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1 Department of Physiological Science and 2 Brain Research Institute, University of California, Los Angeles 90095; and 3 Life Science Division, National Aeronautics and Space Administration-Ames Research Center, Moffett Field, California 94035
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The release of a bioassayable form of growth hormone (BGH), distinct from growth hormone as measured by immunoassay (IGH), from the rat pituitary into the blood is differentially regulated by afferent input from fast and slow skeletal muscles. Specifically, activation of low-threshold fast muscle afferents for 15 min increased plasma BGH by 217 and 295% and decreased pituitary BGH by 68 and 45% in male and female rats, respectively. In contrast, activation of slow muscle afferents inhibited BGH release, decreasing plasma BGH by ~60% and increasing pituitary BGH by 30-50% in male rats. Female rats from which food had been withheld for ~12 h had elevated basal plasma BGH levels, which then were decreased by 81% after slow muscle nerve stimulation. Plasma IGH concentrations were unchanged after any nerve stimulation condition. These results demonstrate that regulation of BGH release can be differentially mediated through low-threshold afferent inputs from fast or slow skeletal muscle. Furthermore, the results indicate that BGH responses are independent of gender or feeding status.
immunoassay; bioassay; proprioception; electrical stimulation; peripheral nerves; low-threshold afferents
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MULTIPLE MOLECULAR FORMS of growth hormone (GH), ranging from 5 to 100 kDa in size and possessing varied physiological actions, recently have been demonstrated in human plasma and in rat plasma and pituitary tissue (3). However, GH measurements most often are determined by using immunoassays that recognize primarily the 22-kDa form of GH (IGH). It generally is recognized that exercise elevates IGH in humans (25), although no response has been observed in exercised rats (6). The existence of multiple GH forms along with the presence of two binding proteins, one receptor related with high affinity for IGH and one with low affinity, which circulate in plasma and are capable of further modifying IGH action (3), suggests that measurement of IGH alone likely does not provide a complete profile of GH at rest or in response to exercise. Our laboratories have previously shown that another form of GH, measurable by bioassay (BGH), is released in response to sensory afferent input from fast skeletal muscles in rats (14, 15, 17). In the present study, we have continued to examine the mechanisms by which muscle activity could modulate BGH.
The evidence that there are alternative forms of GH, measurable by bioassay but not detectable by immunoassay, is substantial (9-11, 15, 21, 29). Fractionation studies have shown that a 60- to 80-kDa peptide is released from pituitary somatotrophs, both constitutively and in response to extrapituitary stimuli that stimulates tibial epiphyseal growth in a dose-dependent fashion (9-11). To date, BGH has been found in human (9, 11, 29), bovine (11), cat (unpublished observations), and rat (9-11, 14-17) plasma as well as in the anterior pituitary of rats (9-11, 14-17, 21). Although the mechanism(s) for regulating BGH secretion have not been identified, basal levels of BGH are reduced after spaceflight in rats (21) and the normal exercise-induced increase in BGH is inhibited during bed rest in humans (29), suggesting a link between the level of proprioceptive input and the secretion of BGH.
We have reported previously that 15-min bouts of electrical stimulation of the proximal ends of severed nerves innervating predominantly fast muscle (such as the tibial nerve) increase BGH release in anesthetized male rats (15). Furthermore, this response was specific to BGH in that no changes were seen in IGH nor in any other plasma hormones (e.g., testosterone, thyroid hormones, and corticosterone) or metabolites (e.g., glucose, lactate, and triglycerides) measured. The stimulation intensity was of sufficient strength (2 times threshold) to excite group I and possibly group II afferent nerve fibers but was insufficient to excite the higher threshold group III or IV afferents. The BGH response in these experiments, therefore, seemed to be mediated by afferent inputs from muscle spindles and/or possibly Golgi tendon organs.
The present study was designed to test the hypothesis that the same stimulation protocol administered to the soleus nerve, innervating only the slow soleus muscle, which has the highest spindle density of any major hindlimb muscle, will elicit a BGH response similar to that seen after stimulation of the tibial nerve. Because the tibial nerve trunk stimulated in the previous experiment (15) also includes the soleus nerve trunk, the present experiment separates the relative role of afferent input from fast and slow muscle. To further test the generality of these muscle afferent effects, and given that there are gender-dependent differences in the regulation of IGH in rats (8), we compared the responses to stimulation of the proximal end of the severed tibial or soleus nerve in male and female rats. We also tested the robustness of the neuroregulatory effects under conditions when the metabolic state of the rats was perturbed. It has been demonstrated previously that food deprivation in rats depletes pituitary BGH and elevates plasma BGH by approximately threefold (10, 11) but does not affect plasma IGH concentrations (10). We wanted to determine, therefore, whether the nerve stimulation effects were maintained after alteration of baseline BGH secretion by ~12 h of food deprivation. Similar effects of nerve stimulation were observed regardless of gender or the metabolic state of the rats.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals. Male (354 ± 4 g) and female (269 ± 4 g) rats (Taconic Sprague Dawley, Germantown, NY) were housed in shoebox cages in a 25 ± 1°C room with a reversed 12:12-h light-dark cycle. All male rats and two groups of female rats were given water and food (Purina rat chow) ad libitum; the remaining four groups of female rats had food withheld for ~12 h before the in situ experiment. After shipment, rats were given at least 1 wk to acclimatize before experimentation. Animal care and use were in accordance with the Guidelines of the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee.
Stimulation protocol.
Peripheral hindlimb (soleus, tibial, or sural) nerves were isolated and
severed in surgically anesthetized (pentobarbital sodium, 50 mg/kg ip)
rats (n = 3-10/group). The nerves were chosen on the basis
of the tissue they innervate: 1) the soleus nerve innervates
only the predominantly slow soleus muscle, 2) the tibial nerve
innervates all of the posterior calf and plantar foot muscles (predominantly fast muscles and the soleus), and 3) the sural nerve is largely cutaneous and has extremely limited muscle
innervation. The proximal ends of the severed nerves were placed on a
bipolar silver electrode and stimulated in situ with a 20-µs
square-wave pulse for 15 min at a train frequency simulating
electromyographic patterns recorded from rats running on a treadmill at
40 m/min (100 Hz, 150 ms on:150 ms off) (31). Current strength was two times the threshold required to elicit a visible reflex response. This
stimulation level was of sufficient strength to stimulate group I and
II afferents from primary and secondary muscle spindle endings and/or
Golgi tendon organs and well below the level at which group III and IV
afferents are excited (i.e., 5 times threshold or greater; Ref. 28).
This recruitment pattern was verified in a separate experiment where
antidromic compound action potentials were recorded from the sciatic
nerve while the tibial nerve was stimulated (Fig.
1). The recruitment of group I (conduction
velocity = 57 ± 1.8 m/s) and II (conduction velocity = 27 ± 0.9 m/s) afferents was readily evident at stimulation strengths ranging
from 1 to 7 V, whereas no evidence of group III or IV afferents was
apparent at these strengths. These conduction velocities for group I
and II fibers are in agreement with those previously reported in the literature (32). Control rats underwent the same anesthetic and
surgical manipulations but were not stimulated.
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Sample collection.
After the 15-min experimental paradigm, all rats were decapitated after
being bled by cardiac puncture by using heparin sodium as an
anticoagulant. Pituitary glands were cleanly dissected from the sella
turcica, and the anterior lobes were pooled by group and frozen at
70°C. Later, the glands were thawed, weighed, and homogenized with an all-glass hand homogenizer in a small volume of
0.01 M Na2CO3; the homogenate was diluted for
bioassay with 0.85% NaCl. After centrifugation of the heparinized
blood (1,500 g, 30 min, 4°C), an aliquot of plasma from
each rat was drawn off and stored at 70°C with sodium
fluoride as a preservative. The remaining plasma from each rat was
combined into a single pooled sample for each experimental group and
stored without preservatives at 70°C until assayed for BGH.
In individual rat plasma samples, plasma IGH was measured by using an
in-house immunoassay described in IGH and BGH assays, whereas
commercially available kits were used for measurement of other plasma
hormones (inter- and intra-assay coefficients of variation were <10%
for each assay). 3,5,3'Triiodothyronine (T3), thyroxine (T4), and testosterone were
measured by using a solid-phase immunoassay (Diagnostic Products, Los
Angeles, CA) and corticosterone was measured using a double-antibody
immunoassay (ICN Biomedicals, Costa Mesa, CA). Plasma metabolites
(lactate, glucose, triglycerides) were measured with an automated
analyzer (COBAS; Roche Diagnostics, Montclair, NJ).
IGH and BGH assays. A variation of the double-antibody procedure of Schalch and Reichlin (33) was used to measure IGH. The rat GH (VII-38-C; 3 IU/mg), used for immunization, standardization of the immunoassays, and labeling, was produced in house as was the primary antiserum. The hormone was labeled with 125I according to the method of Hunter and Greenwood (20). The primary antibody (monkey anti-rat GH; V-30-G1) was used at a 1:250,000 final dilution, and a goat anti-monkey gamma globulin (1:20) was used as the secondary antibody (Antibodies, Davis, CA). Inter- and intra-assay coefficients of variation for this assay were ~6 and 4%, respectively.
Bioassays for BGH were conducted following the method of Greenspan et al. (16). Female rats were hypophysectomized (parapharyngeal approach) at 26 days of age, and the assays were started 2 wk later. The assay animals were injected intraperitoneally once daily for 4 days (2 ml total volume per rat) with hormone standards or unknowns [pooled plasma and pituitary homogenates (
and 
mg
tissue/ml) from our experimental animals]. The standard (bovine
pituitary GH, XIV-44-C5, 1.5 IU/mg) was produced in house, calibrated
against a US Pharmacopeia preparation, and delivered in total doses of
0 (saline), 1.67, 5, 15, and 45 µg/rat. Plasma samples were assayed
at a single dose level, and pituitary homogenates were assayed at two
dose levels. Bioassay rats were killed by CO2 overdose
~24 h after the final injection, and one tibia was dissected, split
longitudinally, and stained with AgNO3 so that the proximal
growth plate could be visualized. Ten measurements were taken across
each epiphysis, by using an ocular micrometer mounted on a standard
light microscope, and averaged for each rat. Group means then were
compared against the generated standard curve. Concentrations of BGH
were expressed relative to the growth-promoting activity of the
standard rat GH (IGH) reference preparation. The coefficient of
variation within bioassays was ~3.2%.
Statistical methods.
Plasma metabolite and hormone measurements other than BGH were analyzed
by using a one-way analysis of variance to determine overall
differences, followed by a Tukey-Kramer post hoc test to determine
group differences (SuperAnova; Abacus Concepts, Berkeley, CA).
Statistical power calculations were 
80% for all comparisons between
experimental groups. Pituitary BGH measurements (2 dose levels) were
determined by using a four-point assay procedure, whereas the plasma
BGH measurements (1 dose level) were determined by using a bracketed
three-point assay method (34). Differences in BGH concentrations
between groups were determined by using a Student's t-test.
Significance was determined at the P < 0.05 level for all
statistical analyses.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BGH and IGH.
Proximal soleus nerve stimulation decreased plasma and increased
pituitary BGH by 63 and 34%, respectively, in fed male rats (Fig.
2A). In a separate
experiment, proximal stimulation of the sural nerve in fed male rats
had no effect on plasma or pituitary BGH, while stimulation of the
proximal tibial nerve trunk increased plasma and decreased pituitary
BGH by 217 and 68%, respectively (Fig. 2B). Again, stimulation
of the proximal end of the soleus nerve, in contrast, decreased plasma
BGH by 60%, whereas increasing pituitary BGH by 54% in fed male rats
(Fig. 2B). Plasma IGH was unchanged in fed male rats after
either sural, tibial, or soleus nerve stimulation (Fig. 2, A
and B).
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Other plasma hormones and metabolites.
Plasma concentrations of testosterone (male rats), T3,
T4, corticosterone, glucose, lactate, and triglycerides
were measured and are summarized in Tables
1 and 2. Some female rats
from which food had been withheld overnight demonstrated significantly higher corticosterone and T3 levels than did rats that were
fed continuously. This finding is not surprising, however, because food
deprivation is a stressor. No differences in any of the other hormones
or metabolites were seen between any of the stimulation groups and
their appropriate controls.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Afferent regulation of BGH secretion. The present data show that the input from a predominantly fast muscle group stimulates, whereas input from an individual slow muscle inhibits, the release of BGH from the rat pituitary. The inhibition of BGH secretion by afferent input from the slow soleus was contrary to our expectations at the onset of these experiments. In fact, we now reject our hypothesis that afferent input from the soleus would increase BGH secretion equal to or greater than that seen after stimulation of the proximal tibial nerve trunk. Results from male and female rats were similar, demonstrating that this BGH response is not gender specific. We also found that even after deprivation of food overnight (for ~12 h), which elevated basal plasma BGH, stimulation of the slow muscle nerve still inhibited BGH release.
The neural regulation of BGH secretion appears to be specific to BGH, because no effects on IGH release were seen in any of the nerve stimulation experiments in either male or female rats. Furthermore, no changes were observed in plasma testosterone, T3, T4, corticosterone, glucose, lactate, or triglyceride levels after stimulation. Because the nerve stimulation paradigm used in the present study was based on electromyogram recordings taken from exercising rats running on a treadmill at ~40 m/min and because the nerves were severed before stimulation (i.e., no muscle contractions), we were able to separate the neural from the metabolic effects of muscle activation. The results clearly demonstrate a rapid and specific means of stimulating or inhibiting BGH release mediated by some neural, and not metabolic, mechanism involving afferent input from working skeletal muscles. The use of a two times threshold stimulation intensity strongly suggests that group I and possibly group II afferents from muscle spindles and/or Golgi tendon organs are one source of BGH regulation. These large afferents have been shown to be activated at low stimulation intensities (28). The release of BGH was enhanced by afferent input predominantly from fast muscles and inhibited by afferent input from only slow (i.e., soleus) muscle. From the standpoint of the number of muscle afferents that project rostrally, this result is surprising because the soleus has the highest spindle density of any major hindlimb muscle (4) and, therefore, has the most group I and II afferent inputs. It appears, therefore, that different pathways from fast and slow muscles to the site of control of BGH secretion must exist. It should be noted that although the tibial nerve stimulation, which markedly enhanced BGH secretion, primarily involves fast musculature, it also incorporates afferent input from the proximal soleus nerve trunk. Soleus nerve stimulation alone, in contrast, strongly inhibited BGH release. These data indicate that, whereas inputs from fast and slow muscles differ in their ability to regulate BGH release, fast muscle inputs appear to be dominant. Further experiments are needed to clarify the pathway(s) by which afferent input from fast and slow muscle nerves reach the hypothalamus to affect anterior pituitary secretion of BGH.Neural regulation of the anterior pituitary gland. Data from other laboratories provide further evidence that the anterior pituitary can be neurally regulated in addition to its known humoral regulation. First, nerve tracts have been identified that project from the spinal cord to the hypothalamic paraventricular nucleus. This is a site known to have numerous functions in endocrine regulation, including the regulation of IGH secretion by GH-releasing hormone (5, 7). Second, a number of investigators have demonstrated the presence of nerve fibers within the anterior pituitary gland of the rat. These nerve fibers are immunoreactive for factors involved in pituitary regulation, such as substance P (1, 23, 30), calcitonin gene-related peptide (12, 22, 23), somatostatin (23, 35), and serotonin (26). Furthermore, these nerve fibers lie in contact with, or in close apposition to, somatotrophs (27, 35), thyrotrophs (35), and corticotrophs (22, 24, 27), and some respond to changes in the overall hormonal state of the animal (e.g., increasing density of varicosities near corticotrophs after adrenalectomy) (22, 24, 27). Last, a neural mechanism for regulating opioid release from the brain in response to exercise and/or muscle activity has been demonstrated in rats (19). Specifically, the release of ß-endorphin from the hypothalamic arcuate nucleus and anterior pituitary gland was induced by activation of slow-conducting (group III and IV) afferent nerve fibers from skeletal muscle. The combined results from these experiments are consistent with some neural regulation of the anterior pituitary gland by afferent input from the periphery.
Significance of BGH and a neural mechanism for regulation of its secretion. The existence of a factor, BGH, which is secreted from the anterior pituitary and promotes rat tibial epiphyseal growth in a dose-response fashion, has been demonstrated. This growth cannot be accounted for by IGH, which is the only hormone or growth factor known to induce dose-related growth of the epiphysis at physiological levels (16). It has been known for some time that multiple molecular forms of GH, varying in size and physiological action, exist in plasma and are present in and secreted by the anterior pituitary gland (3). Few of these variants are detectable by immunoassay, which is the standard method for measuring GH in plasma. Measuring GH by bioassay, therefore, provides a more complete profile of GH activity in plasma and pituitary tissue and likely takes the activities of more of these variants into account.
Fractionation studies have placed the tibial growth-promoting BGH activity in plasma within the 60- to 80-kDa molecular mass range, far larger than 22-kDa IGH (11). Furthermore, when IGH is removed from whole-plasma fractions by immunoprecipitation with a polyclonal antibody, that plasma fraction is still able to promote tibial epiphyseal growth at the same level as when IGH is present in the plasma fraction (11). The sensitivity of the tibial bioassay is ~1 µg of IGH (16), but plasma IGH concentrations are only ~10 ng/ml or less. Therefore, the contribution of IGH to the growth-promoting activity of plasma is negligible. Other plasma hormones in addition to IGH that are known to affect tibial growth include testosterone, thyroid hormones (T3 and T4), and insulin-like growth factor I (16). However, these hormones do not induce epiphyseal widening in a dose-response fashion, nor are they present in plasma at high enough concentrations to affect tibial growth (16). Furthermore, no changes in plasma testosterone, T3, or T4 were seen after any of the nerve stimulations, demonstrating that the changes in BGH activity between control and stimulated rats cannot be accounted for by these other hormones. A clinical condition recently has been discovered in which some humans deficient in IGH are still capable of attaining normal stature and body composition (13). In addition, patients with pseudoacromegaly display acromegalic features, such as thickening of the brow ridge and enlargement of the hands and feet, but have normal or even subnormal circulating levels of IGH in their plasma (2). Plasma samples from both of these types of individuals have been shown to contain an uncharacterized peptide growth factor with a molecular mass of ~70 kDa (13). This protein is able to induce growth of erythroid progenitor cell colonies in culture, a function that is predominantly stimulated by IGH (2). All of these results suggest the presence of factors other than IGH that have strong growth-promoting functions. In summary, the secretion of BGH, but not IGH, from the anterior pituitary gland into the blood can be activated by afferent input from working fast muscles and inhibited by afferent input from working slow muscles. The afferents involved in regulating BGH release appear to be the large, low-threshold, group I and possibly group II fibers originating from the muscle spindles and/or Golgi tendon organs responsible for proprioceptive signaling from the periphery. The secretion of BGH also is altered by changes in proprioception. Specifically, BGH secretion is reduced after unloading of the musculoskeletal system as occurs in spaceflight (21). Furthermore, BGH is released in rats and humans in response to exercise (14, 15, 17, 29); this exercise response is blunted by bed rest, another condition in which the musculoskeletal system is unloaded and proprioception is decreased (29). The present results also show that this novel regulatory mechanism for BGH is similar in males and females and is present in food-deprived rats when basal plasma BGH levels are elevated, as well as in continuously fed rats.| |
ACKNOWLEDGEMENTS |
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The authors thank Mari Eyestone for assistance in the measurement of plasma metabolites and Kevin Vallance for assistance in producing Fig. 1.
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FOOTNOTES |
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This work was supported by National Aeronautic and Space Administration Grant 199-26-12-09 (to R. E. Grindeland, R. R. Roy, and V. R. Edgerton). K. L. Gosselink was supported by a predoctoral training grant (National Research Service Award) from the National Institute of Dental Research (Grant DE-07212).
Portions of this work have been previously published in abstract form (14, 17).
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 and other correspondence: V. R. Edgerton, Univ. of California, Los Angeles, Dept. of Physiological Science, 1804 Life Sciences, 405 Hilgard Ave., Los Angeles, CA 90095-1527 (E-mail: vre{at}ucla.edu).
Received 11 January 1999; accepted in final form 15 September 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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