Effects of growth hormone on growth and muscle Na(+)-K+ pump concentration in K(+)-deficient rats

1992 ◽  
Vol 262 (4) ◽  
pp. E511-E517 ◽  
Author(s):  
I. Dorup ◽  
A. Flyvbjerg ◽  
M. E. Everts ◽  
H. Orskov
Keyword(s):  
Growth Hormone ◽  
Binding Site ◽  
Serum Insulin ◽  
Human Growth ◽  
Ouabain Binding ◽  
Muscle Weight ◽  
Igf I ◽  
Total Thyroxine ◽  
K Deficiency ◽  
Edl Muscle

K(+)-deficient rats and control rats were injected for 16 days with saline or human growth hormone (hGH, 200 micrograms/day). hGH treatment of K(+)-deficient rats resulted in increased weight gain and soleus muscle weight. Extensor digitorum longus (EDL) muscle weight and tail and tibia length were unchanged. In control rats, hGH induced an increase in all weight and length parameters. K+ deficiency was associated with reduced serum insulin-like growth factor I (IGF-I) and serum insulin but unchanged total 3,5,3'-triiodothyronine (TT3) and total thyroxine. hGH treatment of the K(+)-deficient rats restored serum IGF-I, but not serum insulin, and decreased TT3. In saline-treated K(+)-deficient rats [3H]ouabain binding site concentration decreased by 44 and 39% in soleus and EDL muscle, respectively, as compared with the saline-treated controls. hGH had no effect on the [3H]ouabain binding site concentration in the K(+)-deficient group, but, in control rats, increases of 11 and 8% were observed in soleus and EDL muscle, respectively. When the increase in muscle weight was taken into account, this amounted to relative increases of 24 and 30%, respectively. Low circulating GH and IGF-I levels are not the sole explanation for the growth retardation in K+ deficiency. GH/IGF-I stimulate the synthesis of Na(+)-K+ pumps in rats with an otherwise normal hormonal status.

Effects of IGF-I infusion on growth and muscle Na(+)-K+ pump concentration in K(+)-deficient rats

1993 ◽  
Vol 264 (5) ◽  
pp. E810-E815 ◽  
Author(s):  
I. Dorup ◽  
A. Flyvbjerg
Keyword(s):  
Binding Site ◽  
Control Group ◽  
Recombinant Human Insulin ◽  
Ouabain Binding ◽  
Muscle Weight ◽  
Igf I ◽  
Organ Specific ◽  
K Deficiency ◽  
Edl Muscle

K(+)-deficient rats and control rats were infused for 14 days with vehicle: acetic acid (AcA) or recombinant human insulin-like growth factor-I (IGF-I, 240 micrograms/day) by osmotic minipumps. IGF-I treatment of K(+)-deficient rats did not result in overall growth of carcass or muscles but in marked selective growth of adrenals (+42%) and spleen (+66%). In control rats, IGF-I induced increased body and muscle weight, tibia length, and thymus weight. K+ deficiency was associated with reduced serum IGF-I but unchanged thyroid status. IGF-I treatment of the K(+)-deficient rats restored serum IGF-I and decreased total 3,5,3'-triiodothyronine. In AcA-treated K(+)-deficient rats [3H]ouabain binding site concentration decreased by 63 and 43% in soleus and extensor digitorum longus (EDL) muscle, respectively, compared with the AcA-treated controls. IGF-I had no effect on the [3H]ouabain binding site concentration in the control group, but in K(+)-deficient rats a significant lowering of 26% was observed in EDL. K+ deficiency causes relative organ-specific resistance to the growth-promoting effects of IGF-I, comparable to the effects seen in protein-restricted rats. Reduced circulating IGF-I is not the only cause of the downregulation of Na(+)-K+ pumps in K+ deficiency, and IGF-I treatment of control animals in vivo has no stimulatory effect on the synthesis of Na(+)-K+ pumps.

Effects of four years' treatment with biosynthetic human growth hormone (GH) on body composition in GH-deficient hypopituitary adults

1996 ◽  
Vol 135 (5) ◽  
pp. 559-567 ◽  
Author(s):  
Kamal AS AI-Shoumer ◽  
Brian Page ◽  
Elizabeth Thomas ◽  
Margaret Murphy ◽  
Salem A Beshyah ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Composition ◽  
Body Weight ◽  
Human Growth Hormone ◽  
Serum Insulin ◽  
Human Growth ◽  
Fat Free Mass ◽  
Gh Treatment ◽  
Igf I ◽  
Total Body

Al-Shoumer KAS, Page B, Thomas E, Murphy M, Beshyah SA, Johnston DG. Effects of four years' treatment with biosynthetic human growth hormone (GH) on body composition in GH-deficient hypopituitary adults. Eur J Endocrinol 1996;135:559–67. ISSN 0804–4643 Short-term trials of growth hormone (GH) substitution in hypopituitary adults have shown beneficial effects on body composition. To evaluate the long-term effects on body composition, we followed thirteen GH-deficient adults (GH < 6 mU/l following standard provocative tests) for 4 years of GH replacement. At yearly intervals, serum insulin-like growth factor I (IGF-I), body weight, body mass index (BMI), waist, waist-to-hip circumference ratio (WHR) and resting systolic (SBP) and diastolic blood pressure (DBP) were determined, and body composition was assessed using three independent methods: total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA). Compared to baseline, IGF-I levels increased significantly at 1 (p = 0.0001), 2 (p = 0.0004), 3 (p = 0.006) and 4 years (p = 0.002). Body weight and BMI changed minimally at 1, 2 and 3 years and increased significantly only at the fourth year (p = 0.012 and p = 0.0009, respectively) of GH therapy. Waist and WHR decreased significantly at 1, 2 and 4 years (waist: p = 0.0009, p = 0.0004, p = 0.049; WHR: p = 0.0025, p = 0.012, p = 0.047, respectively). Neither resting SBP nor DBP changed significantly. Fat-free mass (FFM) derived from TBK and BIA increased significantly at 1 (p = 0.004; p = 0.004), 2 (p = 0.003; p = 0.05), 3 (p = 0.005; p = 0.04) and 4 years (p = 0.02; p = 0.002). Using DXA, the increase in FFM was significant at 1 (p = 0.007) and 2 years (p = 0.008) but not at 3 and 4 years. Percentage body fat measured by TBK, BIA and DXA decreased significantly at 1 (p = 0.008; p = 0.003; p = 0.03), 2 (p = 0.018; p = 0.06; p = 0.049) and 4 years (p = 0.03; p = 0.002; p = 0.04). A rise in total body water, calculated from BIA, was observed at 1 year (p = 0.004) and was maintained throughout the treatment period. These data demonstrate that 4 years of GH treatment in hypopituitary adults is associated with sustained improvement in body composition. Kamal AS Al-Shoumer, Unit of Metabolic Medicine, Imperial College School of Medicine at St. Mary's Hospital, Norfolk Place, London W2 1PG, UK

scholarly journals Amino acid substitutions in human growth hormone affect coiled-coil content and receptor binding

2021 ◽  
Author(s):  
Andrei Rajkovic ◽  
Sandesh Kanchugal ◽  
Eldar Abdurakhmanov ◽  
Rebecca Howard ◽  
Astrid Gräslund ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Amino Acid ◽  
Binding Site ◽  
Human Growth Hormone ◽  
Receptor Binding ◽  
Coiled Coil ◽  
Human Growth ◽  
Zinc Binding ◽  
Amino Acid Substitutions ◽  
Great Relevance

The interaction between human Growth Hormone (hGH) and hGH Receptor (hGHR) has great relevance to human diseases such as acromegaly and cancer. HGH has been extensively engineered by other workers to improve binding and other properties. We used a computational screen to select substitutions at single hGH positions within the hGHR-binding site. We find that, while many successfully slow down dissociation of the hGH-hGHR complex once bound, they also slow down the association of hGH to hGHR. We are particularly interested in E174 which belongs to the hGH zinc-binding triad, and which spans coiled-coil helices and obeys the coiled-coil heptad pattern. Surprisingly, substituting E174 with A leads to substantial increase in an experimental measure of coiled-coil content. E174A is known to increase affinity of hGH against hGHR; here we show that this is simply because the off-rate is slowed down more than the on-rate, in line with what has been found for other affinity-improving mutations. For E174Y (and mutations at other sites) the slowdown in on-rate was greater, leading to decreased affinity. The results point to a link between coiled-coiling, zinc binding, and hGHR-binding affinity in hGH, and also suggest rules for choosing affinity-increasing substitutions.

Maintenance of myonuclear domain size in rat soleus after overload and growth hormone/IGF-I treatment

1998 ◽  
Vol 84 (4) ◽  
pp. 1407-1412 ◽  
Author(s):  
G. E. McCall ◽  
D. L. Allen ◽  
J. K. Linderman ◽  
R. E. Grindeland ◽  
R. R. Roy ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Domain Size ◽  
Cross Sectional Area ◽  
Sectional Area ◽  
Muscle Weight ◽  
Cross Sectional ◽  
Igf I ◽  
Myonuclear Domain ◽  
The Difference ◽  
Saline Vehicle

The purpose of this study was to determine the effects of functional overload (FO) combined with growth hormone/insulin-like growth factor I (GH/IGF-I) administration on myonuclear number and domain size in rat soleus muscle fibers. Adult female rats underwent bilateral ablation of the plantaris and gastrocnemius muscles and, after 7 days of recovery, were injected three times daily for 14 days with GH/IGF-I (1 mg/kg each; FO + GH/IGF-I group) or saline vehicle (FO group). Intact rats receiving saline vehicle served as controls (Con group). Muscle wet weight was 32% greater in the FO than in the Con group: 162 ± 8 vs. 123 ± 16 mg. Muscle weight in the FO + GH/IGF-I group (196 ± 14 mg) was 59 and 21% larger than in the Con and FO groups, respectively. Mean soleus fiber cross-sectional area of the FO + GH/IGF-I group (2,826 ± 445 μm2) was increased compared with the Con (2,044 ± 108 μm2) and FO (2,267 ± 301 μm2) groups. The difference in fiber size between the FO and Con groups was not significant. Mean myonuclear number increased in FO (187 ± 15 myonuclei/mm) and FO + GH/IGF-I (217 ± 23 myonuclei/mm) rats compared with Con (155 ± 12 myonuclei/mm) rats, although the difference between FO and FO + GH/IGF-I animals was not significant. The mean cytoplasmic volume per myonucleus (myonuclear domain) was similar across groups. These results demonstrate that the larger mean muscle weight and fiber cross-sectional area occurred when FO was combined with GH/IGF-I administration and that myonuclear number increased concomitantly with fiber volume. Thus there appears to be some mechanism(s) that maintains the myonuclear domain when a fiber hypertrophies.

scholarly journals A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly

2018 ◽  
Vol 179 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Peter J Trainer ◽  
John D C Newell-Price ◽  
John Ayuk ◽  
Simon J B Aylwin ◽  
Aled Rees ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Human Growth ◽  
Phase 2 ◽  
Open Label ◽  
Parallel Group ◽  
Igf I ◽  
Secondary Endpoints ◽  
Efficacy Measures ◽  
Hormone Binding Protein ◽  
Antisense Oligonucleotide Therapy

Objective ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. Design Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. Methods The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Results and conclusions Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.

Human growth hormone effect on serum IGF-I and muscle function in poliomyelitis survivors

1994 ◽  
Vol 75 (8) ◽  
pp. 889-894 ◽  
Author(s):  
Krishan L. Gupta ◽  
Kaup R. Shetty ◽  
James C. Agre ◽  
Mary C. Cuisinier ◽  
Inge W. Rudman ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Human Growth Hormone ◽  
Muscle Function ◽  
Human Growth ◽  
Hormone Effect ◽  
Igf I

Urinary growth hormone excretion in acromegaly: diagnostic value in mild disease activity

1993 ◽  
Vol 129 (5) ◽  
pp. 409-413 ◽  
Author(s):  
Katharina M Main ◽  
Jörgen Lindholm ◽  
Mark Vandeweghe ◽  
Niels E Skakkebaek
Keyword(s):  
Growth Hormone ◽  
Disease Activity ◽  
Clinical Symptoms ◽  
Serum Insulin ◽  
Elevated Serum ◽  
Diagnostic Value ◽  
Activity Score ◽  
Clinical Activity ◽  
Igf I ◽  
Serum Gh

The biochemical assessment of disease activity in acromegaly still presents a problem, especially in treated patients with mild clinical symptoms. We therefore examined the diagnostic value of the measurement of urinary growth hormone (GH) excretion in seventy unselected patients with acromegaly of different activity by comparing it to serum GH, serum insulin-like growth factor I (IGF-I) and clinical activity. There were highly significant, positive correlations between urinary GH and serum GH, serum IGF-I as well as clinical activity score (p<0.00005), although some overlap between the groups was observed. In seven patients with low serum GH values (<2.0 μg/l) discordant results were found. Two of the seven patients were clinically mildly active, but only IGF-I was either elevated or within the upper normal range; in three other patients who appeared clinically cured either IGF-I (N = 1) or urinary GH (n = 2) alone were increased. In the remaining two patients elevated serum IGF-I and urinary GH as well as activity score suggested disease activity. Thus, in the majority of cases, urinary GH was significantly correlated to the other three parameters, but added little information to that obtained by serum IGF-I. In conclusion, urinary GH measurements in difficult cases may provide a more direct information on the GH status than IGF-I.

Hemoglobin level is linked to growth hormone-dependent proteins in short children

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 2075-2081 ◽  
Author(s):  
E Vihervuori ◽  
M Virtanen ◽  
H Koistinen ◽  
R Koistinen ◽  
M Seppala ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Skeletal Dysplasia ◽  
Recombinant Human Growth Hormone ◽  
Body Height ◽  
Human Growth ◽  
Gh Treatment ◽  
Blood Hemoglobin ◽  
Igf I ◽  
Igfbp 3

Erythropoiesis was investigated in 32 children wih short stature and in eight children with skeletal dysplasia by studying blood hemoglobin in relation to growth and to serum concentrations of insulin-like growth factor I (IGF-I), IGF binding protein-3 (IGFBP-3), and erythropoietin (EPO) before, during, and after 12 months of recombinant human growth hormone (GH) treatment. Blood hemoglobin concentration was positively correlated with relative body height and with serum IGF-I and IGFBP-3 levels (P = .001 to .02), but not with the concentrations of EPO. The normal age-dependency of hemoglobin was lacking. Hemoglobin levels and their responses to GH treatment were similar in the patients with GH deficiency and those with normal GH secretion. Treatment with GH accelerated growth and elevated the concentrations of hemoglobin, IGF- I, and IGFBP-3. In the eight patients with skeletal dysplasia, body mass increased similarly, but gain in height was less than in the other patients, and the increase in hemoglobin was markedly pronounced. In this group, the correlations between hemoglobin, IGF-I, and IGFBP-3 were extremely close (r = 0.80 to 0.85, P = .031 to .008). These findings are in accord with earlier observations from in vitro and animal studies, and suggest that the GH-IGF axis is involved in the physiologic elevation of hemoglobin levels during childhood.

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