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Biomedical subjects

S Mohan

Publications and source records attributed to S Mohan.

At least 91 records · Page 5Linked to original sources
PubMed1999

Hammerhead ribozyme-mediated cleavage of the human insulin-like growth factor-II ribonucleic acid in vitro and in prostate cancer cells.

Insulin-like growth factor (IGF)-II plays an important role in fetal growth and development. IGFs are potent mitogens for a variety of cancer cells. A paracrine/autocrine role of IGF-II in the growth of breast and prostate cancer cells has been suggested. To test the role of IGF-II in cancer cell growth, hammerhead ribozymes targeted to human IGF-II RNA were constructed. Single (R)- and double (RR)-ribozymes were catalytically active in vitro whereas mutant ribozymes (M or MM) did not cleave IGF-II RNA. RR was more active than R. In human prostate cancer PC-3 cells, both R and RR similarly suppressed IGF-II messenger RNA (mRNA) levels (approximately 40%) compared with the level in parental or M-expressing PC-3 cells. Polymerase II and III promoter-driven R similarly suppressed IGF-II mRNA levels. Suppression of IGF-II mRNA levels by R was associated with suppression of IGF-II protein levels. R- (or RR-) expressing PC-3 cells did not grow under serum-starved conditions and showed prolonged doubling times in the presence of 10% FCS compared with those of parental or M-expressing cells. These results substantiated that IGF-II plays a critical role in prostate cancer cell growth.

Base Sequence↗
PubMed1999

Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein-4 (IGFBP-4) and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group.

Children with chronic renal failure (CRF) have high serum levels of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), -2, and -6. The excess IGFBP-2 and -1 may play a role in the growth failure of CRF children by sequestering IGF peptides. In contrast, IGFBP-3 levels rise with GH treatment of CRF children, suggesting a role for IGFBP-3 in their accelerated growth. The present studies used sensitive and specific antisera to characterize levels and forms of IGFBP-4 and -5 in serum from CRF children. By RIA, the mean baseline serum level of IGFBP-4 was high in CRF children compared to that in normal children, but the IGFBP-4 level in CRF serum did not correlate with height SD score; by immunoblot, high CRF levels were associated with increases in both intact and fragmented IGFBP-4. Mean RIA levels of IGFBP-5 were comparable in sera from CRF and normal children. Treating CRF children with GH for 12 months increased serum IGFBP-4 levels by 26% and IGFBP-5 levels by 49%, as determined by RIA; levels of IGFBP-5, but not IGFBP-4, correlated significantly with serum levels of IGF-I, IGF-II, IGFBP-3, and acid-labile subunit and with growth rate in these GH-treated children. In summary, IGFBP-4 levels are high in serum of CRF children, and GH increases serum levels of IGFBP-4 and IGFBP-5 in these children. The data suggest a role for IGFBP-5 in the accelerated growth of GH-treated CRF children, perhaps as part of a ternary complex with acid-labile subunit and IGFs. Additional studies on the relationship between intact IGFBP-4 levels and growth are needed to determine what role IGFBP-4 plays in the linear growth process in vivo.

Body Height↗
PubMed1999

Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness.

Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of the metabolic effectiveness of this novel trophic endocrine strategy. Fourteen patients (mean +/- SD age, 68 +/- 11 yr), critically ill for 40 +/- 28 days, were compared to a matched group of community-living control subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1 + 1 microg/kg x h) infusion in random order. At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol. After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. -6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectably altered. In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.

Adult↗
PubMed1999

Studies on the potential mediators of skeletal changes occurring during puberty in girls.

In this study we evaluated the role of cytokines and insulin-like growth factor (IGF) system in mediating the skeletal changes that occur during puberty by determining the relationship between serum levels of cytokines and IGF system components vs. 1) bone formation and resorption parameters in serum and urine, 2) bone density, and 3) metacarpal bone indexes in 65 pubertal girls. Lumbar bone mineral density and metacarpal width increased significantly both between Tanner stages (TS) II and III and between TS III and IV, whereas metacarpal length and serum levels of stimulatory IGF system components increased significantly only between TS II and III. Biochemical markers of bone turnover were significantly less in TS IV girls than in TS II and III girls. In general, serum levels of IGF system components showed a significant positive correlation to bone density in TS II and III girls, whereas bone resorption markers corrected for creatinine showed a significant negative correlation to bone density in TS III and IV girls. Serum levels of IGF system components showed a significant positive correlation to serum osteocalcin levels as well as metacarpal width in TS II girls, whereas urinary levels of bone resorption markers showed a significant negative correlation to metacarpal width in TS IV girls. Serum levels of interleukin-6 were decreased during late puberty and were negatively correlated with bone density in TS III and IV girls. Our data are consistent with a model in which the sex steroid hormone-induced increase in the IGF system leads to an increase in longitudinal growth and periosteal bone expansion, whereas the sex steroid hormone-induced reduction in bone turnover (possibly via cytokines) leads to an increase in cortical thickness via endosteal regulation.

Adolescent↗
PubMed1999

Mechanical strain stimulates ROS cell proliferation through IGF-II and estrogen through IGF-I.

The mechanism by which mechanical strain stimulates bone cell proliferation was investigated and compared with that of estrogen in ROS 17/2.8 cells. Similarity of strain-related responses between ROS cells and osteoblasts was established by demonstrating that ROS cells respond to a short single period of strain in their substrate (1000-3500 microepsilon, 600 cycles, 1 Hz) by a similar strain magnitude-related increase in glucose 6-phosphate dehydrogenase activity as rat osteoblasts and osteocytes in explants in situ. ROS17/2.8 cells also showed similar proliferative responses to strain and 17beta-estradiol, as assessed by [3H]thymidine incorporation and cell counting, as primary cultures of long bone-derived osteoblast-like cells. Strain-related increase in proliferation in ROS cells was accompanied by a 4-fold increase in levels of insulin-like growth factor-II (IGF-II) in conditioned medium. Neither strain nor estrogen had an effect on the conditioned medium levels of IGF-I. Exogenous truncated IGFs tIGF-I and tIGF-II both increased proliferation in a dose-dependent manner. The neutralizing monoclonal antibody (nMAb) to IGF-I blocked proliferation stimulated by tIGF-I but not that due to tIGF-II and vice versa. IGF-I receptor blocking antibody (IGF-IRBAb) blocked the proliferative effect of tIGF-I but not that to tIGF-II. The proliferative effect of estrogen was abolished by IGF-I nMAb and IGF-IRBAb, but these antibodies had no effect on the proliferative response to strain. In contrast IGF-II nMAb abolished the proliferative effect of strain but had no effect on that of estrogen. These data show that ROS17/2.8 cells have similar responses to strain and estrogen qualitatively and quantitatively as rat osteoblasts in situ and rat long bone-derived osteoblast-like cells in primary culture. Estrogen-related proliferation in ROS17/2.8 cells appears to be mediated by IGF-I acting through the IGF-I receptor and does not involve IGF-II. In contrast, strain-related proliferation appears to be mediated by IGF-II and does not involve either IGF-I or the IGF-I receptor.

Animals↗
PubMed1999

Studies on the role of human insulin-like growth factor-II (IGF-II)-dependent IGF binding protein (hIGFBP)-4 protease in human osteoblasts using protease-resistant IGFBP-4 analogs.

To characterize the insulin-like growth factor binding protein-4 (IGFBP-4) protease produced by human osteoblasts (hOBs), we localized and determined the role of the proteolytic domains in human IGFBP-4 (hIGFBP-4) in modulating IGF-II actions. N-terminal amino acid sequence and mass spectrometric analyses of the 6xHis-tagged IGFBP-4 proteolytic fragments revealed that Met135-Lys136 was the only cleavage site recognized by the IGF-II-dependent IGFBP-4 protease produced by hOBs. This cleavage site was confirmed by the finding that deletion of His121 to Pro141 blocked proteolysis. However, unexpectedly, deletion of Pro94 to Gln119 containing no cleavage site had no effect on IGF-II binding activity but blocked proteolysis. Addition of the synthetic peptide corresponding to this region at concentrations of 250 or 1000 molar excess failed to block IGFBP-4 proteolysis. These data suggest that residues 94-119 may be involved in maintaining the IGFBP-4 conformation required to expose the cleavage site rather than being involved in direct protease-substrate binding. To determine the physiological significance of the IGF-II-dependent IGFBP-4 protease, we compared the effect of the wild-type IGFBP-4 and the protease-resistant IGFBP-4 analogs in blocking IGF-II-induced cell proliferation in normal hOBs, which produce IGFBP-4 protease, and MG63 cells, which do not produce IGFBP-4 protease. It was found that protease-resistant IGFBP-4 analogs were more potent than the wild-type protein in inhibiting IGF-II-induced cell proliferation in hOBs but not in MG63 cells. These data suggest that IGFBP-4 proteolytic fragments are not biologically active and that IGFBP-4 protease plays an important role in regulating IGFBP-4 bioavailability and consequently the mitogenic activity of IGFs in hOBs.

Amino Acid Sequence↗
PubMed1999

Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis.

Both a decrease in bone formation and an increase in bone resorption have been implicated in the pathogenesis of age-related (type II) femoral neck osteoporosis. While the increase in the bone resorption rate has been shown to be partially related to secondary hyperparathyroidism, the mechanisms underlying the decline in bone formation have not yet been identified. The aim of the present study was to test the hypothesis that the bone formation deficit associated with type II osteoporosis might be due to secondary hyperparathyroidism and/or to a deficiency of the insulin-like growth factor (IGF) system. Circulating concentrations of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, 25-hydroxycholecalciferol (25(OH)D3), and intact parathyroid hormone (PTH) were measured in 50 elderly women after sustaining a hip fracture and in 50 healthy age-matched controls. In addition, serum levels of osteocalcin (OC), skeletal alkaline phosphatase, and N-terminal procollagen peptide and urinary pyridinium cross-links were determined as markers of bone remodeling, and bone mineral density (BMD) was assessed at the proximal femur. In the patient group, serum was drawn within 18 h of the fracture and prior to surgery. Circulating protein concentrations did not change over this time frame. No difference was found between mean IGFBP-4 serum levels in the two groups studied, while mean levels of IGF-I, IGF-II, IGFBP-3, IGFBP-5, 25(OH)D3, and markers of bone formation were significantly lower (p < 0.006) in patients as compared with healthy subjects. Serum PTH and urinary pyridinium cross-links, however, were markedly increased (p < 0.001) in the osteoporotic group. In pooled data from the normal and osteoporotic populations, age-adjusted multiple regression models based on IGF-I, IGF-II, IGFBP-3, and IGFBP-5 were found to be highly predictive of serum OC (R2 = 19%, p < 0.001) and BMD of femoral neck (R2 = 49%, p < 0.0001), consistent with an effect of the anabolic IGF components on overall bone formation rate. Similar models based on 25(OH)D3 and PTH, however, were statistically unrelated to OC. To address further the potential impact of trauma on circulating IGF system components, we measured IGF system component levels in 10 male patients within 18 h following tibial fracture and in 10 age-matched normal male subjects. There was no significant difference in serum level of any of the IGF system components between the two groups. Although limited by its cross-sectional design, the present study suggests that, in addition to bone resorption resulting from secondary hyperparathyroidism, impaired bone formation associated with deficiency of the IGF system might predispose elderly women to fragility fracture of the proximal femur.

Age Factors↗
PubMed1998

Regulation of insulin-like growth factors I and II and their binding proteins in human bone marrow stromal cells by dexamethasone.

Glucocorticoids inhibit the proliferation, but induce the differentiation, of bone marrow stromal cells into osteoblast-like cells. The mechanisms, however, are still conjectural. Since insulin-like growth factors (IGFs) have profound effects on osteoblast growth and differentiation, it is possible that glucocorticoids exert their effects on bone marrow stromal cells in part via regulation of IGFs. Therefore, we analyzed the effects of dexamethasone (Dex) on the expression of IGF I and IGF II in cultured preosteoblastic normal human bone marrow stromal cells (HBMSC). Whereas Dex decreased the concentration of IGF I in the conditioned medium since early in the treatment, the concentration of IGF II was increased progressively as culture period lengthened. As the activities of IGF I and IGF II are regulated by the IGF binding proteins (IGFBPs), we analyzed the effects of Dex on the expression of IGFBPs. Dex increased IGFBP-2 in a time-dependent manner. The increase in IGFBP-2, however, was only to the same extent as that of IGF II at most, depending on the length of treatment. Therefore, the increase in IGFBP-2 would dampen, but not eliminate, the increased IGF II activities. By contrast, Dex decreased IGFBP-3 levels, the latter increasing the bioavailability of IGF II. Although IGFBP-4 mRNA levels were stimulated by Dex, IGFBP-4 concentration in the conditioned medium was unchanged as measured by RIA. IGFBP-5 and IGFBP-6 mRNA levels were decreased by Dex in a time-dependent fashion. IGFBP-5 protein level was also decreased 1-4 days after Dex treatment. IGFBP-1 mRNA was not detectable in HBMSC. These accumulated data indicate that Dex regulates IGF I and IGF II and their binding proteins differentially in normal human bone marrow stromal cells. The progressive increase in IGF II may contribute to Dex-induced cell differentiation.

Blotting, Northern↗
PubMed1998

Structure-function analysis of the human insulin-like growth factor binding protein-4.

To identify the molecular mechanism by which insulin-like growth factor binding protein-4 (IGFBP-4) exerts its inhibitory effects on insulin-like growth factor (IGF) actions, we localized and determined the role of the IGF binding domain in modulating IGF actions in human osteoblasts. Deletion analysis using IGFBP-4 expressed in bacteria revealed that the N-terminal sequence Leu72-Ser91 was essential for IGF binding. The C-terminal fragments (His121-Glu237 or Arg142-Glu237) did not bind to IGF but loss of these regions decreased IGF binding activity. Detailed deletion analysis identified the residues Cys205-Val214 as the motif to facilitate IGF binding. Mitogenic studies revealed that an IGFBP-4 mutant (His74 replaced by Pro74) and an N-terminal peptide (N terminus to Thr71) with little IGF binding activity failed to inhibit IGF-II-induced human osteoblast proliferation. An N-terminal peptide (N terminus to Asn182) with reduced IGF binding activity inhibited IGF action but with lower potency. In contrast, an IGFBP-4 mutant (His74 replaced with Ala74) exhibited similar IGF binding activity and potency in inhibiting the activity of IGF-II compared with the wild type. Therefore, the N-terminal sequence (Leu72-Ser91) and the C-terminal sequence (Cys205-Val214) are necessary to form the high affinity IGF binding domain, which is the major structural determinant of the IGFBP-4 function.

Amino Acid Sequence↗
PubMed1998

Modulation of insulin-like growth factor actions in L6A1 myoblasts by insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5: a dual role for IGFBP-5.

We have previously shown that the insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of skeletal muscle cells in culture, and that these actions in L6A1 muscle cells may be modulated by three secreted IGF binding proteins (IGFBPs), IGFBP-4, -5, and -6. Since we found that the temporal expression pattern of IGFBP-4 and IGFBP-5 differed dramatically during the transition from proliferating myoblasts to differentiated myotubes, we undertook the current study to examine the effects of purified IGFBP-4 and IGFBP-5 on IGF-stimulated actions in L6A1 muscle cells. As has been shown for other cell types, we found that IGFBP-4 had only inhibitory actions, inhibiting IGF-I and IGF-II-stimulated proliferation and differentiation. In contrast, IGFBP-5 exhibited both inhibitory and stimulatory actions. When added in the presence of 30 ng/ml IGF-I, IGFBP-5 (250 ng/ml) inhibited all markers of the early proliferative response: the tyrosine phosphorylation of the cytoplasmic signaling molecules IRS-1 and Shc, the activation of the MAP kinases, ERK1 and 2, the elevation of c-fos mRNA, the early inhibition of the elevation in myogenin mRNA, and the increase in cell number. In contrast, IGFBP-5 stimulated all aspects of the myogenic response to IGF-I: the later rise in myogenin mRNA, the elevation of creatine kinase activity, and the fusion of myoblasts into myotubes. This dual response to IGFBP-5 was greatest when it was added at a molar ratio of IGFBP-5 to IGF-I of 2:1. In contrast, when IGFBP-5 was added in the presence of IGF-II, it inhibited both proliferation and differentiation. Neither IGFBP had any effect when added in the presence of R3 IGF-I, an analog with substantially reduced affinity for IGFBPs. Our results suggest that the role of IGFBP-4 is mainly to sequester excess IGFs, and thus inhibit all actions. IGFBP-5, however, is capable of eliciting a dual response, possibly due to its unique ability to associate with the cell membrane.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Erythrocyte insulin-like growth factor-L binding in younger and older males.

OBJECTIVE: Insulin-like growth factor-1 (IGF-l) levels are lower in older compared with younger subjects. We tested the hypothesis that the reduction in circulating IGF-l would be accompanied by upregulation in tissue IGF-l binding in at least some tissues. We tested erythrocyte IGF-l binding since blood is an accessible tissue in humans, and there is growing evidence to suggest that erythrocyte IGF-l binding is influenced by circulating IGF-l. DESIGN AND PATIENTS: We compared 9 healthy older males (61-68 years old) with 9 healthy younger males (15-19 years old). MEASUREMENTS: Standard techniques were used to assay circulating IGF-l and IGF binding proteins 1-5 (IGFBPs 1-5). Erythrocyte IGF-l binding was first measured by studies in which native [125l]-IGF-l was displaced with unlabelled native IGF-l. In order to determine a possible role for IGF binding proteins (IGFBP), native [125l]-IGF-l was displaced with des-(1-3)IGF-1, which binds with IGF receptors but not IGFBPs. RESULTS: As expected, circulating IGF-l was significantly lower in the older compared with the younger subjects. In addition, IGFBP-3 and 5 were significantly lower, and IGFBP-4 higher, in older compared with younger subjects. When native [125l]-IGF-l was displaced with unlabelled native IGF-l, the number of IGF-l binding sites per erythrocyte was higher in the older subjects (43 +/- 5 vs. 18 +/- 2, older vs. younger, respectively; P < 0.05). In contrast, when native [125l]-IGF-l was displaced with des-(1-3), IGF-l binding capacity was not different between the two age groups. CONCLUSIONS: Erythrocyte IGF binding was increased in older compared with younger subjects. Surprisingly, the mechanism of the increase may not be a simple up regulation of IGF-l receptors in response to reduced circulating IGF-l, but possibly by an increase in the levels of as yet unidentified erythrocyte membrane-associated IGF binding proteins.

Adolescent↗
PubMed1998

An epidemic of dengue haemorrhagic fever/dengue shock syndrome in tropical India.

An epidemic of dengue haemorrhagic fever/dengue shock syndrome occurred in Chennai, South India in 1989 during and following the rainy season. Sixty-nine infants and children admitted to the Institute of Child Health and Hospital for Children with a brief febrile illness associated with skin and mucous membrane bleeds and/or shock were studied. Forty-nine had antibodies to dengue viruses. The specific serotype of the virus responsible could not be identified owing to cross-reacting antibodies. Primary infection occurred in 11 cases, secondary infection in 17 cases, antibodily titres were indicative of 'probable' dengue infection in 16 and were uninterpretable in five. In 11 cases, serology could not be done. The pattern of disease in these 60 cases was similar, with a high mortality. Haemoconcentration was not a feature in the majority and the Hess test was negative in all those tested. Nine cases with a similar but milder illness tested negative for dengue.

Blood Transfusion↗
PubMed1998

Effects of zinc and other nutritional factors on insulin-like growth factor I and insulin-like growth factor binding proteins in postmenopausal women.

Insulin-like growth factor I (IGF-I) is a critical factor in the regulation of various physiologic effects, including bone formation and protein metabolism. Nutrient intake is a main regulator of circulating IGF-I. The relation of zinc status and IGF-I in adulthood has not been studied adequately even though suboptimal intakes of zinc are reported widely in the elderly. This study examined the relation between calculated nutrient intakes from 119 postmenopausal women and concentrations of IGF-I and IGF binding proteins (IGFBPs). Dietary intake was evaluated by 4-d weighed diet records at baseline and 2 y. Mean intakes of 25 nutrients were calculated. Concentrations of IGF-I and IGFBPs were measured by radioimmunoassays at baseline and 2 y. Mean age (63 +/- 4 y), weight (66 +/- 9 kg), and nutrient intake were correlated with the mean IGF-I concentration at baseline (172 +/- 57 microg/L) and 2 y (142 +/- 43 microg/L). IGF-I concentrations were significantly correlated with mean protein and zinc intake at baseline (r = 0.313, P = 0.001; r = 0.298, P = 0.001, respectively) and 2 y (r = 0.256, P = 0.008; r = 0.331, P = 0.001, respectively). After age, weight, and other nutrient intakes were adjusted for in multiple regression at baseline and 2 y, zinc remained the major determinant of IGF-I concentrations. These results suggest that low zinc intake is associated with low IGF-I concentrations in healthy postmenopausal women and that the effects of zinc may be independent of protein intake.

Aged↗
PubMed1998

Peak oxygen uptake, muscle volume, and the growth hormone-insulin-like growth factor-I axis in adolescent males.

PURPOSE: The growth effects of exercise appear to be mediated in part by central neuroendocrine control reflected in circulating levels of growth hormone (GH), insulin-like growth factor-I (IGF-I), and their binding proteins (BP). In previous studies positive correlations between peak VO2 and circulating IGF-I have been demonstrated. The relationship between peak oxygen uptake and these potential regulating factors has not been examined in adolescent males where patterns of GH pulsatility and levels of IGF-I are rapidly changing. METHODS: Forty-three healthy adolescent males (age 16 +/- 0.7 yr, 70% at Tanner V) performed cycle ergometry to determine p oxygen uptake (peak VO2), and magnetic resonance images to determine the thigh muscle volume. Baseline blood samples were collected for GHBP, the extracellular portion of the GH tissue receptor (by ligand mediated immunofunctional assay), IGF-I (by RIA), and IGFBPs 1-5 (by RIA). Mean GH was determined from samples obtained every 20 min overnight. RESULTS: Peak VO2/kg was positively correlated with mean overnight GH levels (r = 0.41, P < 0.005). Both peak VO2/kg and thigh muscle volume/kg were negatively correlated with GHBP (r = -0.33, P < 0.02) and IGFBP-4 (r = -0.52, P < 0.005). There were no correlations between peak VO2/kg and IGF-I or IGFBPs 1-3, and 5. CONCLUSIONS: GH pulsatility is increased adolescent males who have higher peak VO2, but this did not translate into increases in IGF-I. We speculate that in the fitter males, lower GHBP levels may reduce hepatic sensitivity to GH. Thus, circulating IGF-I was unchanged despite higher mean GH in subjects with higher peak VO2. IGFBP-4 which is known to inhibit IGF-I was negatively correlated with peak VO2 leading, possibly, to increased IGF-I bioactivity. Fitness (as assessed by muscle mass and peak VO2) does modulate the GH-IGF-I axis, but not solely through circulating IGF-I; both GHBP and IGFBPs play important roles.

Adolescent↗
PubMed1998

Increased physical activity and the growth hormone-IGF-I axis in adolescent males.

Insulin-like growth factor-I (IGF-I) is associated with muscle hypertrophy, and circulating IGF-I levels are correlated with fitness. To test the hypothesis that IGF-I increases with increased physical activity in adolescent males, 38 subjects (16 +/- 0.7 yr old) were randomized to control (n = 18) or increased physical activity groups for 5 wk. Before and after the intervention, we measured thigh muscle volume using magnetic resonance imaging and serum levels of mean growth hormone (GH) by overnight multiple sampling, GH binding protein (GHBP), IGF-I, and IGFBPs 1-5 by standard assays. Energy expenditure was assessed with the doubly labeled water technique toward the end of the study. In the training subjects there was 1) a significant increase in thigh muscle volume (+3.6 +/- 1%), 2) 15.5 +/- 3.3% greater energy expenditure than in controls, and 3) no evidence of weight loss (+1.44 +/- 0.4%). In contrast to our hypothesis, but similar to our recent observations in adolescent females, training decreased IGF-I (-12 +/- 4%, P < 0. 005). Moreover, training substantially reduced GHBP (-21 +/- 4%, P < 0.00002) and increased IGFBP-2 (+40 +/- 16%, P < 0.008). Brief training increased muscle volume in weight-stable adolescent males and, surprisingly, influenced not only IGF-I but GHBP and IGFBP-2 as well in a manner typically found in energy-deficient states.

Adolescent↗