Measurement of IGF-1, IGFBP-3 and free IGF-1 levels by ELISA in growth hormone (GH) deficient children before and after GH replacement

Serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels reflect the growth hormone (GH) status. A few percent of IGF-1 circulate in a free form which is believed to represent the IGF biological activity. We retrospectively studied the changes of serum IGF-1, serum IGFBP-3, and plasma free IGF-1 levels in growth hormone deficient (GHD) children before and after treatment with recombinant human growth hormone (rhGH) for a period of 6 months and 1 year. Twenty-one GHD children (16 boys and 5 girls) who had the mean chronological and bone ages of 7.7 +/- 0.7 and 4.8 +/- 0.6 years, respectively, were treated with a mean rhGH dose of 11.66 +/- 0.42 U/m2 body surface area/week. Serum IGF-1 level increased from 162.5 +/- 42.9 ng/ml before treatment to 252.8 +/- 49.5 ng/ml (p = 0.007) and 282.7 +/- 86.9 ng/ml after treatment for 6 months and 1 year, respectively. Plasma free IGF-1 also increased from 0.38 +/- 0.30 ng/ml before treatment to 1.21 +/- 0.30 (p = 0.001) and 1.17 +/- 0.42 ng/ml after 6 months and 1 year of treatment. However, serum IGFBP-3 did not significantly increase after treatment. In addition, the free/total IGF-1 ratio decreased after treatment with rhGH. The height velocities at 6 months and 1 year after treatment were negatively correlated with plasma free IGF-1 before treatment. In conclusion, therefore, plasma free IGF-1 levels could serve as a good predictor of growth hormone responses. Furthermore, their circulating levels would be modified by serum IGF-1 status, and possibly, IGFBP-3 protease activity.     

IGF-1R,IGF-1 and IGF-2 expression as potential prognostic and predictive markers in colorectal-cancer

Insulin-like growth factors (IGF-1 and IGF-2) and the IGF-1 membrane receptor (IGF-1R) have been found to play a critical role in the carcinogenesis of several tumors, among them colorectal cancer (CRC). To study the prognostic impact of these molecules, a total number of 713 cases of CRC were examined for the expression of IGF-1, IGF-2, and IGF-1R. The results were correlated with other clinicopathological data and clinical follow-up. IGF-1 expression was noted in 53 (7.5%), IGF-2 in 88 (12.6%), and IGF-1R in 698 (99.6%) of the cases. There were significant associations between the two growth factors (P<0.00001), between IGF-1 and Ki-67 proliferation activity (P<0.05), and between IGF-2 and tumor stage (P<0.005). IGF-2 positivity was significantly correlated to a worse clinical outcome (P<0.005) only in univariate, but not in multivariate, survival analysis. A similar trend was obtained for patients with IGF-1-positive CRC, but reached statistical significance only in limited tumor stages (pT1/pT2; P<0.01). Although the synchronous expression of IGF-1, IGF-2, and IGF-1R in a subset of CRC is consistent with an auto-/paracrine loop of cancer cell autostimulation, the prognostic effect of IGF-1 and IGF-2 expression seems to be of limited value. However, the identification of IGF-positive CRC might be beneficial for predictive reasons, as new molecular therapeutic approaches are aimed at the IGF system and related pathways.     

TGF-beta 1 and IGF-1 expression in atrophic post-menopausal endometrium

OBJECTIVES: Endometrial cells may synthetize cytokines and growth factors which may modulate some of the molecular mechanisms of endometrial proliferation and differentiation. PATIENTS AND METHODS: We investigated the role of transforming growth factor beta-1 (TGF-beta 1), insulin-like growth factor-1 (IGF-1) and relative receptors in five tissue samples from atrophic post-menopausal endometria. The control group was represented by proliferative and secretory endometria from 10 healthy, normally-menstratued women. TGF-beta 1 and IGF-1 m-RNA expression was evaluated by Northern hybridization analysis, while TGF-beta 1 and IGF-1 receptors distribution was studied by immunohistochemistry. RESULTS: In atrophic endometria Northern hybridization analysis showed a significant decrease of IGF-1 expression, and an increase of TGF-beta 1 expression compared to proliferative and secretory endometria. By immunohistochemistry it was demonstrated that TGF-beta 1 and IGF-1 receptors were both localized in cell cytoplasm, mainly in the stromal compartment. CONCLUSIONS: The results of our study would suggest a possible role of IGF-1 and TGF-beta 1 in maintaining the quiescent differentiative state of atrophic post-menopausal endometrium. The persistence of IGF-1 and TGF-beta 1 receptors in epithelial compartment could play a key role in proliferative response of atrophic endometrium to exogenous hormone replacement therapy (HRT) or endogenous intervening high estrogens levels.     

Cyclin D1在肌萎缩侧索硬化症转基因小鼠大脑皮层和海马中的表达

目的:通过检测细胞周期相关蛋白D1(Cyclin D1)在肌萎缩侧索硬化症(ALS)转基因小鼠大脑皮层和海马中的表达变化,探讨Cyclin D1表达改变与ALS发病的关系。方法:选取成年ALS小鼠和同窝野生型小鼠,于发病早、中、晚期(95 d,108 d,122 d)取材,应用免疫荧光技术检测Cyclin D1在大脑皮层和海马的表达规律及与神经元和星形胶质细胞的共定位关系,应用RT-PCR检测Cyclin D1 mRNA表达情况,应用免疫印迹法检测蛋白表达量的改变。结果:ALS小鼠和野生型小鼠大脑皮层和海马中均可检测到Cyclin D1阳性细胞,且与神经元共表达。在发病早、中、晚期,ALS小鼠大脑皮层中Cyclin D1 mRNA和蛋白表达较野生型鼠增多(P0.05,P0.01,P0.001);与同窝野生型小鼠相比,ALS小鼠海马中Cyclin D1 mRNA和蛋白在发病的早、中、晚期表达均降低(P0.05,P0.01,P0.001)。Cyclin D1阳性细胞主要分布在海马CA区(包括CA1、CA2和CA3),DG区仅散在表达。结论:Cyclin D1在ALS转基因小鼠大脑皮层和海马中表达异常,表明Cyclin D1调节的细胞周期改变与ALS大脑皮层和海马区病变密切相关。     

Depressed nNOS expression during spine transition in the developing hippocampus of FMR1 KO mice

Nitric oxide (NO), synthesized as needed by NO synthase (NOS), is involved in spinogenesis and synaptogenesis. Immature spine morphology is characteristic of fragile X syndrome (FXS). The objective of this research was to investigate and compare changes of postnatal neuronal NOS (nNOS) expression in the hippocampus of male fragile X mental retardation 1 gene knockout mice (FMR1 KO mice, the animal model of FXS) and male wild-type mice (WT) at postnatal day 7 (P7), P14, P21, and P28. nNOS mRNA levels were analyzed by real-time quantitative PCR (N = 4-7) and nNOS protein was estimated by Western blot (N = 3) and immunohistochemistry (N = 1). In the PCR assessment, primers 5′-GTGGCCATCGTGTCCTACCATAC-3′ and 5′-GTTTCGAGGCAGGTGGAAGCTA-3′ were used for the detection of nNOS and primers 5′-CCGTTTCTCCTGGCTCAGTTTA-3′ and 5′-CCCCAATACCACATCATCCAT-3′ were used for the detection of β-actin. Compared to the WT group, nNOS mRNA expression was significantly decreased in FMR1 KO mice at P21 (KO: 0.2857 ± 0.0150, WT: 0.5646 ± 0.0657; P < 0.05). Consistently, nNOS immunoreactivity also revealed reduced staining intensity at P21 in the FMR1 KO group. Western blot analysis validated the immunostaining results by demonstrating a significant reduction in nNOS protein levels in the FMR1 KO group compared to the WT group at P21 (KO: 0.3015 ± 0.0897, WT: 1.7542 ± 0.5455; P < 0.05). These results suggest that nNOS was involved in the postnatal development of the hippocampus in FXS and impaired NO production may retard spine maturation in FXS.     

ERK1/2信号通路在IGF-1诱导新生小鼠海马神经干细胞增殖分化中的作用

目的:探讨细胞外信号调节激酶1/2(ERK1/2)信号通路在胰岛素样生长因子-1(insulin-like growth factor-1,IGF-1)诱导新生小鼠神经干细胞(neural stem cells,NSCs)增殖分化中的作用。方法:取新生C57BL/6J小鼠海马体外分离、培养NSCs,分别加入终浓度100 ng/ml的IGF-1和20μmol/L的抑制剂U0126。CCK-8试剂盒检测IGF-1对NSCs增殖的影响;免疫荧光细胞染色法检测IGF-1对细胞分化的影响;Western blot检测ERK1/2和p-ERK1/2蛋白的表达,并对各组进行比较。结果:CCK-8测定细胞增殖,第3 d U0126组相对OD值显著低于IGF-1组,第7 d时IGF-1组OD值则显著高于对照组和U0126组(P<0.05)。倒置荧光显微镜下可观察到IGF-1组βⅢTubulin和GFAP阳性分化率均明显高于对照组和U0126组(P<0.05)。Western blot结果显示:IGF-1组蛋白表达量显著高于对照组和U0126组(P<0.05),IGF-1促进ERK磷酸化,U0126则抑制ERK的活化。结论:IGF-1可显著诱导NSCs的增殖和分化,ERK1/2信号通路可能具有重要作用,同时IGF-1可能参与ERK1/2的活化。     

携带小鼠IGF-1基因的慢病毒载体构建及其在神经干细胞中的表达

目的:构建含有小鼠胰岛素样生长因子-1(IGF-1)基因的慢病毒载体,鉴定其在神经干细胞(NSCs)中的表达。方法:采用RT-PCR方法从小鼠的骨骼肌细胞中扩增IGF-1基因,克隆入pcDNA3.1质粒,构建慢病毒载体pXZ9-IGF-1。用脂质体介导三质粒共转染法转染293FT细胞,获得病毒上清。分离培养神经干细胞,Nestin免疫荧光化学鉴定。慢病毒感染神经干细胞,显微镜下观察GFP表达情况,通过RT-PCR及ELISA试剂盒分别从mRNA和蛋白水平检测IGF-1的表达。结果:通过RT-PCR法从小鼠的骨骼肌细胞中扩增出IGF-1基因并克隆入pcDNA3.1载体,经亚克隆成功构建慢病毒质粒pXZ9-IGF-1。质粒经脂质体转染293FT细胞获高滴度慢病毒颗粒,体外高效感染神经干细胞。神经干细胞经感染后,IGF-1基因mRNA和培养基中蛋白水平均高表达。结论:成功构建含小鼠IGF-1基因的慢病毒载体pXZ9-IGF-1,并在神经干细胞内获得表达。     

Effect of training on GH and IGF-1 responses to a submaximal exercise in football players

To study the effects of regular football training on basal and exercise induced levels of growth hormone (GH) and insulin-like growth factor (IGF-1), 13 young football players were investigated by a submaximal exercise at the beginning of the sporting season in October (S1), at the middle of the season in January (S2) and at the end in May (S3). At each session, an exercise test on an ergogycle was performed for 25 min, beginning with an incremental exercise to reach 90% of theoretical maximal heart, which was maintained for the last 10 min of the test. Venous blood samples were collected at rest, at the end of the exercise and at 30 and 60 min during the recovery period. Plasma lactate and glucose concentrations increased during exercise with no difference found between sessions. GH level increased with exercise at each session but the response was significantly higher in S1 than in S2 and S3 (P<0.01). The GH area under the curve decreased significantly all along the football season (P<0.01); the IGF-1 level did not significantly change during exercise nor with training. Basal insulin-like growth factor binding protein-3 (IGFBP3) remained stable during the three sessions. Football training decreased significantly the exercise-stimulated GH levels all along the football season but did not have any significant effect on IGF-1 levels or on basal IGFBP3 levels.     

姜黄素对糖尿病脑病大鼠海马IGF-1/IGF-1R表达的影响

目的观察姜黄素对糖尿病脑病大鼠胰岛素样生长因子1(IGF-1)、胰岛素样生长因子受体(IGF-1R)表达的影响,分析姜黄素的脑保护作用机制。方法实验动物分为4组:正常对照组(A组)、正常姜黄素组(B组)、糖尿病脑病组(C组)和姜黄素治疗组(D组)。以大鼠一次性腹腔注射链脲佐菌素(STZ)建立糖尿病脑病模型,姜黄素持续灌胃12周。观察大鼠的体质量、血糖、糖化血红蛋白变化,采用免疫组化、RT-PCR法检测IGF-1及IGF-1R表达的变化。结果与A组和B组大鼠相比,C组大鼠血糖、糖化血红蛋白明显增高,体质量下降,海马区IGF-1表达明显减少(P<0.05),同样海马神经元IGF-1R表达减少(P<0.05)。经姜黄素治疗后,D组大鼠糖化血红蛋白下降,体质量增加,血糖变化不大,海马神经元IGF-1表达增多(P<0.05),随之海马神经元IGF-1R表达增多(P<0.05)。结论大鼠海马IGF-1/IGF-1R表达的减少可能在糖尿病脑病发病机制中发挥着重要的作用,姜黄素有脑保护作用,其机制可能是通过调控IGF-1信号通路调节实现的。     

Increased IGF-1 in muscle modulates the phenotype of severe SMA mice

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1(NEG) and mIGF-1(POS) SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients.     

Nestin expression and glial response in the hippocampus of mice after trimethyltin treatment

Nestin is a protein of embryonic intermediate filaments expressed by multipotent neural stem cells. In the present study, the nestin expression pattern in the mouse hippocampus 1, 2, 3, 4, and 8 days after treatment with trimethyltin (TMT) was examined to explore the possible role played by nestin in chemically induced hippocampal injury. TMT treatment (2.5 mg/kg, intraperitoneally) selectively injured the dentate gyrus (DG) of the mouse hippocampus. The level of hippocampal mRNA encoding nestin increased significantly 2 and 3 days post-treatment and thereafter decreased (at 4 and 8 days post-treatment). The level of nestin protein significantly increased 2 – 4 days post-treatment, particularly in the injured region of the DG, and predominantly in glial fibrillary acidic protein-positive astrocytes in the hippocampal DG. Ki67-positive proliferating cells were increased following TMT treatment and co-localized with nestin-positive reactive astrocytes. Thus, we suggest that nestin contributes to remodeling of the chemically injured DG via glial scar formation and the alteration of neurogenesis.     

IGF-1 regulate the expression of uncoupling protein 2 via FOXO1

Abstract

Mitochondria uncoupling protein2 (UCP2) expressed ubiquitously is a key molecule of energy metabolism. Insulin-like growth factor-1 (IGF-1) is a hormone, a target molecule of growth hormone (GH) signal pathway, which is also known as the drug “mecasermin” for clinical usages. IGF-1 is seemed to be closely related to metabolic diseases, such as adult GH deficiency. However, there has not been reports depicted possible relationship with each other. So, we sought to elucidate the mechanisms by which expression of UCP2 is regulated by IGF-1 via FOXO1. The findings suggested that three sequences in the consensus UCP2 promoter play complementary functional roles in the functional expression of FOXO1. So, we found that FOXO1 is involved in IGF-1-mediated energy metabolism greater than that of direct action of GH via STAT5. Our findings suggested that IGF-1 was involved in energy metabolism by regulating the expression of UCP2 via the PI3K/Akt/FOXO1 pathway.     

Effects of exogenous IGF-1 delivery on the early expression of IGF-1 signaling molecules by alginate embedded chondrocytes

Cartilage tissue engineering remains a significant challenge for both researchers and clinicians. Many strategic approaches, such as the delivery of growth factors to an in vitro cultured cartilage construct, continue to receive significant attention. However, the effects of delivering exogenous signaling molecules on endogenous signaling pathways within an engineered tissue are not well understood. In order to address this concern, we have investigated how the delivery of insulin-like growth factor-1 (IGF-1, delivered at concentrations of 0, 10, 50, and 100 ng/mL) affects the endogenous expression of IGF-1, its receptor (IGF-1R), and a well known IGF-1 binding protein (IGFBP-3) by articular chondrocytes embedded in alginate hydrogels over 8 days. To the best of our knowledge, this is the first report of delivery effects upon endogenous signal expression in a three-dimensional system relevant to tissue engineering objectives. Results showed significant differences in mRNA expression of IGF-1, IGF-1R, type II collagen, and type I collagen by day 8 between the induced versus noninduced IGF-1 groups. At day 8, the induced IGF-1 groups expressed IGF-1 mRNA four times lower than the 0 ng/mL IGF-1 group. Further, the IGF-1R mRNA expression was five times higher for the groups exposed to exogenous IGF-1 versus the 0 ng/mL IGF-1 case. Interestingly, the expression of IGFBP-3 decreased for all groups. Type II collagen expression was the highest and type I collagen was the lowest for the IGF-1 delivered samples. Finally, the different concentrations of IGF-1 investigated did not demonstrate significantly different trends in mRNA expression levels. Overall, results indicate that exogenous IGF-1 delivery does affect signaling molecule expression by chondrocytes embedded in alginate hydrogels, particularly downregulating the delivered signal while upregulating its receptor.     

转录因子EB及下游自噬相关基因Beclin1在肌萎缩侧索硬化症转基因鼠海马中的表达变化

目的:探讨TFEB及其下游自噬相关基因Beclin1在95、108 d和122 d肌萎缩侧索硬化症(ALS)转基因鼠大脑海马中的表达情况。方法:分别取95、108 d和122 d ALS转基因鼠和野生型鼠的海马,应用RT-PCR、免疫印迹和免疫荧光,检测TFEB和Beclin1在大脑海马区的表达变化。结果:与同窝野生型鼠比较,ALS转基因鼠TFEBmRNA和蛋白水平在95d升高,108 d和122 d均降低。免疫荧光结果显示,与同窝野生型鼠比较,95 d TFEB免疫阳性反应增强,108 d和122 d减弱。自噬相关基因Beclin1表达情况与TFEB一致。结论:TFEB和Beclin1在ALS转基因鼠海马中表达异常,表明TFEB和Beclin1调节的自噬与ALS发生密切相关。     

Single-nucleotide polymorphism analysis of GH, GHR,and IGF-1 genes in minipigs

Tibetan (TB) and Bama (BM) miniature pigs are two popular pig breeds that are used as experimental animals in China due to their small body size. Here, we analyzed single-nucleotide polymorphisms (SNPs) in gene fragments that are closely related to growth traits [growth hormone (GH), growth hormone receptor (GHR), and insulin-like growth factor (IGF)-1)] in these pig breeds and a large white (LW) control pig breed. On the basis of the analysis of 100 BMs, 108 TBs, and 50 LWs, the polymorphic distribution levels of GH, GHR, and IGF-1 were significantly different among these three pig breeds. According to correlation analyses between SNPs and five growth traits - body weight (BW), body length (BL), withers height (WH), chest circumference (CC), and abdomen circumference (AC) - three SNP loci in BMs and four SNP loci in TBs significantly affected growth traits. Three SNP sites in BMs and four SNP sites in TBs significantly affected growth traits. SNPs located in the GH gene fragment significantly affected BL and CC at locus 12 and BL at locus 45 in BMs, and also BW, WH, CC, and AC at locus 45 and WH and CC at locus 93 in TBs. One SNP at locus 85 in the BM GHR gene fragment significantly affected all growth traits. All indices were significantly reduced with a mixture of alleles at locus 85. These results provide more information regarding the genetic background of these minipig species and indicate useful selection markers for pig breeding programs.     

IGF-1在先天性肥厚性幽门狭窄中的表达

目的研究细胞因子IGF-1在先天性肥厚性幽门狭窄中的表达。方法应用RT-PCR方法,对16例先天性肥厚性幽门狭窄病例的幽门肌组织及相对应的胃壁肌肉组织的IGF-1mRNA表达水平进行半定量检测。结果幽门肌组织中IGF-1mRNA的水平为0.6858±0.1639,高于胃壁肌肉组织的0.4063±0.0935,差别有统计学意义(P<0.001)。结论先天性肥厚性幽门狭窄患儿幽门肌中IGF-1mRNA表达增加,可能在幽门肌肥厚的过程中起了一定的作用。     

Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice

Prostate-specific antigen (PSA) is a serine protease and one of the most abundant proteins secreted by the human prostate epithelium. PSA is used as a well-established marker of prostate cancer. The involvement of PSA in several early events leading to the development of malignant prostate tumors has made it a target for prevention and intervention. It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3), providing increased local levels of IGF-1, leading to tumor growth. Separately, there are data that suggest an enzymatic regulatory role for dietary boron, which is a serine protease inhibitor. In this study we have addressed the use of boric acid as a PSA inhibitor in an animal study. We have previously reported that low concentrations (6 ug/mL) of boric acid can partially inhibit the proteolytic activity of purified PSA towards a synthetic fluorogenic substrate. Also, by Western blot we have followed the degradation of fibronectin by enzymatically active PSA and have found significant inhibition in the presence of boric acid. We proposed that dietary supplementation with boric acid would inhibit PSA and reduce the development and proliferation of prostate carcinomas in an animal model. We tested this hypothesis using nude mice implanted subcutaneously with LNCaP cells in Matrigel. Two groups (10 animals/group) were dosed with boric acid solutions (1.7, 9.0 mgB/kg/day) by gavage. Control group received only water. Tumor sizes were measured weekly for 8 weeks. Serum PSA and IGF-1 levels were determined at terminal sacrifice. The size of tumors was decreased in mice exposed to the low and high dose of boric acid by 38% and 25%, respectively. Serum PSA levels decreased by 88.6% and 86.4%, respectively, as compared to the control group. There were morphological differences between the tumors in control and boron-dosed animals, including a significantly lower incidence of mitotic figures in the boron-supplemented groups. Circulating IGF-1 levels were not different among groups, though expression of IGF-1 in the tumors was markedly reduced by boron treatment, which we have shown by immunohistochemistry. These data indicate that low-level dietary boron supplementation reduced tumor size and content of a tumor trophic factor, IGF-1.This promising model is being evaluated in further studies.     

Evidence for growth hormone (GH) autoregulation in pituitary somatotrophs in GH antagonist-transgenic mice and GH receptor-deficient mice

Growth hormone (GH) modulates the hypothalamic release of somatostatin and GH-releasing hormone; however, there has been no evidence of GH autoregulation on the pituitary somatotroph. To determine the effects of GH on its own regulation, we examined the pituitaries of giant transgenic mice expressing a GH agonist (E117L), dwarf transgenic mice expressing a GH antagonist (G119K), and dwarf mice devoid of the GH receptor/binding protein (GHR/BP). In the E117L transgenic mice, the number and distribution of pituitary GH-immunoreactive cells were unchanged from nontransgenic littermate controls; an ultrastructural examination revealed typical, densely granulated somatotrophs. In contrast, the pituitaries of the G119K mice contained both moderately granulated somatotrophs and a sparsely granulated (SG) population with well-developed synthetic organelles and a distinct juxtanuclear globular GH-staining pattern. GHR/BP-deficient mice exhibited a marked reduction in the intensity of cytoplasmic GH immunoreactivity; however, prominent GH staining in the juxtanuclear Golgi was seen. GH-immunoreactive cells were increased in number, and the reticulin network pattern was distorted; stains for proliferating cell nuclear antigen confirmed mild hyperplasia. Electron microscopy showed that the somatotrophs were hyperactive SG cells with prominent endoplasmic reticulum membranes, large Golgi complexes, and numerous mitochondria. These findings are consistent with synthetic and secretory hyperactivity in pituitary somatotrophs due to the reduced GH feedback regulation. The changes are most striking in animals that are devoid of GHR/BP and less marked in animals expressing a GH antagonist; both models had reduced insulin-like growth factor-I levels, but the more dramatic change in the GHR/BP animals can be explained by abrogated GH signaling. This represents the first evidence of direct GH feedback inhibition on pituitary somatotrophs, which may have implications for the use of GH analogs in different clinical settings.     

Modulation of GH/IGF-1 axis: potential strategies to counteract sarcopenia in older adults

Aging is associated with progressive decline of skeletal muscle mass and function. This condition, termed sarcopenia, is associated with several adverse outcomes, including loss of autonomy and mortality. Due to the high prevalence of sarcopenia, a deeper understanding of its pathophysiology and possible remedies represents a high public health priority. Evidence suggests the existence of a relationship between declining growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and age-related changes in body composition and physical function. Therefore, the age-dependent decline of GH and IGF-1 serum levels may promote frailty by contributing to the loss of muscle mass and strength. Preclinical studies showed that infusion of angiotensin II produced a marked reduction in body weight, accompanied by decreased serum and muscle levels of IGF-1. Conversely, overexpression of muscle-specific isoform of IGF-1 mitigates angiotensin II-induced muscle loss. Moreover, IGF-1 serum levels have been shown to increase following angiotensin converting enzyme inhibitors (ACEIs) treatment. Here we will review the most recent evidence regarding age-related changes of the GH/IGF-1 axis and its modulation by several interventions, including ACEIs which might represent a potential novel strategy to delay the onset and impede the progression of sarcopenia.