United States Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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Studies have shown that protein
synthesis in skeletal muscle of neonatal pigs is uniquely sensitive to
a physiological rise in both insulin and amino acids. Protein synthesis
in cardiac muscle, skin, and spleen is responsive to insulin but not
amino acid stimulation, whereas in the liver, protein synthesis
responds to amino acids but not insulin. To determine the response of
protein synthesis to insulin-like growth factor I (IGF-I) in this
model, overnight-fasted 7- and 26-day-old pigs were infused with IGF-I (0, 20, or 50 µg · kg1 · h
1) to achieve
levels within the physiological range, while amino acids and glucose
were clamped at fasting levels. Because IGF-I infusion lowers
circulating insulin levels, an additional group of high-dose
IGF-I-infused pigs was also provided replacement insulin (10 ng · kg
0.66 · min
1). Tissue
protein synthesis was measured using a flooding dose of
L-[4-3H]phenylalanine. In 7-day-old pigs,
low-dose IGF-I increased protein synthesis by 25-60% in various
skeletal muscles as well as in cardiac muscle (+38%), skin (+24%),
and spleen (+32%). The higher dose of IGF-I elicited no further
increase in protein synthesis above that found with the low IGF-I dose.
Insulin replacement did not alter the response of protein synthesis to
IGF-I in any tissue. The IGF-I-induced increases in tissue protein
synthesis decreased with development. IGF-I infusion, with or without
insulin replacement, had no effect on protein synthesis in liver,
jejunum, pancreas, or kidney. Thus the magnitude, tissue specificity,
and developmental change in the response of protein synthesis to acute physiological increases in plasma IGF-I are similar to those previously observed for insulin. This study provides in vivo data indicating that
circulating IGF-I and insulin act on the same signaling components to
stimulate protein synthesis and that this response is highly sensitive
to stimulation in skeletal muscle of the neonate.
neonate; insulin action; nutrition; translation initiation; growth
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INTRODUCTION |
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THE RELATIVE RATES OF GROWTH and protein deposition, particularly in skeletal muscle, are rapid during the neonatal period and are sustained by elevated rates of protein synthesis (10, 16, 21, 52). With the advancement of development, fractional rates of growth and protein synthesis decline. During this period of rapid growth, skeletal muscle protein synthesis is uniquely sensitive to insulin and amino acids (11, 12, 14, 15, 48, 50).
Studies in the neonatal pig have shown that, when amino acids and glucose are maintained at fasting levels, a rise in circulating insulin concentrations within the physiological range increases protein synthesis in skeletal muscle, particularly in those muscles with predominantly fast-twitch, glycolytic characteristics (12, 50). The infusion of physiological levels of an amino acid mixture, in the presence of fasting insulin and glucose levels, also increases protein synthesis in these same muscles (14). By contrast, protein synthesis in cardiac muscle, skin, and spleen is responsive to insulin but not amino acid stimulation, whereas other tissues are responsive to amino acids but not insulin. The developmental decline in the response of muscle protein synthesis to insulin and amino acids parallels the developmental decline in insulin receptor abundance (42), as well as the abundance of the protein kinase mammalian target of rapamycin, known as mTOR (31), which is important in transmitting the signal generated by both amino acids and insulin (29, 40). Because the receptors for insulin and insulin-like growth factor I (IGF-I) share considerable structural homology, and both insulin and IGF-I act on some of the same intracellular signaling pathways (8, 9, 34, 44), we wished to determine whether muscle protein synthesis in the neonate is also acutely sensitive to stimulation by IGF-I and whether the response is developmentally regulated.
Stimulatory effects of acute IGF-I infusion in vivo and in situ have been observed in some (2, 24, 47) but not all (4, 37) studies. For example, short-term infusion of IGF-I in adult mice increased protein synthesis in skeletal and cardiac muscles, although not in other tissues (2). By contrast, acute IGF-I infusion had no effect on hindlimb protein synthesis in the fetal lamb (4). Differing results among studies may indicate developmental regulation of the anabolic action of IGF-I or may be attributable to methodological differences. Importantly, both hormone and substrate status have not been maintained concurrently in any previously reported study in which the effect of IGF-I on protein synthesis has been determined, and an IGF-I-stimulated fall in insulin, amino acids, and/or glucose could limit the ability of IGF-I to stimulate protein synthesis.
The aim of this study was to determine whether an acute infusion of IGF-I to raise circulating levels within physiological limits can also stimulate protein synthesis in the neonatal pig. During the infusion of IGF-I, amino acids and glucose were clamped at fasting levels to maintain substrate concentration, as in our previous insulin infusion studies (12, 50). Because the neonatal pig is uniquely sensitive to the anabolic effects of insulin (12, 14), an additional group of IGF-I-infused pigs was provided replacement insulin so as to determine whether the effects of IGF-I on protein synthesis are independent of insulin concentration. Herein, we compared the effects of acute changes in IGF-I on protein synthesis in three skeletal muscles that differ in their metabolic properties with the effects of IGF-I on protein synthesis in a variety of other tissues. We also examined whether the response to IGF-I changes with development.
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METHODS |
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Animals and surgery. Multiparous crossbred (Yorkshire × Landrace × Hampshire × Duroc) sows (n = 4; Agriculture Headquarters, Texas Department of Criminal Justice, Huntsville, TX) were housed in lactation crates in individual, environmentally controlled rooms and maintained on a commercial diet (5084, PMI Feeds, Richmond, IN) throughout a 28-day lactation period. Sows delivered 8-11 piglets, and these remained with the sows and were not given supplemental creep feed. Piglets were studied at 7 (2.2 ± 0.1 kg; n = 17) and at 26 days of age (7.2 ± 0.3 kg; n = 22). Three to five days before the infusion studies, pigs were anesthetized, and catheters were inserted into a jugular vein and a carotid artery (49). Piglets were returned to the sow until studied. The protocol was approved by the Animal Care and Use Committee of Baylor College of Medicine. The study was conducted in accordance with the National Research Council's Guide for the Care and Use of Laboratory Animals.
Infusions.
Pigs were fasted overnight with free access to water. The following
morning, pigs were placed unanesthetized in a sling restraint system.
Piglets within each litter were randomly assigned to one of four
treatment groups: 1) control, 2) low IGF-I,
3) high IGF-I, and 4) high IGF-I plus insulin
replacement. During a 30-min basal period, blood samples were obtained
and immediately analyzed for glucose (YSI 2300 STAT Plus, Yellow
Springs Instruments, Yellow Springs, OH) to establish the average basal
concentration of blood glucose that needed to be maintained for
euglycemia during the IGF-I infusion period (20). Plasma
samples were analyzed for total branched-chain amino acids (BCAA) by
use of a rapid enzymatic kinetic assay (3) to establish
the average basal concentration of BCAA that needed to be maintained
for euaminoacidemia during the IGF-I infusion period. The IGF-I
infusions were initiated with a primed, constant (12 ml/h) infusion of
recombinant human IGF-I (Genentech, San Francisco, CA) at 0, 20, or 50 µg · kg1 · h
1. Because
IGF-I infusion can lower circulating insulin concentrations, replacement insulin was provided (10 ng · kg
0.66 · min
1) in a
group of pigs infused with the high IGF-I dose. Venous blood samples
(0.2 ml) were acquired every 5 min and immediately analyzed for BCAA
and glucose concentrations. The infusion rate of dextrose (Baxter
Healthcare, Deerfield, IL) was adjusted as necessary to maintain blood
glucose concentration within ±10% of the average basal concentration.
Euaminoacidemia was obtained by adjusting the infusion rate of an amino
acid mixture (see next paragraph) to maintain the plasma BCAA
concentration within ±10% of the fasting level. Blood samples were
collected hourly for the determination of plasma IGF-I, insulin, and
IGF-binding protein-3 (IGFBP-3) concentrations.
Tissue protein synthesis in vivo.
Fractional rates of protein synthesis were measured with a flooding
dose of L-[4-3H]phenylalanine
(25) injected 3.5 h after the initiation of the
clamp. Blood samples were taken at 5, 15, and 30 min after the
injection for measurement of the specific radioactivity of the
extracellular free pool of phenylalanine. Pigs were killed at 4 h
after the initiation of the clamp. Samples of longissimus dorsi (from
approximately the 10th thoracic to the 1st lumbar vertebra),
gastrocnemius (the entire belly portion), masseter (all), and cardiac
(left ventricular wall) muscles and skin, liver, jejunum, pancreas,
kidney, and spleen were collected, rapidly frozen in liquid nitrogen,
and stored at 70°C. Total protein was isolated from all tissues
sampled. The specific radioactivities of the protein hydrolysates,
homogenate supernatants, and blood supernatants were determined as
previously described (16).
Plasma insulin and amino acids. Plasma immunoreactive insulin concentrations were measured using a porcine insulin radioimmunoassay kit (Linco, St. Louis, MO). Plasma amino acid concentrations were measured with a high-performance liquid chromatography method (PICO-TAG reverse-phase column, Waters, Milford, MA), as previously described (17). Blood glucose concentrations were rapidly analyzed during the infusion period with a glucose oxidase reaction (YSI 2300 STAT Plus, Yellow Springs Instruments). Plasma total IGF-I and IGFBP-3 concentrations were measured using immunoradiometric assay kits (Diagnostic System Laboratories, Webster, TX).
Calculations and statistics.
Fractional rates of protein synthesis (Ks;
percentage of protein mass synthesized in a day) were calculated as
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RESULTS |
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Infusions.
Our previous studies showed that, in both 7- and 26-day-old pigs,
circulating IGF-I concentrations are doubled by feeding (10). In the current study, 7- and 26-day-old pigs were
fasted overnight and infused with a low dose of IGF-I to raise
circulating IGF-I concentrations ~75% and a high dose of IGF-I to
raise circulating IGF-I concentrations ~150% (Table
1). As we have found previously (10), the fasting IGF-I concentration, as well as the
increase in IGF-I levels brought about by IGF infusion in 7-day-old
pigs, was about one-half of that in 26-day-old pigs (P < 0.01). The replacement dose of insulin restored the insulin
concentrations to values similar to those of control pigs. Circulating
IGFBP-3 concentrations were unaffected by IGF-I infusion
(P > 0.05) but increased with age (P < 0.01). By design, the plasma glucose concentrations were maintained
at basal fasting levels during the infusion of IGF-I.
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Tissue protein synthesis.
Ks values in skeletal muscles with different
metabolic properties of 7- and 26-day-old pigs are shown in Fig.
4. Ks values in
all skeletal muscles were higher in 7- than in 26-day-old pigs (P < 0.001). In 7-day-old pigs, low-dose IGF-I
infusion increased protein synthesis in longissimus dorsi,
gastrocnemius, and masseter muscles by 54, 60, and 25%, respectively
(P < 0.005). Infusion of the high IGF-I dose in
7-day-old pigs increased protein synthesis in the three muscles by 69, 79, and 45%, respectively (P < 0.005), and this
response to high IGF-I did not differ significantly from that to low
IGF-I (P > 0.05). In the presence of insulin
replacement, a high IGF-I infusion rate increased protein synthesis in
longissimus dorsi, gastrocnemius, and masseter muscles in 7-day-old
pigs by 71, 75, and 40%, respectively, compared with controls
(P < 0.01). Skeletal muscle protein synthesis rates
did not differ between high-dose IGF-I with insulin replacement and
high-dose IGF-I without insulin replacement (P > 0.05).
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DISCUSSION |
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Previous studies in the neonatal pig have shown marked and consistent tissue-related differences in the response of protein synthesis to insulin and amino acids (12, 14, 50). Specifically, protein synthesis in the liver responds to amino acids but not to insulin, whereas in cardiac muscle, skin, and spleen, protein synthesis responds to insulin but not to amino acids. Skeletal muscle protein synthesis is uniquely sensitive to both insulin and amino acids. Because insulin and IGF-I share common signaling pathways, in the current study we wished to determine whether skeletal muscle protein synthesis is also sensitive to the infusion of physiological levels of IGF-I. We found that the pattern of responsiveness to insulin was mimicked by that to IGF-I, inasmuch as IGF-I infusion increased protein synthesis in skeletal muscle, cardiac muscle, skin, and spleen but had no effect on protein synthesis in liver, jejunum, kidney, or pancreas. The developmental decline in insulin responsiveness that we have identified in previous work was also found with IGF-I stimulation of tissue protein synthesis. Reversing the suppressive effect of IGF-I infusion on insulin levels did not alter the magnitude of the response.
Some (2, 23, 24, 47) but not all (4, 37, 38) studies have demonstrated an anabolic effect of acute IGF-I infusion on protein synthesis in skeletal muscle. The lack of effect of IGF-I on muscle protein synthesis in some studies does not appear to be dependent on IGF-I dose, as three- to fivefold increases in circulating IGF-I concentrations have been shown to increase muscle protein synthesis by ~50% in some studies (2, 23) but not in others (4, 38). In the current study, a 50% increase in muscle protein synthesis was elicited by an increase in circulating IGF-I concentrations of only 50%, suggesting that muscle protein synthesis in the neonate is acutely sensitive to the anabolic effects of IGF-I.
An important consideration in evaluating the anabolic effects of IGF-I is that of substrate availability and hormonal status, which ideally should remain constant during the IGF-I treatment period so that the independent effects of IGF-I can be ascertained. IGF-I promotes glucose and amino acid uptake and inhibits insulin secretion (28). Reductions in circulating concentrations of glucose (24, 38), amino acids (4, 24, 30, 37, 51), and insulin (2, 4, 24, 30, 37, 38, 51) have been described in nearly all IGF-I infusion studies, and these changes do not appear to be dependent on age or species, although the responses may be blunted at very low IGF-I doses. Moreover, the circulating levels of glucose, amino acids, and insulin have not been maintained concurrently in any previously reported study in which protein synthesis has been measured, and the IGF-I-stimulated fall in amino acids, insulin, and/or glucose could limit the ability of IGF-I to stimulate protein synthesis. In a study conducted in mature rats, IGF-I infusion had no effect on muscle protein synthesis except when the rats were infused with either replacement amino acids or replacement insulin (30). However, in that study, IGF-I infusion with insulin replacement lowered circulating amino acid concentrations, and IGF-I infusion with amino acid replacement lowered plasma insulin levels and raised the concentration of some amino acids.
In the current study, amino acids and glucose were maintained at the fasting level during the infusion of low and high doses of IGF-I, similar to our previous insulin infusion studies (12, 14, 50). We found that the magnitude of the stimulation of protein synthesis by the infusion of physiological doses of IGF-I differed between muscles and that the responses were greater in muscles that exhibit glycolytic compared with oxidative properties, an effect that is similar to the response to insulin infusion in neonatal pigs (12) and IGF-I in adult mice (2). IGF-I infusion also stimulated protein synthesis in skin and spleen, an effect that was similar to our findings with regard to insulin in a previously reported study (14). In the youngest pigs, protein synthesis rates in skeletal and cardiac muscles, skin, and spleen were stimulated at both the low and the high doses of IGF-I, with no additional effect at the higher dose of IGF-I.
The stimulation of protein synthesis in skeletal and cardiac muscles, when expressed both in absolute terms and in terms of percentage increases and in response to both low and high doses of IGF-I, like the response to insulin (12, 14), was blunted and more variable in the older pigs. By contrast, IGF-I infusion stimulated protein synthesis in the skin and spleen of 7- but not 26-day-old pigs, consistent with our previously reported findings on the effects of insulin in neonatal pigs (14) and the lack of effect of IGF-I in mature mice (2) in these tissues. The stimulatory effect of IGF-I on protein synthesis in skeletal muscle in the 7-day-old pig, and the developmental decline in this response during the suckling period, contrast with the lack of effect of IGF-I on protein synthesis in the hindlimb of the fetal lamb (4). Amino acids play an important role in the regulation of protein synthesis in young, adult, and elderly populations (11, 14, 35, 46, 48), and thus the decline in circulating amino acids in the fetal lamb infused with IGF-I (4) may have limited any potential change in protein synthesis.
Because the neonatal pig is highly sensitive to the anabolic effects of insulin (12), in the current study an additional group of high-dose IGF-I-infused pigs was provided replacement insulin (as well as replacement glucose and amino acids) to determine the effect of IGF-I on protein synthesis independent of changes in insulin. We found that the infusion of IGF-I, in the presence of euinsulinemia, stimulated protein synthesis in skeletal and cardiac muscles, skin, and spleen of 7-day-old pigs, and that the rate of protein synthesis achieved did not differ from that in the presence of hypoinsulinemia. The lack of effect of euinsulinemia compared with hypoinsulinemia, in the presence of an elevation in IGF-I levels, on muscle protein synthesis could indicate that basal fasting insulin levels have no effect on muscle protein synthesis and that higher insulin levels are required to elicit a response. An alternative explanation is that maximum rates of protein synthesis were achieved by IGF-I infusion in this model, and that provision of insulin, albeit at the replacement level, had no further effect. In addition, the ability of IGF-I to stimulate protein synthesis in the presence of either hypoinsulinemia or euinsulinemia suggests that insulin is not required for the stimulation of protein synthesis by IGF-I in the neonate.
The results also indicate that the IGF-I-induced stimulation of muscle protein synthesis was not associated with any change in the binding protein IGFBP-3, which can bind to the IGF-I receptor and limit the effect of IGF-I (36). Recently, circulating IGFBP-3 levels were shown to increase in the fetal sheep during an infusion of IGF-I in which circulating amino acid concentrations were maintained at the fasting level with our amino acid clamp technique (41). However, the rise in circulating IGF-I concentrations was much higher and the length of infusion was longer in that study than in the current study, and protein synthesis rates were not determined.
It perhaps is not surprising that the tissue specificity and the responsiveness of protein synthesis to IGF-I infusion in the neonatal pig are similar to those for insulin. The receptors for both IGF-I and insulin share considerable homology of structure and function (8, 34, 44) and are abundant in skeletal muscle of the neonatal animal (39, 42). Hybrid insulin-IGF-I receptors are also expressed in a number of tissues, and these receptors bind to and are activated by both IGF-I and insulin (1). Preliminary data from our laboratory indicate that these hybrid receptors are present in skeletal muscle of the neonatal pig (A. Suryawan and T. A. Davis, unpublished data). Insulin and IGF-I act on some of the same intracellular signaling pathways, including the phosphatidylinositol 3-kinase pathway, and this pathway has been implicated in the regulation of protein synthesis by IGF-I and insulin (9, 42). Both insulin and IGF-I have been shown to stimulate protein synthesis in the perfused hindlimb of mature rats by increasing the amount of the active eukaryotic translation initiation factor (eIF) complex, eIF4E · eIF4G, that regulates the binding of mRNA to the ribosome (33, 47), similar to our recently reported findings on the effects of feeding in the neonatal pig (19, 31, 32).
Although evidence from current and previous studies (12, 14, 50) shows commonality in the protein synthetic response to insulin and IGF-I, the results also suggest divergence in the response of other metabolic processes. Previous studies showed a marked developmental decline in the ability of insulin to stimulate amino acid disposal at the whole body level (49), but the results of the current study suggest that IGF-I-stimulated whole body amino acid disposal does not change with development. Because net amino acid disposal in this model represents the balance between whole body protein synthesis and degradation, this suggests that the developmental regulation of protein degradation by insulin and IGF-I may differ. Insulin-stimulated glucose disposal changes little during early postnatal development (12, 14). By contrast, IGF-I-stimulated glucose disposal in the current study increased with development, consistent with the lack of effect of IGF-I infusion on glucose uptake in the hindlimb of the fetal lamb (4) and the stimulation of glucose uptake by IGF-I in the forearm of the adult human (24). This suggests that the developmental regulation of glucose uptake by insulin and IGF-I may also differ.
Perspectives. The results of the current study demonstrate that exogenous provision of IGF-I stimulates muscle protein synthesis in the neonate, similar to the response to insulin in our previously reported studies (12, 14, 50). In these studies, IGF-I and insulin were infused at doses that reproduce circulating levels in the fed state, and this resulted in the stimulation of muscle protein synthesis to rates normally present in the fed state. Although this suggests that both IGF-I and insulin play a role in the feeding-induced stimulation of muscle protein synthesis, we think that this is unlikely for the following reasons. First, the rise in circulating IGF-I concentrations after feeding is not immediate (5, 10, 27, 43), in contrast to the rapid increase in both insulin levels and muscle protein synthesis rates after a meal in the neonate (17, 10). Second, the postprandial changes in muscle protein synthesis in neonatal pigs are positively correlated with changes in circulating insulin, but not IGF-I, concentrations (6, 11, 13). Third, with development, circulating IGF-I levels increase, whereas skeletal muscle protein synthesis rates decrease (10).
Thus it appears that exogenous provision of IGF-I stimulates protein synthesis in skeletal muscle and other insulin-sensitive tissues in the neonate, because IGF-I acts on the same signaling pathway as insulin that leads to translation initiation (9, 31, 33, 47), and which we have shown to be highly sensitive to stimulation in the neonate (19, 31, 32, 42). However, given the delayed responsiveness of IGF-I to feeding, unlike insulin, it cannot be a physiologically significant regulator of the feeding-induced stimulation of skeletal muscle protein synthesis and the assimilation of nutrients after eating in the neonate. Nonetheless, this does not negate the potential role of IGF-I as a long-term regulator of growth, as has been suggested by others (5, 22, 45), or the potential usefulness of IGF-I as an anabolic agent in a variety of clinical conditions in which protein deposition is reduced (7). ![]() |
ACKNOWLEDGEMENTS |
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We thank W. Liu, J. Rosenberger, J. Henry, and X. Chang for technical assistance, J. Cunningham and F. Biggs for care of the animals, E. O. Smith for statistical assistance, L. Loddeke for editorial assistance, A. Gillum for graphics, and J. Croom for secretarial assistance. We thank Genentech for the generous donation of IGF-I, and Eli Lilly for the generous donation of porcine insulin.
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FOOTNOTES |
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This work is a publication of the USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX. This project has been funded in part by National Institute of Arthritis and Musculoskeletal and Skin Diseases Institute Grant R01 AR-44474 and the US Department of Agriculture, Agricultural Research Service under Cooperative Agreement number 58-6250-6-001. This research was also supported in part by National Institutes of Health Training Grant T32 HD-07445. The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
Present address of P. J. Reeds: University of Illinois, Department of Animal Sciences, 1207 W. Gregory, Room 432, Urbana, IL 61801. Present address of R. Vann: CMREC, Mississippi State University, 1320 Seven Springs Rd., Raymond, MS 39154.
Address for reprint requests and other correspondence: T. A. Davis, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1100 Bates St., Houston, TX 77030 (E-mail: tdavis{at}bcm.tmc.edu).
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. Section 1734 solely to indicate this fact.
May 28, 2002;10.1152/ajpendo.00081.2002
Received 26 February 2002; accepted in final form 24 May 2002.
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