43, 47). We suggest that muscle is likely to be the major site of the decreased prostaglandin production because there is considerably more muscle than there is of bone, and muscle is a more metabolically active tissue. A study on unweighted rats by Ku and Thomason (19) reported that skeletal muscle continuously adjusts its protein synthesis rate to accommodate workload. It would be expected, therefore, that the associated mediators would also respond rapidly to alterations in muscle tension, and this is what was found with prostaglandins in this experiment (Figs. 4 and 6).
Although cortisol can inhibit prostaglandin release, this is not a likely explanation for the inflight decrease in prostaglandin production. Cortisol functioning alone cannot confer the specificity of the inflight response. Second, PGF-M excretion was increased postflight at a time when cortisol excretion was also increased. Cortisol was essentially unchanged for the flight and recovery periods, i.e., it was marginally elevated throughout (Fig. 1). It is improbable that similar increases in cortisol during and after flight can have an inhibitory effect on prostaglandin production inflight and a stimulatory effect postflight.
PGE2 and
PGF2 stimulate muscle protein
degradation and synthesis, respectively (30, 42). Of particular
relevance to the spaceflight-induced muscle atrophy is that, in vitro,
PGE2 and
PGF2
function as autocrine
second messengers in regulating stretch-induced changes in muscle
protein synthesis and breakdown (28, 43). Furthermore, cell culture
studies by Vandenburgh and colleagues (43, 44) demonstrated that muscle
cells release PGE2 and
PGF2
into the medium, and the
amount released varies with the tension applied to the cells.
Prostaglandin release decreases as tension is decreased. In rats, the
PGE2 secreted by muscle acts
synergistically with NO to dilate the microcapillaries in the muscle
(18). Conversely, a decrease in
PGE2 release leads to constriction
of the blood vessels. Histological examination of human quadriceps
muscle biopsies taken immediately after landing showed a decrease in
the number of capillaries per muscle fiber (5).
A possible consequence of decreased blood flow is a decrease in nutrient availability, which thereby initiates a localized starvation response in the muscle. Without adequate oxygen and substrate delivery, muscle cells adapt by conserving energy, decreasing protein synthesis, and remodeling. The process is one of adaptation; the decrease in cell protein content and distribution can be selective, with the possibility of strength being conserved at the expense of some other property, for example, increased fatigability (5). As soon as the resting muscles experience tension, prostaglandin release occurs, resulting in the dilation of the capillaries and increasing nutrient availability for the replacement of lost muscle proteins.
Whereas we believe our measurements relate primarily to muscle loss,
similar prostaglandin mechanisms may also be involved in the
spaceflight-induced loss of calcium from bone. Both
PGE2 and
PGF2 are powerful stimulators
of bone resorption. The prostaglandins produced by osteoblasts and
osteoclasts in response to mechanical stress are involved in the local
regulation of bone metabolism (24, 29). The resultant prostaglandins
promote angiogenesis by stimulating the release of vascular endothelial factor by osteoblasts (14). Conversely, decreased prostaglandin release
will lead to microcapillary constriction.
In summary, the principal findings from this study are that 1) T3 and prostaglandin activity is reduced during spaceflight; 2) the inflight data support a major role for decreased prostaglandin production in the protein loss by muscle; and 3) the lack of consistent changes in GH, ACTH, and cortisol makes it unlikely that the HPA axis hormones are a major factor in the chronic muscle loss.
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ACKNOWLEDGEMENTS |
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We thank the numerous people in the Space and Life Sciences Directorate of the National Aeronautics and Space Administration (NASA)-Lyndon Baines Johnson Space Center at Houston and Lockheed-Martin Government Services Division for implementing this experiment. Special thanks are due to the crews of SLS1 and SLS2 for their cooperation. We also acknowledge and thank 1) Dr. Helen Lane and the urine monitoring system team at the Johnson Space Center for their efforts over the years to ensure accurate collection of the dietary data and usable urine samples; 2) Dr. Carolyn L. Huntoon, the Principal Investigator of experiment E192 for providing us with the dietary data, catecholamine values, and some of the cortisol data as part of the SLS1 and SLS2 investigators' data-sharing agreement; 3) Dr. C. M. Schroeder for assistance with the statistical analyses, and 4) Dr. C. E. Wade of NASA-Ames Research Center for helpful discussions.
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FOOTNOTES |
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This work was supported by NASA contract BE9-17276 and by National Institute of General Medical Sciences Grant GM-40586.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: T. P. Stein, Dept. of Surgery, Univ. of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, 2 Medical Center Dr., Stratford, NJ 08084.
Received 16 June 1998; accepted in final form 8 September 1998.
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