ArticleLiterature Review

Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: Roles in skeletal muscle growth and differentiation

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... The GH/IGF network is a conserved endocrine signaling network in vertebrates that regulates growth, among other functions ( Butler et al. 2002 ;Gahete et al. 2009 ). Growth hormone releasing hormone (GHRH) is secreted by the hypothalamus and binds to growth hormone releasing hormone receptors (GHRHR) in the pituitary gland to stimulate the release of growth hormone (GH) ( Hall et al. 1986 ). GH circulates to target tissues (e.g., liver, muscle) and subsequently binds to growth hormone receptors (GHR) to stimulate production and secretion of insulin-like growth factors IGF-1 and IGF-2 ( Duan et al. 2010 ). While the liver is the primary source of circulating IGF peptides, many other tissues of the body also express IGF transcripts ( Butler et al. 2002 ). ...
... Insulin-like growth factors bind to IGF receptors (IGF1R, IGF2R) in target tissues to initiate cellular responses that often involve insulin signaling and the mTOR (mechanistic target of rapamycin) networks ( Butler et al. 2002 ;Gahete et al. 2009 ;McGaugh et al. 2015 ). IGF binding proteins (IGFBPs) are also produced and secreted by the liver to modulate the bioactivity and longevity of IGF peptides in circulation ( Clemmons 1993 ;Duan and Xu 2005 ;Duan et al. 2010 ;Allard and Duan 2018 ). The effects of IGF-2 are also mediated by IGF-2 binding proteins (IGF2BPs), which bind to mRNA and have diverse and less well understood cellular functions ( Bell et al. 2013 ). ...
... However, research in humans (Supplementary Information in Fagerberg et al. 2014 ) and other vertebrates, including lizards and snakes, has revealed post-natal expression of both IGF-1 and IGF-2 in multiple tissues ( McGaugh et al. 2015 ;Beatty and Schwartz 2020 ). Likewise, there are many IGFBPs in mammals, with a core set of six (IGFBP1-6) that serve an important role in IGF function ( Clemmons 1993 ;Jones and Clemmons 1995 ;Hwa et al. 1999 ;Duan and Xu 2005 ;Duan et al. 2010 ;Allard and Duan 2018 ). However, the function of IGFBPs varies greatly among non-mammalian vertebrates ( Haramoto et al. 2014 ;Garcia de la Serrana and Macqueen 2018 ), and predictions based upon molecular structure of IGFBP6 suggest that it can no longer efficiently bind IGFs in squamates ( McGaugh et al. 2015 ). ...
Article
Full-text available
Synopsis Sexual size dimorphism is widespread in nature and often develops through sexual divergence in growth trajectories. In vertebrates, the growth hormone/insulin-like growth factor (GH/IGF) network is an important regulator of growth, and components of this network are often regulated in sex-specific fashion during the development of sexual size dimorphism. However, expression of the GH/IGF network is not well characterized outside of mammalian model systems, and the extent to which species differences in sexual size dimorphism are related to differences in GH/IGF network expression is unclear. To begin bridging this gap, we compared GH/IGF network expression in liver and muscle from 2 lizard congeners, one with extreme male-biased sexual size dimorphism (brown anole, Anolis sagrei), and one that is sexually monomorphic in size (slender anole, A. apletophallus). Specifically, we tested whether GH/IGF network expression in adult slender anoles resembles the highly sex-biased expression observed in adult brown anoles or the relatively unbiased expression observed in juvenile brown anoles. We found that adults of the 2 species differed significantly in the strength of sex-biased expression for several key upstream genes in the GH/IGF network, including insulin-like growth factors 1 and 2. However, species differences in sex-biased expression were minor when comparing adult slender anoles to juvenile brown anoles. Moreover, the multivariate expression of the entire GH/IGF network (as represented by the first two principal components describing network expression) was sex-biased for the liver and muscle of adult brown anoles, but not for either tissue in juvenile brown anoles or adult slender anoles. Our work suggests that species differences in sex-biased expression of genes in the GH/IGF network (particularly in the liver) may contribute to the evolution of species differences in sexual size dimorphism.
... Both mature IGF1 and IGF2 are conserved single-chain polypeptide growth factors (Jones and Clemmons, 1995). They mediate their biological actions via binding on their receptors to activate the PI3K/Akt pathway and MAPK/Erk pathway (Reinecke et al., 2005;Duan et al., 2010). In addition, most circulating IGFs form complexes with IGFBPs that protect them from degradation and modulate their actions (Reinecke et al., 2005;Duan et al., 2010). ...
... They mediate their biological actions via binding on their receptors to activate the PI3K/Akt pathway and MAPK/Erk pathway (Reinecke et al., 2005;Duan et al., 2010). In addition, most circulating IGFs form complexes with IGFBPs that protect them from degradation and modulate their actions (Reinecke et al., 2005;Duan et al., 2010). ...
Article
Insulin-like growth factors (IGFs) are key regulators of development and growth. Here, we characterized the igf2 gene from olive flounder (Paralichthys olivaceus) and determined its temporal and spatial expression. We set up an in-vitro protein expression system in eukaryotic human embryonic kidney (HEK293T) cells and explored its effects on cell proliferation. The flounder igf2 cDNA contained a 648-bp open reading frame (ORF) encoding a protein of 215 amino acids (aa), which spanned the complete signal peptide (47 aa), mature peptide (70 aa), and E domain (98 aa). In adult flounder, igf2 mRNA was detected in all selected tissues. In early development, igf2 mRNA was detected throughout development from unfertilized eggs to hatching-stage embryos. In-situ hybridization analysis indicated that igf2 mRNA was specially expressed in the brain region, floor plate, hypochord, otic vesicle, and pectoral fin during embryogenesis. Western blotting analysis indicated that the soluble recombinant flounder IGF2 protein was successfully produced through eukaryotic expression in HEK293T cells. In addition, the recombinant IGF2 protein significantly promoted the proliferation of human cervical carcinoma (HeLa) and HEK293T cells. These results provide new information about the structural and functional conservation, expression patterns, and biological activity of the igf2 in teleosts.
... Two ghrs subtypes were found in Mozambique tilapia, ghr1 and ghr2 (Kajimura et al., 2004;Pierce et al., 2007), with ghr2 encoding the primary Gh receptor (Kajimura et al., 2004;Pierce et al., 2007Pierce et al., , 2012. Gh regulates growth and development directly through the Ghr2 and indirectly through the stimulation of Igfs (Butler and Le Roith, 2001;Duan, 1998;Duan et al., 2010;Le Roith et al., 2001;Reindl and Sheridan, 2012). Also secreted by the pituitary gland, follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) regulate gametogenesis and the production of gonadal hormones in males and females (Levavi-Sivan et al., 2010;Schulz et al., 2001;Swanson et al., 2003). ...
... In muscle, Ghr2 and Igfs are stimulated by Gh, which in turn induce a variety of growth-promoting effects (Butler and Le Roith, 2001;Duan et al., 2010;Le Roith, 2003;Mommsen, 2001;Wood et al., 2005). Consistent with these patterns, ghr2 and igf1 transcript levels were diminished following hypophysectomy and subsequently stimulated by oGH. ...
Article
Across the vertebrate lineage, sexual dimorphism in body size is a common phenomenon that results from trade-offs between growth and reproduction. To address how key hormones that regulate growth and reproduction interact in teleost fishes, we studied Mozambique tilapia (Oreochromis mossambicus) to determine whether the activities of luteinizing hormone (Lh) are modulated by growth hormone (Gh), and conversely, whether targets of Gh are affected by the presence of Lh. In particular, we examined how gonadal morphology and specific gene transcripts responded to ovine GH (oGH) and/or LH (oLH) in hypophysectomized male and female tilapia. Hypophysectomized females exhibited a diminished gonadosomatic index (GSI) concomitant with ovarian follicular atresia. The combination of oGH and oLH restored GSI and ovarian morphology to conditions observed in sham-operated controls. A similar pattern was observed for GSI in males. In control fish, gonadal gh receptor (ghr2) and estrogen receptor β (erβ) expression was higher in females versus males. A combination of oGH and oLH restored erβ and arβ in females. In males, testicular insulin-like growth factor 3 (igf3) expression was reduced following hypophysectomy and subsequently restored to control levels by either oGH or oLH. By contrast, the combination of both hormones was required to recover ovarian igf3 expression in females. In muscle, ghr2 expression was more responsive to oGH in males versus females. In the liver of hypophysectomized males, igf2 expression was diminished by both oGH and oLH; there was no effect of hypophysectomy, oGH, or oLH on igf2 expression in females. Collectively, our results indicate that gene transcripts associated with growth and reproduction exhibit sex-specific responses to oGH and oLH. These responses reflect, at least in part, how hormones mediate trade-offs between growth and reproduction, and thus sexual dimorphism, in teleost fishes.
... It has been stated that fasting promotes the growthinhibiting actions of GH rather than the growth-promoting actions (Norbeck et al. 2007) as GH levels are being shown to become dissociated under certain conditions such as malnutrition. Still, the correlation between IGF-I and growth persisted (Duan et al. 2010). ...
... IGF1 plays a crucial role in vertebrates' growth regulation (Sjögren et al. 1999;Chauvigné et al. 2003;Peterson and Waldbieser 2009;Vélez et al. 2017). It is well known in vertebrates that IGF-1 enhances PI3K/Akt cascade activation, thus enhancing protein synthesis and hypertrophic muscle growth (Engert et al. 1996;Glass 2003;Sacheck et al. 2004;Kandarian and Jackman 2006;Zhang et al. 2008;Duan et al. 2010;Fuentes et al. 2003;Rescan et al. 2017). ...
Article
Full-text available
The current study investigated how different fasting and refeeding regimes would impact Nile tilapia growth performance, histopathological examination, and gene expression of myostatin, myogenin, GH , IGF-1 , and NPYa . Nile tilapia fish ( n = 120) were randomly allocated into four groups, including the control group fed on a basal diet for 6 weeks (F6), group A starved for 1 week and then refed for 5 weeks (S1F5), group B starved for 2 weeks and then refed for 4 weeks (S2F4), while group C starved for 4 weeks and then refed for 2 weeks (S4F2). Fasting provoked a decrease in body weight coincided with more extended starvation periods. Also, it induced muscle and liver histological alterations; the severity was correlated with the length of fasting periods. Gene expression levels of GH , MSTN , MYOG , and NPYa were significantly increased, while IGF1 was markedly depressed in fasted fish compared to the control group. Interestingly, refeeding after well-planned short fasting period (S1F5) modulated the histopathological alterations. To some extent, these changes were restored after refeeding. Restored IGF-I and opposing fasting expression profiles of the genes mentioned above thus recovered weights almost like the control group and achieved satisfactory growth compensation. Conversely, refeeding following more extended fasting periods failed to restore body weight. In conclusion, refeeding after fasting can induce a compensatory response. Still, the restoration capacity is dependent on the length of fasting and refeeding periods through exhibiting differential morphological structure and expressions pattern for muscle and growth-related genes. Graphical abstract
... Igfbps bind to Igfs and thus modulate their bioavailability and activity [97,98]. They are found most commonly in the liver but also other tissues like the gonads [99][100][101][102]. ...
... In the present study, igfbp5a, igfbp3, igfbp6b and igfbp7 were upregulated in d-male testis with expression levels between 4 and 43 TPM. According to Wang et al. [97] igfbp5 is involved in anabolic metabolism in teleost muscles. In zebrafish, it was found that igfbp5b is expressed at much higher rates than igfbp5a and that the latter is not regulated by Fsh nor 11-KT [109]. ...
Article
Full-text available
African cichlids are well established models for studying social hierarchies in teleosts and elucidating the effects social dominance has on gene expression. Ascension in the social hierarchy has been found to increase plasma levels of steroid hormones, follicle stimulating hormone (Fsh) and luteinizing hormone (Lh) as well as gonadosomatic index (GSI). Furthermore, the expression of genes related to gonadotropins and steroidogenesis and signaling along the brain-pituitary-gonad axis (BPG-axis) is affected by changes of an animal’s social status. In this study, we use RNA-sequencing to obtain an in-depth look at the transcriptomes of testes and pituitaries from dominant and subordinate male Nile tilapia living in long-term stable social hierarchies. This allows us to draw conclusions about factors along the brain-pituitary-gonad axis that are involved in maintaining dominance over weeks or even months. We identify a number of genes that are differentially regulated between dominant and subordinate males and show that in high-ranking fish this subset of genes is generally upregulated. Genes differentially expressed between the two social groups comprise growth factors, related binding proteins and receptors, components of Wnt-, Tgfβ- and retinoic acid-signaling pathway, gonadotropin signaling and steroidogenesis pathways. The latter is backed up by elevated levels of 11-ketotestosterone, testosterone and estradiol in dominant males. Luteinizing hormone (Lh) is found in higher concentration in the plasma of long-term dominant males than in subordinate animals. Our results both strengthen the existing models and propose new candidates for functional studies to expand our understanding of social phenomena in teleost fish.
... In fishes, growth is controlled at the endocrine level, especially by the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis (Björnsson, 1997;Wood et al., 2005;Duan et al., 2010;Vélez et al., 2017). This axis is modulated by both biotic and abiotic conditions, such as the nutritional or thermal environment (Beckman, 2011;Reindl and Sheridan, 2012;Breves et al., 2016). ...
... In muscle tissue, IGF-1 has a role in the regulation of metabolism, facilitating the uptake of substrates that contribute to muscle growth and may promote the expression of other important genes involved in the myogenesis process (fiber regulation, activation of satellite cells, proliferation, differentiation, and maturation; e.g. Duan et al., 2010;Vélez et al., 2016). Specifically, the myosin (myo) gene is involved in the two final stages of the myogenesis process, i.e. differentiation and maturation (Vélez et al., 2017). ...
Article
Full-text available
Deepwater redfish Sebastes mentella will be among the most important resource-sustaining commercial bottom-fish fisheries in the years to come in the Estuary and Gulf of St. Lawrence (EGSL). In 2011, 2012, and 2013, three strong cohorts were recruited to the stock; their abundance in 2018 was 80 times higher than that of the 1993–2012 period. The main goal of this work was to deepen our knowledge of their growth regulation and metabolism in order to identify molecular indicators and determine how they are influenced by natural environmental conditions. Fish weight and water temperature explained 11% of the variation in relative mRNA levels of specific gene targets in liver and muscle among seven sites where deepwater redfish were captured in the EGSL. The relative expression of liver insulin-like growth factor-1 (igf-1) and white muscle A-chain lactate dehydrogenase (ldh-a) correlate positively with weight, whereas heavy chain muscle myosin (myo), heart citrate synthase (cs), and white muscle pyruvate kinase (pk) correlate negatively. The relative expression of heart cytochrome c oxidase subunit 1 (cox-1) and white muscle igf-1 receptor isoform a (igf-1ra) correlate negatively with temperature. Deepwater redfish from the estuary were smaller than those caught at other sites. Since the growth potential of deepwater redfish was strongly correlated with temperature (being enhanced by higher temperatures), this study suggests an ecological advantage for this species in a climate-warming context.
... The increase in plasma levels of sex steroids during the sexual maturation of fish in correlation with changes in plasma growth hormone (GH) level supports the fact that sex steroids regulate GH secretion (Holloway et al., 1999). The growth and development of vertebrates, in particular, teleost fish, are essentially mediated by growth hormone (GH)/insulin-like growth factor (Igf) signalling (Duan et al., 2010). GH can directly enhance growth by holding as ). ...
... Subsequently, Igfs can regulate tissue growth by directing the cellular processes that involve differentiation, proliferation, migration and survival (Castillo et al., 2004;Codina et al., 2008). In addition, Igf-binding proteins (Igfbps) affect Igf availability, transport and receptor binding and play substantial modulatory roles for growth balance mechanism (Duan et al., 2010). ...
Article
Egyptian aquaculture production has dramatically increased in recent years and is anticipated to represent a yield of 1.8MMT in 2018. Increased demand for fish production has led to a higher intensification of aquaculture to face these challenges. However, the current aquaculture practices and restricted governmental legislation can prompt raised concerns about aquaculture pollution. The current review summarizes our knowledge concerning general Egyptian aquaculture, legislation and practices that can lead to persistent pollutant exposure in farmed finfish. Xenosteroids are critical pollutants influencing fish health, as detailed in this review, and are considered significant health hazards not only to cultured fish but also to human wellbeing, raising a public health concern. Additional research studies are warranted to better understand their public health concerns and develop strategic plans and policies to prevent these impacts and maintain fish welfare and aquaculture sustainability.
... The IGF-1 signaling pathway plays an important role in maintaining the long-term health of many organisms. Among the components of this signaling pathway are two IGFs, IGF-1 and IGF-2 [46,47], six IGF Binding Proteins (IGFBP-1-6) [48,49], IGFBP proteases [50], as well as several other IGFBP-interacting molecules [51]. In physiology, they play an important role primarily in pre-and postnatal somatic growth and development [19,52,53]. ...
... IGF-1 has a diverse effect on cells and tissues [1,57]. It performs important roles in the development of organs and tissues, their postnatal growth, regulates homeostasis of mature muscle tissue, and determines the survival of the body [47,80]. The main target of IGF-1 are skeletal muscles, where it elicits its insulin-sensitizing effects [8]. ...
Article
Full-text available
Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.
... Takano et al. (2005) found that short-term low-intensity training with the reduction of muscle blood flow can effectively promote the upregulation of hormones such as growth hormone (HGH) related to muscle synthesis, which peaks at half an hour after exercise training. Other studies have also shown that BFRT causes an increase in HGH and insulin-like growth factor-1 (IGF-1) concentrations in the blood, which can promote the proliferation and differentiation of muscle satellite cells, and ultimately enhance muscle strength (Duan et al., 2010;Schoenfeld, 2013b). In addition, this study found that after 8 weeks of rehabilitation training, in addition to the enhancement of quadriceps strength, the balance function of patients after APM was also significantly improved. ...
Article
Full-text available
Purpose: To explore the effect of blood flow restriction training (BFRT) on the recovery of knee function in patients after arthroscopic partial meniscectomy (APM). Methods: Forty patients undergoing APM surgery were included in this parallel group, two-arm, single-assessor blinded, randomized clinical trial. The subjects were randomly divided into two groups: routine rehabilitation group (RR Group, n = 20) and routine rehabilitation + blood flow restriction training group (RR + BFRT Group, n = 20). One subject in each group dropped out during the experiment. All patients received 8 weeks of routine rehabilitation starting from the second day after APM. In addition, patients in the RR + BFRT group required additional BFRT twice a week. Visual analogue scale (VAS) score, range of motion (ROM), one-leg standing test (OLST) score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference were evaluated at preoperative, postoperative, 4 and 8 weeks after surgery. SPSS 25.0 software was used for statistical analysis of the data. Repeated measures ANOVA was used if the data were normally distributed and had homogeneity of variance. Generalized estimating equations were chosen if the data were not normally distributed or had homogeneity of variance. Results: There were no significant differences in VAS score, ROM, OLST score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference between the two groups before surgery ( p > 0.05). Compared with postoperative, VAS score, ROM, OLST score, Lysholm knee score, and thigh circumference were significantly improved in the RR group ( p < 0.05), while quadriceps muscle strength and quadriceps thickness were not significantly enhanced at 8 weeks postoperatively ( p > 0.05). However, VAS score, ROM, OLST score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference were all significantly improved in the RR + BFRT group at 8 weeks postoperatively ( p < 0.05). Furthermore, compared with the RR group, VAS score (50% vs. 86%), ROM (7.9% vs. 16.0%), OLST score (57.3% vs. 130.1%), Lysholm knee score (38.4% vs. 55.7%), relative peak torque (11.0% vs. 84.7%), mean power (20.6% vs. 88.1%), rectus femoris thickness (0.40% vs. 13.0%), vastus medialis (0.29% vs. 5.32%), vastus lateralis (0% vs. 6.2%), vastus internus (0% vs. 5.8%), and thigh circumference (2.7% vs. 5.8%) in the RR + BFRT group were significantly improved at 4 and 8 weeks postoperatively ( p < 0.05). Conclusion: BFRT combined with routine rehabilitation training can better promote the recovery of knee joint function in patients after APM, especially the improvement of quadriceps muscle strength and thickness.
... To further explore the growth of O. macrolepis broodstock fish, two genes growthrelated properties were determined. The ifg1, being a growth hormone/insulin-like growth factor (IGF), regulates growth and cellular metabolism [39] and plays essential role in the growth and development of many fish, e.g., Micropterus salmoides [39], Oncorhynchus kisutch [40], and Lateolabrax japonicus [41], and ifg1 gene expression was generally affected by nutritional status in fish [42,43]. The gldh, glutamate dehydrogenase (GDH), reversibly catalyzes glutamate deamination with the production of ammonia and plays a key role in nitrogen metabolism and the production of plasma ammonia [44,45]. ...
Article
Full-text available
To assess the lipid requirements of O. macrolepis broodstock, five iso-nitrogenous diets (39 g kg−1) with five lipid levels, 50 (5 L), 70 (7 L), 90 (9 L),110 (11 L), and 130 (13 L; g kg−1), were made. A total of 105 three-year-old individuals (50.11 ± 2.86 g per fish) were divided into five groups (triplicate per group) and were fed with the diets, respectively, for eight weeks. Then, the fish were sampled, and items were determined. The results showed that growth rate and feed efficiency ratio were not significantly affected by diets (p > 0.05). A clear dose–response effect of dietary lipid was observed on somatic indexes of gonad indexes of the O. macrolepis brookstock, with the highest values corresponding to fish fed 9 and 11 g kg−1 lipids, in contrast, gonad indexes were reduced as dietary lipid moved away from this level. The other somatic indexes, such as viscerosomatic index, perivisceral fat index, etc., were not significantly affected by diets (p > 0.05). The content of crude lipid and crude protein in carcass, hepatopancreas, and gonad were not significantly affected by dietary lipid levels (p > 0.05). The gonad fatty acids of 16:0 and 22:6n-3 decreased and 18:2n-6 increased with the increasing lipid level, being significantly altered by diets (p < 0.05). The histological features of the gonad showed no significant difference among the five diets (p > 0.05). The relative expression of sex steroid-synthesizing proteins (fshr, 3β-hsd, 17β-hsd, aro., and star.) in the gonad of fish was most significantly highly expressed in the 9 L and 11 L groups (p < 0.05). The results suggested that a proper dietary lipid level of 90–110 g kg−1 could maintain gonad development of O. macrolepis broodstock without affecting growth performance.
... Hence, this is in accordance with the results of the present study, where the highest IGF-1 plasma levels (at week 8) were found in the same experimental groups with upregulated igfbp-5b. In addition, this binding protein is induced during myogenic differentiation and its importance in such a process in teleost fish has been well established (Duan et al., 2010;Garcia de la serrana and Macqueen, 2018). In line with this, the relative expression of the cytoplasmic protein dock5, a regulator of the myoblast/myocyte fusion process (Moore et al., 2007;Chen et al., 2020), was also modulated by diet composition. ...
Article
Full-text available
The dietary inclusion of plant-based products in fish feeds formulation is required for the sustainable development of aquaculture. Moreover, considering functional diets, hydroxytyrosol, one of the major phenolic compounds found in olives (Olea europaea), has been identified as a potential candidate to be used in the aquafeeds industry due to its health promoting abilities. The aim of this study was to evaluate the effects of the inclusion of an olive juice extract rich in hydroxytyrosol as an additive (0.52 g HT/kg feed) in a high-fat (24% lipids) diet in gilthead sea bream (Sparus aurata) juveniles. Moreover, the experimental diets, with or without the extract, were administered daily at a standard (3% of total biomass in the tank) or restricted ration (40% reduction) for 8–9 weeks. Growth and biometric parameters, insulin-like growth factor 1 (IGF-1) plasma levels and growth hormone/IGF axis-, myogenic- and osteogenic-related genes expression in liver, white muscle and/or bone were analyzed. Moreover, in vitro cultures of vertebra bone-derived cells from fish fed the diets at a standard ration were performed at weeks 3 and 9 to explore the effects of hydroxytyrosol on osteoblasts development. Although neither body weight or any other biometric parameter were affected by diet composition after 4 or 8 weeks, the addition of the hydroxytyrosol-rich extract to the diet increased IGF-1 plasma levels, regardless of the ration regime, suggesting an anabolic condition. In muscle, the higher mRNA levels of the binding protein igfbp-5b and the myoblast fusion marker dock5 in fish fed with the hydroxytyrosol-rich diet suggested that this compound may have a role in muscle, inducing development and a better muscular condition. Furthermore in bone, increased osteogenic potential while delayed matrix mineralization after addition to the diet of the olive juice extract was supported by the upregulated expression of igf-1 and bmp4 and reduced transcript levels of osteopontin. Overall, this study provides new insights into the beneficial use of hydroxytyrosol as a dietary additive in gilthead sea bream functional diets to improve muscle-skeletal condition and, the aquaculture industry.
... In teleosts, gametogenesis is a very complex process controlled by various hormones and cytokines in multiple ways (Eduarda et al. 2001;Laurence et al. 2012;Nagahama 1994;Rüdiger et al. 2010). A large amount of energy is needed to maintain the smooth progress of spermatogenesis and oogenesis (Johnl and Steven 1988;Teresa and Duane 1991), and many studies have demonstrated that IGFs play an important role in regulating energy and gonadal development in fish (Duan et al. 2010). Unlike igf1 and igf2, igf3 is a gonad-specific IGF subtype that was first discovered in Nile tilapia (Wang et al. 2008). ...
Article
Full-text available
Insulin-like growth factor 3 plays an important role in gonad development in teleost fish. Previous studies found that igf3 was specifically expressed in gonads of silver pomfret (Pampus argenteus). Unlike in other fish, IGF3 is a membrane protein in silver pomfret, and its specific role in gonads is unclear. Herein, we explored the importance of IGF3 in oogenesis and spermatogenesis in silver pomfret by analyzing gene expression and cellular localization. During follicular development, igf3 was detected in ovaries at both mRNA and protein levels during the critical stages of vitellogenesis (IV–VI). Localization analysis detected igf3 mRNA and protein in somatic cells, including theca and granulosa cells around oocytes. Similar to cathepsin L and cathepsin K, igf3 was consistently expressed in ovaries during vitellogenesis, suggesting that it might play a key role in vitellogenesis of oocytes. During spermatogenesis, igf3 mRNA and protein levels were high in stages II, IV, and V, similar to sycp3 and dmc1, and the highest igf3 mRNA and protein levels were reached in stage VI. Furthermore, igf3 mRNA and protein were detected in spermatogonia, spermatocytes, spermatids, and surrounding Sertoli cells, but not in spermatozoon, indicating that IGF3 might be involved in differentiation and meiosis of spermatogonia.
... IGF-1 consists of four subunits: A, B, C, and D. The structures of subunits A and B are similar to that of insulin, the function of subunit C is different from that of insulin, and insulin does not have subunit D. IGF-1 can promote cell proliferation and angiogenesis and resist apoptosis (Duan et al., 2010). Although IGF-1 secretion is increased during high-intensity of aerobic training, the serum concentration of its ligand remained unchanged (Nishida et al., 2010). ...
Article
Full-text available
Ischemic diseases are a major cause of mortality or disability in the clinic. Surgical or medical treatment often has poor effect on patients with tissue and organ ischemia caused by diffuse stenoses. Promoting angiogenesis is undoubtedly an effective method to improve perfusion in ischemic tissues and organs. Although many animal or clinical studies tried to use stem cell transplantation, gene therapy, or cytokines to promote angiogenesis, these methods could not be widely applied in the clinic due to their inconsistent experimental results. However, exercise rehabilitation has been written into many authoritative guidelines in the treatment of ischemic diseases. The function of exercise in promoting angiogenesis relies on the regulation of blood glucose and lipids, as well as cytokines that secreted by skeletal muscle, which are termed as myokines, during exercise. Myokines, such as interleukin-6 (IL-6), chemokine ligand (CXCL) family proteins, irisin, follistatin-like protein 1 (FSTL1), and insulin-like growth factor-1 (IGF-1), have been found to be closely related to the expression and function of angiogenesis-related factors and angiogenesis in both animal and clinical experiments, suggesting that myokines may become a new molecular target to promote angiogenesis and treat ischemic diseases. The aim of this review is to show current research progress regarding the mechanism how exercise and exercise-induced myokines promote angiogenesis. In addition, the limitation and prospect of researches on the roles of exercise-induced myokines in angiogenesis are also discussed. We hope this review could provide theoretical basis for the future mechanism studies and the development of new strategies for treating ischemic diseases.
... Biochemical, physiological, and molecular mechanisms could be determined through the interaction between nutrition and gene function concerning the changes in feed formulation [51]. The relative mRNA level of IGF-I gene in fish tissues is measured as a growth indicator [52]. IGFs regulate many biological functions, including cell division, cell proliferation, and cell growth. ...
Article
Full-text available
A 9-week growth trial was carried out to assess the influence of replacing poultry by-product meal protein with conventional cottonseed meal protein (CCMP) or low gossypol cottonseed meal protein (LGCMP) on growth, feed utilization, gut micromorphology, and immunity of hybrid grouper (Epinephelus fuscoguttatus♀× Epinephelus lanceolatus♂) juveniles fed low-fish meal (18.53%, dry matter) diets. Eleven experimental diets were prepared. The control diet (PBMP) contained 46.15% poultry by-product meal protein. Both conventional cottonseed meal protein (CCMP) and low-gossypol cottonseed meal protein (LGCMP) were used in replacement ratios of 20, 40, 60, 80, and 100% of poultry by-product meal protein (PBMP) from the control diet, forming ten experimental diets (CCMP20, CCMP40, CCMP60, CCMP80, CCMP100, LGCMP20, LGCMP40, LGCMP60, LGCMP80, and LGCMP100). Results demonstrated that weight-gain percentage (WG%) was not different between different sources of cottonseed meal (CCMP and LGCMP). However, values of WG% significantly differed among different replacement levels, with CCMP80 and LGCMP40 having significantly higher values compared to other treatments. Fish fed CCMP80 and LGCMP40 exhibited higher protein efficiency ratios (PERs) than fish fed other experimental diets. The regression analysis from a second-order or third-order polynomial model based on WG% showed that the optimal PBMP replacement levels by CCMP and LGCMP are 74% and 33%, respectively. The whole-body lipid contents remarkably decreased as dietary CCMP or LGCMP inclusion levels increased. The relative mRNA expression of insulin-like growth factor-1(IGF-1) in liver was higher in fish fed CCMP80 and LGCMP40 diets compared to fish fed other diets. Generally, in low-FM diets of hybrid grouper, CCMP and LGCMP could replace 74% and 33% of PBMP, respectively.
... [18][19][20]35,46 BFR-LIX has also been observed to rapidly increase systemic growth hormone release 29 and to chronically increase systemic IGFs, 3,53 known to play a role in satellite cell proliferation and differentiation and bone anabolism during recovery from exercise. 16,49 Therefore, it is possible that the present findings may result from both increased motor unit recruitment and an increased presence of systemic anabolic effectors. However, further study is needed to determine direct cause and effect. ...
Article
Full-text available
Background Muscle atrophy is common after an injury to the knee and anterior cruciate ligament reconstruction (ACLR). Blood flow restriction therapy (BFR) combined with low-load resistance exercise may help mitigate muscle loss and improve the overall condition of the lower extremity (LE). Purpose To determine whether BFR decreases the loss of LE lean mass (LM), bone mass, and bone mineral density (BMD) while improving function compared with standard rehabilitation after ACLR. Study Design Randomized controlled clinical trial Methods A total of 32 patients undergoing ACLR with bone-patellar tendon-bone autograft were randomized into 2 groups (CONTROL: N = 15 [male = 7, female = 8; age = 24.1 ± 7.2 years; body mass index [BMI] = 26.9 ± 5.3 kg/m2] and BFR: N = 17 [male = 12, female = 5; age = 28.1 ± 7.4 years; BMI = 25.2 ± 2.8 kg/m2]) and performed 12 weeks of postsurgery rehabilitation with an average follow-up of 2.3 ± 1.0 years. Both groups performed the same rehabilitation protocol. During select exercises, the BFR group exercised under 80% arterial occlusion of the postoperative limb (Delfi tourniquet system). BMD, bone mass, and LM were measured using DEXA (iDXA, GE) at presurgery, week 6, and week 12 of rehabilitation. Functional measures were recorded at week 8 and week 12. Return to sport (RTS) was defined as the timepoint at which ACLR-specific objective functional testing was passed at physical therapy. A group-by-time analysis of covariance followed by a Tukey’s post hoc test were used to detect within- and between-group changes. Type I error; α = 0.05. Results Compared with presurgery, only the CONTROL group experienced decreases in LE-LM at week 6 (−0.61 ± 0.19 kg, −6.64 ± 1.86%; P < 0.01) and week 12 (−0.39 ± 0.15 kg, −4.67 ± 1.58%; P = 0.01) of rehabilitation. LE bone mass was decreased only in the CONTROL group at week 6 (−12.87 ± 3.02 g, −2.11 ± 0.47%; P < 0.01) and week 12 (−16.95 ± 4.32 g,−2.58 ± 0.64%; P < 0.01). Overall, loss of site-specific BMD was greater in the CONTROL group ( P < 0.05). Only the CONTROL group experienced reductions in proximal tibia (−8.00 ± 1.10%; P < 0.01) and proximal fibula (−15.0±2.50%, P < 0.01) at week 12 compared with presurgery measures. There were no complications. Functional measures were similar between groups. RTS time was reduced in the BFR group (6.4 ± 0.3 months) compared with the CONTROL group (8.3 ± 0.5 months; P = 0.01). Conclusion After ACLR, BFR may decrease muscle and bone loss for up to 12 weeks postoperatively and may improve time to RTS with functional outcomes comparable with those of standard rehabilitation.
... From mammalian studies, IGFs are known to play key roles in muscle growth and cell proliferation (Duan et al., 2010; but see Atherton and Smith, 2012), but are also important for responding to environmental challenges related to resource availability and activity levels (Fontana et al., 2008;Rahmani et al., 2019). Our results provide one more piece to the puzzle of how this pathway functions in a reptile: when green anoles invest energy into movement, the insulin and insulin like signaling network is implicated in the response. ...
Article
Full-text available
Locomotor performance is a key predictor of fitness in many animal species. As such, locomotion integrates the output of a number of morphological, physiological, and molecular levels of organization, yet relatively little is known regarding the major molecular pathways that bolster locomotor performance. One potentially relevant pathway is the insulin and insulin-like signaling (IIS) network, a significant regulator of physiological processes such as reproduction, growth, and metabolism. Two primary hormones of this network, insulin-like growth factor 1 (IGF1) and insulin-like growth factor 2 (IGF2) are important mediators of these processes and, consequently, of life-history strategies. We sprint-trained green anole (Anolis carolinensis) females to test the responsiveness of IGF1 and IGF2 hepatic gene expression to exercise training. We also tested how sprint training would affect glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and eukaryotic elongation factor 2 (EEF2). The former is a crucial enzyme for glycolytic function in a cell, and the latter is necessary for protein synthesis. Resistance exercise forces animals to increase investment of resources towards skeletal muscle growth. Because IGF1 and IGF2 are important hormones for growth, and GAPDH and EEF2 are crucial for proper cellular function, we hypothesized that these four genes would be affected by sprint training. We found that sprint training affects IGF and EEF2 expression, such that larger sprint-trained lizards express hepatic IGF1, IGF2, and EEF2 to a lesser extent than similarly sized untrained lizards. These results demonstrate that the IIS, and pathways connected to it, can react in a size-dependent manner and are implicated in the exercise response in reptiles.
... Skeletal muscle development relies on myoblast differentiation and proliferation, and is a crucial factor influencing growth rate, meat quality and yield, as well as other important economic traits of livestock [18]. Myogenesis is tightly modulated, with multiple critical genes involved, such as the MRF (myogenic regulatory factor) [19,20] and MEF2 (myocyte enhancer factor-2) [21,22] families, MSTN (Myostatin) [23,24], and IGFs (Insulin-like growth factors) [25,26]. However, apart from these widely known genes, many other genes influencing myogenesis remain unidentified and/or uncharacterized. ...
Article
Full-text available
Skeletal myogenesis is a complicated biological event that involves a succession of tightly controlled gene expressions. In order to identify novel regulators of this process, we performed mRNA-Seq studies of goat skeletal muscle satellite cells (MuSCs) cultured under proliferation (GM) and differentiation (DM1/DM5) conditions. A total of 19,871 goat genes were expressed during these stages, 198 of which represented novel transcripts. Notably, in pairwise comparisons at the different stages, 2551 differentially expressed genes (DEGs) were identified (p < 0.05), including 1560 in GM vs. DM1, 1597 in GM vs. DM5, and 959 in DM1 vs. DM5 DEGs. The time-series expression profile analysis clustered the DEGs into eight gene groups, three of which had significantly upregulated and downregulated patterns (p < 0.05). Functional enrichment analysis showed that DEGs were enriched for essential biological processes such as muscle structure development, muscle contraction, muscle cell development, striated muscle cell differentiation, and myofibril assembly, and were involved in pathways such as the MAPK, Wnt and PPAR signaling pathways. Moreover, the expression of eight DEGs (MYL2, DES, MYOG, FAP, PLK2, ADAM, WWC1, and PRDX1) was validated. These findings offer novel insights into the transcriptional regulation of skeletal myogenesis in goats.
... Our data showed that bmp7b knockout in zebrafish resulted in a significant downregulation of gh1, and its receptor ghra was also significantly downregulated. In addition, the main target tissue of insulin-like growth factors, igf1 and igf2, is the skeletal muscle in mammals (Duan et al., 2010), and they exert their biological effects by binding to igf1r (Glass, 2005;Wu and Zhu, 2011). The significantly reduced expression of igf2a/2b at 60 and 90 dpf (p < 0.05) might lead to a slower growth of muscle cells in mutants. ...
Article
Full-text available
Bone morphogenetic protein 7 (BMP7) belongs to the transforming growth factor β (TGF-β) family, which not only induces cartilage and bone formation, but also regulates eye development and melanoma tumorigenesis in mammals. In teleosts, BMP7 differentiates into two subtypes, bmp7a and bmp7b, which have clearly differentiated structures. To fully understand the functional differentiation of bmp7a and bmp7b in fish species, we successfully constructed bmp7a and bmp7b gene deletion mutants in zebrafish using CRISPR/Cas9-mediated gene editing technology. Our results showed that bmp7a mutation caused abnormal development of the embryo’s dorsal-ventral pattern that led to death; bmp7b mutation induced growth inhibition and increased melanin production in the skin and eye of mutants. Histological analysis revealed that melanin in the retina of the eyes in bmp7b mutants increased, and behavioral observation showed that the vision and sensitivity to food of the mutants were reduced. Transcriptome analysis of the skin and eye tissues showed that the expression changes of wnt7ba and gna14 in bmp7b mutants might promote the increase of melanin. Additionally, the eye transcriptome analysis indicated that changes in the structure of the eyes in bmp7b mutants led to defects in phototransduction, and seven DEGs (rgs9a, rgs9b, rcvrn2, guca1d, grk1b, opn1mw4, and gc2) were identified as key candidate genes that affected the photonic response of the eyes. The study revealed the functional differentiation of bmp7a and bmp7b in teleosts and the first report about the inhibitory effect of bmp7b on melanogenesis may provide useful information for the future research on human melanoma-related diseases.
... Notably, both GH and IFGs have been shown to play an important role in satellite cell proliferation and differentiation during recovery. [57][58][59] Therefore, because of the multinucleated nature of skeletal muscle, BFR may indirectly yield chronic training responses via increased potential for future growth in response to exercise. 21,31 These systemic signaling mechanisms have been postulated to have impact in both the occluded limb undergoing BFR as well as tissues proximal to the site of occlusion (discussion to follow). ...
Article
Full-text available
The use of blood flow restriction (BFR) within rehabilitation is rapidly increasing as further research is performed elucidating purported benefits such as improved muscular strength and size, neuromuscular control, decreased pain, and increased bone mineral density. Interestingly, these benefits are not isolated to structures distal to the occlusive stimulus. Proximal gains are of high interest to rehabilitation professionals, especially those working with patients who are limited due to pain or postsurgical precautions. The review to follow will focus on current evidence and ongoing hypotheses regarding physiologic responses to BFR, current clinical applications, proximal responses to BFR training, potential practical applications for rehabilitation and injury prevention, and directions for future research. Interestingly, benefits have been found in musculature proximal to the occlusive stimulus, which may lend promise to a greater variety of patient populations and conditions. Furthermore, an increasing demand for BFR use in the sports world warrants further research for performance research and recovery. Level of Evidence Level V, expert opinion.
... In contrast, the concentration of IGF-1 may be higher than that of estrogen in cow's milk, since in some countries, cows are administered synthetic growth hormone (somatotropin-rbST) [43] in order to increase the yield of milk. Since IGF-1 stimulates cell growth and differentiation and inhibits apoptosis, the presence of this hormone in milk has the potential to influence the development of cancerous tumors [44] and the development of breast cancer [45,46]. In many studies, saturated fatty acids were thought to increase the risk of breast cancer [47][48][49]. ...
Article
Full-text available
Lack of consistency in the relationship between dairy products consumption and breast cancer (BC) risk motivated us to evaluate this association in a case-control study of BC among Polish women. The study includes 1699 women 26–79 years of age, 823 BC cases identified in Cancer Registries and 876 randomly selected controls from the national population registry. Using a validated, semiquantitative food frequency questionnaire (FFQ), the consumption of dairy products was collected for a time period of 10–15 years prior to BC diagnosis. We used logistic regression, adjusting for potential confounders, to assess the relationship between total dairy consumption as well as individual dairy groups of milk, cottage cheese and hard cheese and BC risk for premenopausal and postmenopausal women. For total consumption, a significant decrease in BC risk was observed with increased consumption of one serving/week, OR trend = 0.98, 2% decrease in risk, for premenopausal women only. For milk, a significant decrease in BC risk was observed for an increase in consumption of one glass/week, OR trend = 0.95, 5% decrease, in both strata of menopause. In contrast, for hard cheese, a significant increase in the risk of 10% was observed only in premenopausal women, OR trend = 1.10. Cottage cheese consumption significantly reduced BC risk by 20%, OR trend = 0.80, for an increase in one serving/week for postmenopausal women only. Our results show that individual dairy products have a statistically significant but bi-directional relationship with BC risk, which differs for premenopausal and postmenopausal women.
... This stimulates the release of insulin-like growth factor-I (Igf-I; Fu et al., 2016;Norbeck et al., 2007) and activates the metabolism of fats, carbohydrates and proteins (Norbeck et al., 2007). Although the function of these hormones has been well studied in some model fish species (Duan et al., 2010), few studies have investigated the thermal phenotypic plasticity of their gene expression in the main organs of the somatotropic axis simultaneously. ...
Article
Full-text available
Abstract Ectotherm species, such as marine fishes, depend on environmental temperature to regulate their vital functions. In finfish aquaculture production, being able to predict physiological responses in growth and other economic traits to temperature is crucial to address challenges inherent in the selection of grow‐out locations. This will become an even more significant issue under the various predicted future climate change scenarios. In this study, we used the marine teleost silver trevally (Pseudocaranx georgianus), a species currently being explored as a candidate for aquaculture in New Zealand, as a model to study plasticity in gene expression patterns and growth in response to different temperatures. Using a captive study population, temperature conditions were experimentally manipulated for 1 month to mimic seasonal extremes. Phenotypic differences in growth were measured in 400 individuals, and gene expression patterns of pituitary gland and liver were determined in a subset of 100 individuals. Results showed that growth increased 50% in the warmer compared with the colder condition, suggesting that temperature has a large impact on metabolic activities associated with growth. A total of 265,116,678 single‐end RNA sequence reads were aligned to the trevally genome, and 28,416 transcript models were developed (27,887 of these had GenBank accessions, and 17,980 unique gene symbols). Further filtering reduced this set to 8597 gene models. 39 and 238 differentially expressed genes (DEGs) were found in the pituitary gland and the liver, respectively (|log2FC| > 0.26, p‐value
... IGF-I and IGF-II are the mitogenic peptides, which are regulated by the nutritional status of fish. IGFs play important roles which includes somatic growth, development and functional maturation of the central nervous system (CNS), skeletal tissues, and reproductive organs (Duan et al., 2010). Myocyte hypertrophy during regeneration of muscles, proliferation and differentiation of muscle precursor cells (myoblast or satellite cells) as well as growth stimulation are controlled by Insulin-like growth factors (Florini et al., 1996;Musaro et al., 1999;Terova et al., 2007). ...
Article
Full-text available
Fish meal and fish oil have been the mostly used ingredients (protein and lipid respectively) in aquaculture feeds due to their excellent source of well-balanced amino acid profile and n-3 long chain polyunsaturated fatty acids (LC-PUFA) respectively. However, due to escalating prices and fluctuation in production, there are calls for alternative protein and lipid sources to be used. Plant based ingredients have been recognized as alternatives that could enhance growth performance as well as reduction in cost of production. The regulation of muscle growth by plant based lipids and protein is not fully elucidated. Growth performance and muscle growth of fish is affected by diets. Acceleration of growth through alteration of genes by diets can be useful as it can reduce cost and decrease time of production. The objective of this review is to discuss the genes that affect muscle growth of fish and how plant based ingredients affect these genes.
... Growth hormone and the IGF system are components of the somatotropic axis and are essential for controlling growth and reproduction (Lucy et al., 1991;Le Roith et al., 2001). The liver secretes IGF-1 and IGF-2 into circulation in response to GH stimulation (Liu and LeRoith, 1999;Duan et al., 2010). The IGF system is expressed throughout the body, including the reproductive tract (Rhoads et al., 2008) where it regulates preimplantation embryo and placental development (Wathes et al., 1998). ...
Article
The objective of this study was to examine the effects of recombinant bovine somatotropin (bST) administration on uterine hemodynamics and subsequent fetal programming in suckled cows during the first trimester of gestation. Crossbred beef cows (n = 152) were stratified by breed, days postpartum, parity, cyclicity status, and body condition score (BCS) before being assigned to either receive injections of bST every other week (BST; 500-mg/14 d) starting at fixed-time artificial insemination (TAI; d 0) until d 97 or to receive no bST (CTL). Blood samples were collected until d 97 for analysis of plasma concentrations of insulin-like growth factor 1 (IGF-1). Pregnancy was assessed via transrectal ultrasonography on d 41 and 173. A subset of pregnant cows (BST, n = 24; CTL, n = 28) were selected for assessment of uterine arterial blood flow (BF), pulsatility index, and resistance index (RI) of the uterine arteries ipsilateral and contralateral to the conceptus via color Doppler ultrasonography on d 97 and 233 of gestation. No differences (P = 0.99) were detected in body weight (BW) or BCS of dams; however, plasma concentrations of IGF-1 were greater (P < 0.001) in BST-treated cows. Color Doppler ultrasonography parameters differed whereby a treatment × day interaction (P = 0.007) was detected for RI on d 97 (P = 0.048); however, on d 233, RI did not differ (P > 0.10) but ipsilateral BF for BST-treated cows was greater (P = 0.0319) than controls. Mean heart girth diameter, crown-to-rump length, and neonate BW at 7 ± 5 d of calf age did not differ (P > 0.10). Liver tissue samples from each calf were collected for analysis of mRNA expression of target insulin-like growth factor system ligands. There was no difference in gene expression of hepatic IGF-1 between treatments (P = 0.99). A treatment × sex interaction was determined, where BST heifers had increased mRNA expression of IGFR1 compared to BST bulls (P = 0.03). Bi-weekly administration of bST until d 97 of pregnancy increased plasma concentrations of IGF-1, altered uterine hemodynamics in dams, induced sex-specific changes in liver gene expression of the offspring but failed to alter calf morphometries or calf performance until weaning.
... It also increased expression of IGF binding protein (IGFBP)1. ALS helps to maintain the circulating IGF1 half-life (80), whereas IGFBP1 attenuates IGF action by preventing IGF1 binding to the type 1 IGF receptor (80). These results are consistent with previous studies reporting a modified circulating IGFBP profile in mstn -/mice that would increase the bioavailable fraction of IGF1 (70). ...
Article
Full-text available
Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders and of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerbating muscle loss. Arguably, the most promising treatments in development attempt to disrupt myostatin and activin receptor signaling as these circulating factors are potent inhibitors of muscle growth and regulators of muscle progenitor cell differentiation. Indeed, several studies demonstrated the clinical potential of “inhibiting the inhibitors”, increasing muscle cell protein synthesis, decreasing degradation, enhancing mitochondrial biogenesis and preserving muscle function. Such changes can prevent muscle wasting in various disease animal models yet many drugs targeting this pathway failed during clinical trials, some from serious treatment-related adverse events and off-target interactions. More often, however, failures resulted from the inability to improve muscle function despite preserving muscle mass. Drugs still in development include antibodies and gene therapeutics, all with different targets and thus, safety, efficacy and proposed use profiles. Each is unique in design and, if successful, could revolutionize the treatment of both acute and chronic muscle wasting. They could also be used in combination with other developing therapeutics for related muscle pathologies or even metabolic diseases.
... T3 action is exerted by modulating the expression of selected insulin-like growth factor-binding protein, Igfbps, such as Igfbp1a. These proteins are considered relevant for modulation of insulin growth factors (IGFs) in zebrafish testis [27][28][29]. THs may also regulate the functions of LCs in zebrafish testis, being their steroidogenic capacity increased by T3 [24]. However, the pathway to androgen production is somehow different in zebrafish compared to mammals [30][31][32]. ...
Article
Full-text available
Thyroid hormones (THs) regulate many biological processes in vertebrates, including reproduction. Testicular somatic and germ cells are equipped with the arrays of enzymes (deiodinases), transporters, and receptors necessary to locally maintain the optimal level of THs and their signalling, needed for their functions and spermatogenesis. Pesticides, as chlorpyrifos (CPF) and ethylene thiourea (ETU), impair the function of thyroid and testis, affecting male fertility. However, their ability to disarrange testicular T3 (t-T3) metabolism and signalling is poorly considered. Here, a multi-species analysis involving zebrafish and mouse suggests the damage of t-T3 metabolism and signalling as a mechanism of gonadic toxicity of low-doses CPF and ETU. Indeed, the developmental exposure to both compounds reduces Dio2 transcript in both models, as well as in ex-vivo cultures of murine seminiferous tubules, and it is linked to alteration of steroidogenesis and germ cell differentiation. A major impact on spermatogonia was confirmed molecularly by the expression of their markers and morphologically evidenced in zebrafish. The results reveal that in the adopted models, exposure to both pesticides alters the t-T3 metabolism and signalling, affecting the reproductive capability. Our data, together with previous reports suggest zebrafish as an evaluable model in assessing the action of compounds impairing locally T3 signalling.
... Durant la période post-natale, l'IGF-1 agit comme un modulateur de l'activité des enzymes acide glutamate décarboxylase (GAD) et Choline Acetyl Transferase (ChAT) régulant ainsi l'activité des motoneurones (Brass et al., 1992). A la périphérie, l'IGF-1 peut agir sur la différenciation ou la prolifération des cellules musculaire (Duan et al., 2010). ...
Thesis
Les amyotrophies spinales infantiles (SMA) sont des maladies rares autosomiques récessives survenant dès l'enfance pour laquelle aucune thérapie n'est efficace à ce jour. Les SMA sont caractérisées par une dégénérescence spécifique des motoneurones entrainant des faiblesses musculaires critiques qui, lorsqu'elles atteignent les muscles respiratoires, provoquent le décès des patients. L'origine de ces maladies est la mutation du gène Survival of Motor Neuron 1 (Smn1) qui induit un déficit en protéine Survival of Motor Neuron (SMN). Tous les patients atteints de SMA possède au moins 2 copies du gène Smn2, qui module la sévérité de la maladie en produisant une faible quantité de protéines SMN complète. En effet, du à l'épissage alternatif de l'exon-7 qui code pour un domaine de stabilité de la protéine SMN, les transcrits produits par l'expression de Smn2 sont dans la plupart des cas incomplets, et génèrent des protéines SMN instables, rapidement dégradées. Ainsi, un objectif thérapeutique majeur dans les SMA est d'augmenter les niveaux de protéines SMN chez les patients. En décryptant les mécanismes moléculaires qui sous-tendent les effets bénéfiques de l'exercice physique dans un modèle souris de SMA sévère, le laboratoire a montré que la stimulation directe des récepteurs au NMDA (NMDAR) entraîne une augmentation significative de l'inclusion de l'exon 7 dans les transcrits SMN générés à partir de l'expression du gène Smn2 dans les tissus SMA. Au cours de ma thèse, j'ai participé à l'identification d'un deuxième mécanisme induit par l'exercice, lié à la réduction des niveaux d'expression du récepteur de l'IGF-1 (IGF-1R), qui est surexprimé dans la moelle épinière des souris SMA. La réduction d'IGF-1R suffit à promouvoir l'expression de SMN, à la fois par des effets transcriptionnels et post-transcritionnels. En utilisant une approche transcriptomique visant à identifier les gènes dont l'expression est modifiée de manière comparable par la modulation des NMDAR ou de l'IGF-1R, nous avons identifié un ensemble de gènes qui appartient à la voie de biosynthèse du cholestérol. Des analyses par RT-qPCR et western blot dans la moelle épinière de souris contrôles et modèles de la SMA ont révélées que i) les enzymes de la voie de biosynthèse du cholestérol sont sous-exprimées dans la moelle épinière de souris SMA et dans une culture de fibroblastes issus de patient SMA et ii) le traitement au NMDA ou la réduction d'IGF-1R réactive l'expression des enzymes de la voie de biosynthèse du cholestérol à des niveaux comparables aux témoins. De manière importante, nous avons démontré que l'inhibition spécifique de DHCR24, une enzyme clé de la voie terminale de la biosynthèse du cholestérol, dans les fibroblastes contrôles induit une réduction significative de l'expression de SMN, à la fois au niveau de l'ARNm et de la protéine et qu'à l'inverse, la restauration des niveaux d'expression de DHCR24 dans les fibroblastes SMA humains induit une augmentation significative de l'expression de SMN. De plus, la quantification par GC-MS du cholestérol, de ses métabolites, et de différents oxystérols indique que l'ensemble du métabolisme du cholestérol est altéré dans la moelle épinière de souris SMA, et amélioré par l'activation des NMDAR. L'ensemble de ces résultats mettent en évidence pour la première fois que l'homéostasie du cholestérol est perturbée dans les SMA et que moduler les voies moléculaires dépendantes du cholestérol et de ses dérivés peut constituer une approche thérapeutique prometteuse.
... IGFs are the key mediators of the growth induced by GH and exert their effect in an autocrine, paracrine, and endocrine manner in fish (Le Roith et al., 2001). Two types of IGFs (IGF-1 and IGF-2) are present in vertebrates (Reindl and Sheridan, 2012) and regulate numerous key biological process like synthesis and inhibition of proteolysis, proliferation, differentiation, cell migration and survival, and skeletal muscle elongation (Duan et al., 2010;Reinecke, 2010). Though both GH and IGF-1 promote growth in fish, IGF-1 is recognized as the distal transducer for somatic growth (Triantaphyllopoulos et al., 2019). ...
Article
Water temperature alone can affect the growth, metabolic rates and physiological responses of aquatic organisms. Our earlier study reported that higher temperature affects cellular and hemato-biochemical responses in rohu, Labeo rohita. In this backdrop, the present study assessed the effect of higher acclimation temperature on the regulatory mechanisms of growth and stress responses of juvenile L. rohita acclimatized in three temperature conditions (30°C, 33°C, and 36°C) for a period of 30 days. The relative expression of genes for growth hormone (GH), insulin-like growth factors (IGF-1 and IGF-2) and heat shock proteins (hsp70 and hsp90) were measured by real-time quantitative PCR. The results revealed that the highest acclimation temperature (36°C) significantly decreased the weight gain (WG) and specific growth rate (SGR), and increased the feed conversion ratio (FCR) compared to 30°C (control), while increased WG, SGR and lowered FCR were observed in fish reared at the intermediate temperature (33°C) compared to 30°C. Similarly, the GH gene expression in the pituitary was significantly decreased and increased at 36°C and 33°C, respectively as compared to 30°C. A significantly lower expression of IGF-1 and IGF-2, and higher expression of hsp70 and hsp90 were observed in the liver of fish at 36°C. The results of the present study indicate that although slightly elevated temperature promotes the growth of juvenile L. rohita, the higher acclimation temperature may induce stress response and impair growth performance by suppressing GH/IGF system.
Article
Fish growth can be modulated through genetic selection. However, it is not known whether growth regulatory mechanisms modulated by genetic selection can provide information about phenotypic growth variations among families or populations. Following a five-generation breeding program that selected for the absence of early sexual maturity and increased growth in brook charr we aimed to understand how the genetic selection process modifies the growth regulatory pathway of brook charr at the molecular level. To achieve this, we studied the regulation of growth traits at three different levels: 1) between lines—one under selection, the other not, 2) among-families expressing differences in average growth phenotypes, which we termed family performance, and 3) among individuals within families that expressed extreme growth phenotypes, which we termed slow- and fast-growing. At age 1+, individuals from four of the highest performing and four of the lowest performing families in terms of growth were sampled in both the control and selected lines. The gene expression levels of three reference and ten target genes were analyzed by real-time PCR. Results showed that better growth performance (in terms of weight and length at age) in the selected line was associated with an upregulation in the expression of genes involved in the growth hormone (GH)/insulin growth factor-1 (IGF-1) axis, including the igf-1 receptor in pituitary; the gh-1 receptor and igf-1 in liver; and ghr and igf-1r in white muscle. When looking at gene expression within families, family performance and individual phenotypes were associated with upregulations of the leptin receptor and neuropeptid Y—genes related to appetite regulation—in the slower-growing phenotypes. However, other genes related to appetite (ghrelin, somatostatin) or involved in muscle growth (myosin heavy chain, myogenin) were not differentially expressed. This study highlights how transcriptomics may improve our understanding of the roles of different key endocrine steps that regulate physiological performance. Large variations in growth still exist in the selected line, indicating that the full genetic selection potential has not been reached.
Preprint
Full-text available
This study, it was aimed to investigate the expression levels of transcription factor (TF) genes (MYF6, MYOD1, MYF5, MYOG) and proteins associated with muscle growth in the longissimus dorsi (LD) and gluteal (GL) muscles in sheep. For this purpose, two fat-tailed sheep breeds (Akkaraman (n = 10), İvesi (n = 10)) and two thin-tailed sheep breeds (Kivircik (n = 10) and Karayaka (n = 10)) from Turkey's native sheep breeds were examined. The expression level of RNAs and proteins isolated from fresh tissues and MYF6, MYOD1, MYF5, MYOG proteins were analyzed. As a result of the statistical analysis, in the LD tissue, respectively, MYOG and MYF5 genes in the Karayaka sheep breed; MYOD1 gene in Akkaraman sheep breed; MYF5 gene in Awassi sheep breed were found to be statistically significant (P < 0.05). In GL tissue, respectively, MYOG and MYF6 genes in Akkaraman sheep breed; MYOD1 gene in Karayaka sheep breed; MYF6 gene in Akkaraman and Awassi sheep breed were found to be statistically significant (P < 0.05). In the present study, it was found that the MYOG (fold change 6.87) and MYOD1 (fold change 15.41) genes were upregulated in the GL muscle of the fat-tailed Akkaraman sheep breed. In addition, in the thin-tailed Karayaka sheep breed, down-regulation of MYOD1 (fold change − 0.22) gene in LD muscle and up-regulation of MYOD1 (fold change 6.67) gene in GL muscle was found. As a result, it can be considered that MYOG and MYOD1 genes as candidate genes in molecular selection studies for our fat-tailed and thin-tailed indigenous breeds in terms of muscle development.
Article
Introduction/aims: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. Methods: Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of 9 SMA patients, 6 patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and 4 controls. Results: A significant decrease in IGF-I levels (mean ± SD: -1.39 ± 1.46 vs. 0.017 ± 0.83, p = 0.02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4 ng/mL vs. 1003.4 ± 274.3 ng/mL, p=0.03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway. Discussion: Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.
Chapter
Insulin-like growth factors (IGFs) include IGF I and IGF II. IGF I is an essential regulator of cell division, differentiation, embryonic development, and growth. IGF II, also known as somatomedin A, is mainly involved in the regulation of embryonic growth. Growth hormone may have different effects on IGF-II gene expression in different fish. This chapter reviews some studies on IGFs in fish larva and juvenile, analyzes the expressions of IGF I and IGF II at different time of ontogenesis and incubation temperature, and evaluates the effects of nutrition on IGF expression in Trachinotus ovatus larvae and juveniles. The expression of IGF I increased with the growth of larvae and juveniles, but the influence of water temperature was not significant. The water temperature influences the expression of IGF II. Its expression at 23 °C was significantly higher than that at 26 and 29 °C. The expression of IGFs in fish larvae on 28 DPH was not accompanied by nutrient manipulation. The time-dependent expression of IGF genes of larval fish is crucial to understand the ontogenetic development and larval fish growth in early life.Keywords Trachinotus ovatus Insulin-like growth factorsOntogenesisTemperatureNutrition
Article
This aim of this study was to investigate the effects of dietary aucubin on the growth, flesh quality and metabolomics of grass carp (Ctenopharyngodon idella). Five diets were designed with the aucubin inclusion of 0 (control diet), 0.2, 0.4, 0.6 and 0.8 g/kg (Auc-0.2, Auc-0.4, Auc-0.6, Auc-0.8) and were fed to grass carp with an initial body weight of 17.0 ± 0.2 g for 60 days. The results indicated that dietary aucubin did not significantly affect the growth performance of grass carp (P > 0.05). Compared to the control, dietary supplementation with 0.2-0.8 g/kg aucubin increased flesh hardness, chewiness, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and the contents of total free amino acids (TFAA) and n-3 polyunsaturated fatty acids (n-3 PUFA) (P < 0.05). The contents of malondialdehyde (MDA) and lactic acid (LD) in the flesh were significantly decreased by the addition of 0.4-0.6 g/kg aucubin and by the addition of 0.6-0.8 g/kg aucubin (P < 0.05), respectively, while the content of delicious amino acids (DAA) was significantly enhanced by the addition of 0.4-0.8 g/kg aucubin (P < 0.05). Moreover, the contents of collagen and C22:6n3 (DHA) in the flesh of the Auc-0.8 group were significantly higher than those of the control (P < 0.05). In the metabolomics profiling of flesh, 133 and 135 named differential metabolites were identified in the Auc-0.4 and Auc-0.8 groups, respectively, compared to the control, and these metabolites were found to be involved in the second-grade pathways of “lipid metabolism” and “amino acid metabolism”. Regarding gene expression, the mRNA levels of CuZn-SOD, CAT, COL1A1, COL1A2, Smad4 and FAS in flesh were upregulated in the Auc-0.4 and Auc-0.8 groups, and the expression levels of GPx, Nrf2 and TGF-β1 mRNA were also upregulated in the Auc-0.8 group (P < 0.05). In summary, dietary aucubin did not promote growth, but improved the flesh quality of grass carp, which might be associated with the TGF-β/Smad and Nrf2 pathways. The recommended supplementation level of aucubin in the diet of grass carp was 0.6-0.8 g/kg.
Preprint
Full-text available
Lower extremity peripheral arterial disease (PAD) has continued to increase in prevalence over the past several decades, yet therapeutic development has remained stagnant. Skeletal muscle health and function has been strongly linked to quality of life and medical outcomes in PAD patients. Using a rodent model of PAD, this study demonstrates that treatment of the ischemic limb with adeno-associated virus-mediated expression of insulin-like growth factor 1 (IGF1) significantly increases muscle size and strength, without improving limb hemodynamics. Interestingly, the effect size of IGF1 therapy was larger in female mice compared to their male counterparts, where substantial improvements in muscle specific force and a reduction in the progression of limb necrosis were observed. These findings indicate that clinical trials should carefully examine sex-dependent effects in experimental PAD therapies.
Article
Background: Pappalysins (PAPP-A, PAPP-A2) modulate body growth by increasing IGF-I bioavailability through cleavage of IGFBPs and are inhibited by stanniocalcins (STC1, STC2). Normative data of these novel factors, as well as of free IGF-I and uncleaved fractions of IGFBPs are not well established. Objective: To determine serum concentrations of PAPP-A, PAPP-A2, STC1 and STC2, in relationship with other GH-IGF axis parameters during development. Patients and methods: Full-term newborns (150; gestational age: 39.30 ± 1.10 weeks), 40 preterm newborns (30.87 ± 3.35 weeks) and 1071 healthy individuals (1-30 years old) were included in the study and divided according to their Tanner stages (males and females): I:163 males, 154 females; II:100 males, 75 females; III:83 males, 96 females; IV: 77 males, 86 females; and V:109 males,128 females. Results: Serum concentrations of PAPP-A, PAPP-A2, STC1, STC2, IGFBP-2, total IGFBP-4 and total IGFBP-5 were elevated at birth and declined throughout childhood. In postnatal life, PAPP-A2 concentrations decreased progressively in concomitance with the free/total IGF-I ratio; however, stanniocalcin concentrations remained stable. PAPP-A2 concentrations positively correlated with the free/total IGF-I ratio (r=+0.28 p<0.001) and negatively with the intact/total IGFBP-3 ratio (r=-0.23, p<0.001). PAPP-A concentrations inversely correlated with intact/total IGFBP-4 ratio (r=-0.21, p<0.001), with PAPP-A concentrations being lower in females at all ages. Association studies indicate the importance of stanniocalcins and pappalysins in the control of this axis in an age specific manner. Conclusion: This study provides reference values of pappalysins and stanniocalcins, which modulate IGF-I activity by changing the concentrations of cleaved and uncleaved IGFBPs.
Article
Growth hormone transgenic coho salmon experience increased growth rates, driven primarily through elevated feed intake and feed conversion. However, neuropeptides that signal appetite stimulation have been shown to exhibit variable responses across fed states, suggesting a more complex system mediating growth in these fish. Studies have proposed that growth hormone may have a modulatory role on the energy reserves of fish, possibly through AMP-activated protein kinase (AMPK) activation. AMPK, an energy sensor in cells, has previously been shown to be upregulated in growth hormone transgenic salmon when compared to wild type, however, whether this effect is seen across fed states is unknown. Here, we tested the hypothesis that growth hormone induces an energetic deficit in metabolic tissues, leading to constitutive AMPK activation in growth hormone transgenic salmon. This study compared AMPK activity, ATP, and glycogen, of the liver, heart, and muscle of wild-type, and growth hormone transgenic salmon either fed to satiation or a wild-type ration. The results suggest that white muscle ATP levels in growth hormone salmon are elevated in satiation and rationed conditions. In the liver, growth hormone transgenic salmon fed a rationed wild-type diet experience reductions in ATP level and glycogen. In none of the tissues examined, did AMPK activity change. Taken together, these results indicate that growth hormone transgenic salmon experience metabolic duress when not fed to satiation.
Article
Brown bears conserve muscle and bone mass during six months of inactive hibernation. The molecular mechanisms underlying hibernation physiology may have translational relevance for human therapeutics. We hypothesize that protective mechanisms involve increased tissue availability of the insulin-like growth factors (IGFs). In subadult Scandinavian Brown Bears, we observed that mean plasma IGF-1 and IGF-2 during hibernation was reduced to 36±10% and 56±15%, respectively, compared to the active state (N=12). Western ligand blotting identified IGFBP-3 as the major IGF binding protein in the active state, while IGFBP-2 was co-dominant during hibernation. Acid labile subunit (ALS) levels in hibernation were 41±16% those of the active state (N=6). Analysis of available grizzly bear RNA sequencing data revealed unaltered liver mRNA IGF-1, IGFBP-2, and IGFBP-3 levels, whereas ALS was significantly reduced during hibernation (N=6). Reduced ALS synthesis and circulating levels during hibernation should prompt a shift from ternary IGF/IGFBP/ALS to smaller binary IGF/IGFBP complexes, thereby increasing IGF tissue availability. Indeed, Size Exclusion Chromatography of bear plasma, demonstrate a shift to lower molecular weight IGF-containing complexes in the hibernating versus the active state. Further, we note that the major IGF-2 mRNA isoform expressed in liver in both Scandinavian brown bears and grizzly bears was an alternative splice variant in which Ser29 was replaced with a tetrapeptide possessing a positively charged Arg residue. Homology modelling of the bear IGF-2/IGFBP-2 complex showed the tetrapeptide in proximity to the heparin binding domain involved in bone-specific targeting of this complex. In conclusion, this study provides data which suggest that increased IGF tissue availability combined with tissue-specific targeting contribute to tissue preservation in hibernating bears.
Article
The Onychostoma macrolepis (O. macrolepis) is a rare and endangered fishery species inhabiting the river of Qinling Mountains and some flowing freshwaters in China. The declining population of O. macrolepis caused by asynchrony of male and female development prompted us to focus on genetic regulation of its reproduction. In this study, high-throughput RNA-sequencing technology was applied to assemble and annotate the transcriptome of O. macrolepis testis and ovary. The results showed that a number of 338089335(ovary:163216500, testis:174872835) raw sequences were obtained. After non-redundant analysis, a number of 207826065(ovary:102334008, testis:105492057) high quality reads were obtained and predicted as unigenes, in which 201038682 unigenes were annotated with multiple databases. Taking the ovarian transcriptome as a control, comparative transcriptome analysis showed that 9918 differentially expressed genes (DEGs) up-regulated in the testis and 13095 DEGs down-regulated. Many DEGs were involved with sex-related GO terms and KEGG pathways, such as oocyte maturation, gonadal development, steroid biosynthesis pathways, MAPK signaling pathway and Wnt signaling pathway. Finally, the expression patterns of 19 unigenes were validated by using quantitative real-time polymerase chain reaction (qRT-PCR). This study illustrates a potential molecular mechanism on the unsynchronized male and female development of the O. macrolepis during the reproduction period in June and provides a theoretical basis for future artificial reproduction.
Article
Organic acids are active substances required for improving the productivity and wellbeing of aquatic animals. Herein, the study investigated the effects of sodium propionate on growth performance, antioxidative and immune responses, and growth-related genes expression in beluga sturgeon (Huso huso). For eight weeks, fish fed sodium propionate at 0, 1.2, 2.5, and 5 g kg-1. The final weight, weight gain, and SGR were substantially increased while FCR decreased by dietary sodium propionate at 2.5 and 5 g kg-1 (P < 0.05). The expression of Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) was markedly upregulated (P < 0.05) by dietary sodium propionate in the gills and livers of beluga. The highest mRNA level of GH and IGF-1 has been observed in fish fed a 2.5 g sodium propionate/kg diet. The red blood cells count, and hemoglobin level were meaningfully increased (P < 0.05) by 2.5 and 5 g sodium propionate/kg diet compared with 0 and 1.2 g kg-1 levels. Further, the hematocrit level was increased (P < 0.05) by a dietary 5 g sodium propionate/kg diet. The total protein level and lysozyme activity were meaningfully increased (P < 0.05) by 2.5 and 5 g sodium propionate/kg diet compared with 0 and 1.2 g kg-1 levels. The highest superoxide dismutase was observed in fish fed 2.5 g sodium propionate/kg diet. Catalase activity was significantly higher in fish fed 5 g kg-1 than 1.2 g kg-1. The glutathione peroxidase activity was markedly higher in fish fed 2.5, and 5 g kg-1 than fish fed control diet. The lowest malondialdehyde levels were observed in fish fed 1.2, and 2.5 g sodium propionate/kg diets. Moreover, the highest mucosal total protein, total immunoglobulin and lysozyme were recorded in fish fed 2.5, and 5 g sodium propionate/kg diets. The obtained results indicate that dietary sodium propionate is recommended at 2.5-5 g kg-1 to improve beluga sturgeon's growth performance, feed utilization, and wellbeing.
Preprint
Full-text available
As a new member of IGFs, insulin-like growth factor 3 ( igf3 ) plays an important role in the development of gonads of teleost fish. Previous studies have found that igf3 was specifically expressed in the gonads of silver pomfret ( Pampus argenteus ). Different with other fish, the igf3 protein of silver pomfret is a membrane protein, and its specific role in the gonads was not yet clear. Here, we further studied the importance of igf3 in oogenesis and spermatogenesis in silver pomfret by analyzing its gene expression and cellular localization. During follicular development, igf3 mRNA and protein were significantly expressed in ovaries stayed in the critical period of vitellogenesis (Ⅳ - Ⅵ). Localization studies found that igf3 mRNA and protein were significantly and obviously expressed in somatic cells including theca and granulosa cells around oocytes. Meanwhile, similar with cathepsin L and cathepsin K , igf3 had a high and consistent expression levels in ovaries during vitellogenesis, suggesting igf3 might play a key role in the process of vitellogenesis of oocytes. In the process of spermatogenesis, the expression of igf3 mRNA and protein were high in stages Ⅱ, Ⅳ and Ⅴ, which was similar with the expression of sycp3 and dmc1 . And the highest expression level of igf3 mRNA and protein reached in stage Ⅵ. At the same time, positive signals of igf3 mRNA and protein were detected in spermatogonium, spermatocytes, spermatid and surrounding Sertoli cells, but not expressed on spermatozoon, which indicated that igf3 might be involved in the differentiation and meiosis of spermatogonium.
Article
Insulin-like growth factors (IGFs) have diverse functions in skeletal muscles by acting through multiple signaling pathways, including growth regulation and differentiation, anti-inflammation and anti-oxidation. IGFs have anti-inflammatory effects and also play roles in nociceptive pathways, determining pain sensitivity, in addition to their protective role against ischemic injury in both the nervous system and skeletal muscle. In skeletal muscle, IGFs maintain homeostasis, playing key roles in maintenance, accelerating muscle regeneration and repair processes. As part of their maintenance role, increased levels of IGFs may be required for the repair mechanisms following exercise. Although the role of IGFs in myofascial pain syndrome (MPS) is not completely understood, there is evidence from a recent study that IGF-2 levels in patients with MPS are lower than those of healthy individuals, and are associated with increased levels of inflammatory biomarkers. Importantly, higher IGF-2 levels are associated with increased pain severity in MPS patients. This may suggest that too low or high IGF levels may contribute to musculoskeletal disorder process, while a mid-range levels may optimize healing without contributing to pain hypersensitivity. Future studies are required to address the mechanisms of IGF-2 in MPS and the optimal level as a therapeutic agent.
Article
Insulin-like growth factor binding protein 7 (igfbp7) is a member of the insulin-like growth factor binding protein (IGFBP) superfamily, which is involved in the regulation of insulin-like growth factor (IGF) and insulin signal transduction. Recently, igfbp7 was found to be female-biased expressed in the gonad of Chinese tongue sole (Cynoglossus semilaevis), a marine flatfish exhibited female-biased sexual dimorphism. This study aimed to explore the roles of igfbp7 in the growth and sex differentiation of C. semilaevis. Firstly, C. semilaevis igfbp7 was cloned, and the coding sequence (CDS) was 666 bp encoding 221 amino acids. The phylogenetic and structural analyses revealed that C. semilaevis igfbp7 was clustered with Atlantic halibut (Hippoglossu shippoglossus), sailfin molly (Poecilia latipinna), and so on. The subsequent temporal and spatial expression analyses showed that igfbp7 was mainly expressed in female gonad. During the different gonad developmental stages, the expression of igfbp7 displayed the highest level at 6-month. Methylome data showed that female igfbp7 exhibited lower methylation levels than male and pseudomale across the whole gene region in the gonad. Dual-luciferase experiment revealed that C. semilaevis igfbp7 promoter exhibited strong transcription activity. In addition, pituitary-specific positive transcription factor 1 (POU1F1) and steroid hormone-testosterone significantly enhanced the transcriptional activity of the igfbp7 promoter. In vitro transfection experiment revealed the activation of igfbp7 on the nuclear factor kappa B (NF-κB) signaling pathway. Finally, the activation of insulin-like growth factor 1 receptor (igf1r), serine/threonine kinase 1 (akt) and heat shock 60 protein 1 (hspd1) was observed in C. semilaevis ovary cells transfected by igfbp7 small interfering RNA (siRNA). These results provided causal clues for igfbp7 in growth regulation by influencing igf1r, akt and NF-κB signal.
Chapter
The largest tissue mass in the human body consists of skeletal muscle. It is essential for posture and motion. Different causes are responsible for a critical volume loss of skeletal muscle, e.g., traumatic injury or tumor ablation. This leads to consequences, such as pain, deformity, loss of function, and joint malfunction. The regenerative capacity of skeletal muscle is very low, due to the limited proliferative capability of adult muscle stem cells, the so-called satellite cells. Therefore, mesenchymal stem cells are promising cell alternatives for skeletal muscle tissue engineering, because they can be easily harvested in high numbers from the bone marrow or adipose tissue and differentiated into various cells of the mesodermal lineage, including muscle cells. In a clinical setting, muscle tissue can only be replaced by sacrificing other muscle tissue. Thus, the engineering of artificial and functional skeletal muscle tissue is of interest in biomedical research. The extracellular matrix (ECM) of the skeletal muscle differs from the ECM of other tissues. The special requirements for elasticity and yet high strength represent a specialty in skeletal muscle tissue engineering, which could be achieved by using artificially constructed nanofibers as a growing matrix for muscle precursor cells. In this chapter, we review the application of different polymers for muscle tissue engineering. The use of nanofibers in tissue engineering seems promising because they offer large surfaces for cell attachment to support optimal cell interactions and development. Furthermore, polymers supplemented with conductive and bioactive substances, or mechanically improved structures are used as scaffolds to mimic the natural ECM of skeletal muscle to facilitate cellular development.
Chapter
Aging is one of the key contributors to a broad spectrum of chronic diseases. Reactive oxygen species (ROS) increase oxidative stress in cells and thus induces inflammatory cascades. The antioxidant defense systems are declined during aging. Antioxidant controls the oxidative radical process by suppressing the formation of free radicals and interrupting the propagation and initiation of free radicals through several mechanisms. Considering the crucial roles of oxidative stress in age-related diseases, the manipulation of ROS levels would represent a useful option to delay age-related diseases and attenuate associated symptoms. Numerous compounds with antioxidant activity have demonstrated their potential to alleviate age-related diseases; however, mixed results are yielded. Therefore, this chapter discussed the potential of dietary antioxidants against age-related diseases. We also explored on how dietary choices dampen or exacerbate the inflammation and metabolic disorders. Collectively, this information may shed light on the discovery for potential intervention, and thus promoting healthy longevity.
Article
Full-text available
Abstract SART and PMM are mainly composed of oxidative myofibers and glycolytic myofibers, respectively, and myofiber types profoundly influence postnatal muscle growth and meat quality. SART and PMM are composed of lncRNAs and circRNAs that participate in myofiber type regulation. To elucidate the regulatory mechanism of myofiber type, lncRNA and circRNA sequencing was used to systematically compare the transcriptomes of the SART and PMM of Chinese female Qingyuan partridge chickens at their marketing age. The luminance value (L*), redness value (a*), average diameter, cross-sectional area, and density difference between the PMM and SART were significant (p
Article
As a new member of the Insulin-like growth factors (IGFs) family of proteins, Igf3 has been found to be involved in fish reproduction. To evaluate the functions of Igf3 in grass carp, the igf3 gene was isolated from the gonads via RT-PCR (reverse transcription polymerase chain reaction). The ORF of grass carp igf3 was found to be 606 bp long, encoding 201 amino acids. The grass carp Igf3 precursor contains five domains, termed B-C-A-D-E. Tissues distribution analysis showed that igf3 was widely expressed in multiple tissues, and is highly expressed in the gonads, cerebellum and hypothalamus of grass carp. The oral glucose tolerance test (OGTT) showed that igf3 expression levels increased in the hypothalamus, hepatopancreas and muscle after glucose treatment. The fasting/refeeding showed that igf3 expression in hepatopancreas and muscle were markedly inhibited in the fasting group and were significantly increased in refeeding group. A recombinant grass carp Igf3 protein was obtained using a prokaryotic expression system. The function of this recombinant Igf3 were assessed in vitro and in vivo experiments. The expression of igf1, igf2b, and ghr was significantly increased, and igf2a expression was markedly decreased by Igf3 treatment in vitro and in vivo. The expression of igf3 and igf1r was significantly increased by Igf3 treatment in vitro. The expression of igfbp1 decreased and the expression of igfbp2, igfbp3, akt and pi3k increased after Igf3 treatment in vivo and in vitro. The expression of igfbp5a and igfbp5b were also increased by Igf3 treatment in vitro. The effects of Igf3 treatment on the expression of igf1, igf2, and ghr were relieved after treatment with the PI3K inhibitor wortmannin in grass carp primary hepatocytes. To our knowledge, our study was the first to reveal that Igf3 regulates the expression of growth-related genes in teleosts.
Article
The size of an organ is proportional to the other body parts or the whole body. This relationship is known as allometry. Understanding how allometry is determined is a fundamental question in biology. Here we tested the hypothesis that local insulin-like growth factor (Igf) signaling is critical in regulating organ size and its allometric scaling by organ-specific expression of Igf binding proteins (Igfbp). Overexpression of Igfbp2a or 5b in the developing zebrafish eye, heart, and inner ear resulted in a disproportional reduction in their growth relative to the body. Stable transgenic zebrafish with lens-specific Igfbp5b expression selectively reduced adult eye size. The action is Igf-dependent because an Igf-binding deficient Igfbp5b mutant had no effect. Targeted expression of a dominant-negative Igf1 receptor (dnIgf1r) in the lens caused a similar reduction in relative eye growth. Furthermore, co-expression of IGF-1 with an Igfbp restored the eye size. Finally, co-expression of a constitutively active form of Akt with Igfbp or dnIgf1r restored the relative eye growth. These data suggest that local Igf availability and Igf signaling activity are critical determinants of organ size and allometric scaling in zebrafish.
Article
Insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) plays essential roles in the proliferation of skeletal muscle satellite cells (MuSCs). Increasing evidence has shown that IGF2BP1 regulates the expression of noncoding RNAs and mRNAs. However, the related molecular network remains to be fully understood. Therefore, we performed RNA sequencing and analyzed the microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and mRNAs differentially expressed in goat MuSCs treated with IGF2BP1 overexpressing and empty vectors. A total of 36 miRNAs, 59 lncRNAs, and 44 mRNAs were differentially expressed caused by IGF2BP1. Expectedly, they were enriched in muscle development‐related Rap1, PI3K‐AKT, and FoxO signaling pathways. Finally, we constructed a lncRNA‐miRNA‐mRNA interaction network containing 30 lncRNAs, 15 miRNAs, and 34 mRNAs, in which several miRNAs, including miR‐133a‐3p, miR‐204‐5p, miR‐125a‐3p, miR‐145‐3p, and miR‐423‐5p, relate with cell growth and participate in muscle development. Overall, we constructed an IGF2BP1‐related network, which provides new insight into the myogenic proliferation of goat.
Thesis
Epithelial tissues renew rapidly and continuously by reactivating a pool of quiescent cells. How the quiescent cells are established, maintained, and reactivated is poorly defined. Recent studies suggest that the insulin-like growth factor (IGF)-PI3 kinase-AKT-mTOR signaling pathway plays a key role in regulating epithelial cell quiescence-proliferation decision but the underlying mechanism remains unclear. In my thesis work, I use a zebrafish model to investigate the IGF action in a group of Ca2+-transporting epithelial cells, known as Na+-K+-ATPase-rich (NaR) cells. When zebrafish are kept in normal and physiological [Ca2+] embryo rearing media, NaR cells are quiescent, characterized by a very slow division rate and undetectable Akt and Tor activity. When subjected to low [Ca2+] stress, the NaR cells exit the quiescent state and proliferate due to elevated IGF1 receptor-mediated Akt and Tor activity. To understand how the IGF signaling is activated exclusively in NaR cells under low [Ca2+] stress, I first investigated the role of Igfbp5a, a secreted protein belonging to the IGF binding protein (IGFBP) family. Zebrafish igfbp5a is specifically expressed in NaR cells and genetic deletion of igfbp5a blunted the low Ca2+ stress-induce IGF-Akt-Tor activity and NaR cell reactivation. Similarly, knockdown of IGFBP5 in human colon carcinoma cells resulted in reduced IGF-stimulated cell proliferation. Re-expression of zebrafish or human Igfbp5a/IGFBP5 in NaR cells restores NaR cell proliferation. Mechanistically, Igfbp5a acts by binding to IGFs using its ligand-binding domain and promoting IGF signaling in NaR cells. These results reveal a conserved mechanism by which a locally expressed Igfbp activates IGF signaling and promoting cell quiescence-proliferation transition under Ca2+-deficient states. NaR cells are functionally equivalent to human intestinal epithelial cells, and they contain all major molecular components of the transcellular Ca2+ transport machinery, including the epithelial calcium channel Trpv6. Ca2+ is a central intracellular second messenger controlling many aspects of cell biology. I next investigated the role of Trpv6 and intracellular [Ca2+]. I discovered that NaR cells are maintained in the quiescent state by Trpv6-mediated constitutive Ca2+ influx. Genetic deletion and pharmacological inhibition of Trpv6 promote NaR cell quiescence-proliferation transition. In zebrafish NaR cells and human colon carcinoma cells, Trpv6/TRPV6 elevated intracellular Ca2+ levels and activated PP2A, a group of conserved protein phosphatases, which down-regulates IGF signaling and promotes the quiescent state. Finally, chemical biology screens and genetic experiments identified CaMKK as a link between low Ca2+ stress and IGF signaling activation in NaR cells. Depletion of the ER Ca2+ store abolished NaR cell reactivation and IGF signaling. These results suggest that ER Ca2+ release in response to the low [Ca2+] stress activates CaMKK, which in turn increases IGF signaling and NaR cell reactivation. Taken together, the results of my thesis research provide new insights into the epithelial cell proliferation-quiescence regulation and have deepened our understanding of cellular quiescence regulation. These new findings may also contribute to the future development of strategies in improving wound healing and tissue regeneration.
Article
This paper develops a model for coordinate regulation of feeding, metabolism, and growth based on studies in fish. Many factors involved with the control of feeding [e.g., cholecystokinin (CCK) and ghrelin (GRLN)], energy metabolism [e.g., insulin (INS), glucagon (GLU), glucagon-like peptide (GLP), and somatostatins (SS), produced in the endocrine pancreas; and leptin (LEP) produced broadly], and growth [e.g., GRLN, growth hormone (GH), insulin-like growth factors (IGFs), GH receptors (GHR), IGF receptors (IGFR)] interact at various levels. Many such interactions serve to coordinate these systems to favor anabolic processes (i.e., lipid and protein synthesis, glycogenesis) and growth, including GH promotion of feeding and stimulation of INS production/secretion and the upregulation of GHR and IGFR by GRLN. As nutrient and stored energy status change, various feedbacks serve to curtail feeding and transition the animal from an anabolic/growth state to a catabolic state. Many factors, including LEP and IGF, promote satiety, whereas SS downregulates INS signaling as well as IGF production and GHR and IGFR abundance. As INS and IGF levels fall, GH becomes disconnected from growth as a result of altered linkage of GHR to cell signaling pathways. As a result, the catabolic actions of GH, GLU, GLP, LEP, and SS prevail, mobilizing stored energy reserves. Coordinate regulation involves relative abundances of blood-borne hormones as well as the ability to adjust responsiveness to hormones (via receptor and post-receptor events) in a cell-/tissue-specific manner that results from genetic and epigenetic programming and modulation by the local milieu of hormones, nutrients, and autocrine/paracrine interactions. The proposed model of coordinate regulation demonstrates how feeding, metabolism, and growth are integrated with each other and with other processes, such as reproduction, and how adaptive adjustments can be made to energy allocation during an animal’s life history and/or in response to changes in environmental conditions.
Article
The antidepressant venlafaxine can be found at levels nearing μg/L in waterways receiving municipal wastewater effluent, exposing non-target organisms, such as fish, to this chemical. We showed previously that zygotic exposure to venlafaxine alters neurodevelopment and behaviour in zebrafish (Danio rerio) larvae. Here, we tested the hypothesis that the zygotic deposition of venlafaxine disrupts endocrine pathways related to growth in zebrafish. This was carried out by microinjecting embryos (1–4 cell stage) with either 0, 1, or 10 ng venlafaxine. Zygotic venlafaxine deposition reduced the growth of fish after 30 days post-fertilization. Specific growth rate was particularly impacted by 1 ng venlafaxine. This growth retardation corresponded with the disruption of endocrine pathways involved in growth and metabolism. Venlafaxine exposed embryos displayed reduced transcript abundance of key genes involved in anabolic hormone action. Early-life venlafaxine exposure also reduced whole-body insulin and glucose content in juveniles. Target-tissue glucose uptake measurements indicated that high venlafaxine deposition preferentially increased glucose uptake to the brain. Zygotic venlafaxine did not affect feed intake nor altered the transcript abundance of key feeding-related peptides. Taken together, zygotic venlafaxine deposition compromises zebrafish growth by disrupting multiple endocrine pathways, and this study has identified key markers for potential use in risk assessment.
Article
Full-text available
We have investigated which region(s) of bovine insulin-like growth factor binding protein-2 (bIGFBP-2) interact with insulin-like growth factors (IGFs) using C-terminally truncated forms of bIGFBP-2. Initially to aid in mutant design, we defined the disulfide bonding pattern of bIGFBP-2 C-terminal region using enzymatic digestion. The pattern is Cys¹⁸⁶-Cys²²⁰, Cys²³¹-Cys²⁴², and Cys²⁴⁴-Cys²⁶⁵. In addition, cyanogen bromide cleavage of bIGFBP-2 revealed that the N- and C-terminal cysteine-rich domains were not linked by disulfide bonds. Taking the disulfide bonding pattern into consideration, C-terminal truncation mutants were designed and expressed in COS-1 mammalian cells. Following IGF binding assays, a region between residues 222 and 236 was identified as important in IGF binding. Specifically, mutants truncated by 14, 36, and 48 residues from the C terminus bound IGFs to the same extent as wild type (WT) bIGFBP-2. Removal of 63 residues resulted in a greatly reduced (up to 80-fold) ability to bind IGF compared with WT bIGFBP-2. Interestingly this mutant lacked the IGF-II binding preference of WT bIGFBP-2. Residues 236–270 also appeared to play a role in determining IGF binding specificity as their removal resulted in mutants with higher IGF-II binding affinity.
Article
Full-text available
Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue, accompanied by a characteristic loss in the fastest, most powerful muscle fibers1, 2. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia3. We have generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1). Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathological changes seen in other Igf-1 transgenic models. Expression of GATA-2, a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals. The preservation of muscle architecture and age-independent regenerative capacity through localized mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.
Article
Full-text available
The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular &agr;-subunits activates the tyrosine kinase intrinsic to the cytoplasmic portion of the IGF-1 receptor, leading to autophosphorylation of specific tyrosine residues in the receptor &Bgr;-subunit. One early molecular event that links the receptor kinase to the biologic actions of IGF-1 is tyrosine phosphorylation of the insulin receptor substrate family (IRS-1 to -4). IRS acts as a multisite ’docking’ protein by binding to downstream signal-transducing molecules. Phosphorylation of multiple tyrosine residues results in the association of IRS-1 with the Src homology 2 (SH2) domains of other cytoplasmic signaling proteins, including phosphatidylinositol 3‘ kinase, Syp, Grb2 and Nck. By binding to Grb2, IRS proteins couple the IGF-1 receptor to the Ras/mitogenactivated protein kinase pathway. This pathway regulates cell growth, differentiation and proliferation. Severe pre- and postnatal growth retardation may arise from abnormalities of IGF-1 signaling such as IGF-1-binding alterations and IGF-1 receptor mutations. Knockout studies have shown severe growth impairment in mice lacking IRS family components or Akt. Finally, in human placentas from pregnancies complicated by intrauterine growth retardation, multiple alterations of IGF-1-signaling molecules have recently been described.
Article
Full-text available
Insulin-like growth factors (IGFs) stimulate myoblast proliferation and differentiation. It remains elusive how these mutually exclusive cellular responses are elicited by the same growth factor. Here we report that whereas IGF promotes myoblast differentiation under normoxia, it stimulates proliferation under hypoxia. Hypoxia activates the HIF-1 transcriptional program and knockdown of HIF-1alpha changes the mitogenic action of IGF into myogenic action under hypoxia. Conversely, overexpression of HIF-1alpha abolishes the myogenic effect of IGF under normoxia. Under normoxia, IGF activates the Akt-mTOR, p38, and Erk1/2 MAPK pathways. Hypoxia suppresses basal and IGF-induced Akt-mTOR and p38 activity, whereas it enhances and prolongs IGF-induced Erk1/2 activation in a HIF-1-dependent fashion. Activation of Akt-mTOR and p38 promotes myogenesis, and p38 also inhibits proliferation. Activation of Erk stimulates myoblast proliferation but inhibits differentiation. These results suggest that hypoxia converts the myogenic action of IGFs into mitogenic action by differentially regulating multiple signaling pathways via HIF-1-dependent mechanisms. Our findings provide a mechanistic explanation for the paradoxical actions of IGFs during myogenesis and reveal a novel mechanism by which cells sense and integrate growth factor signals and oxygen availability in their microenvironments.
Article
Full-text available
Insulin-like growth factor binding protein (IGFBP)-5 is a secreted protein that binds to IGF and modulates IGF actions. IGFBP-5 is also found in the nucleus of mammalian cells and has transactivation activity. The structural basis of this transactivation activity and its role in mediating IGF-independent actions are not clear. Here we report that there are 2 igfbp-5 genes in zebrafish and other teleost fish. In zebrafish, igfbp-5a and -5b are expressed in spatially restricted, mostly nonoverlapping domains during early development. The IGF binding site is conserved in both zebrafish IGFBP-5s, and they are both secreted and capable of IGF binding. Both proteins contain a consensus bipartite nuclear localization signal and were found in the nucleus when introduced into cultured cells. Although zebrafish IGFBP-5b possesses transactivation activity, zebrafish IGFBP-5a lacks this activity. Mutational analysis demonstrated that 2 unique amino acids in positions 22 and 56 of IGFBP-5a are responsible for its lack of transactivation activity. These findings suggest that the duplicated zebrafish IGFBP-5s have evolved divergent regulatory mechanisms and distinct biological properties by partitioning of ancestral structural domains and provide new evidence for a conserved role of the IGF binding, nuclear localization, and transactivation domain of this multifunctional IGFBP.
Article
Full-text available
Insulin-like growth factors (IGFs) are key regulators of development, growth, and longevity. In most vertebrate species including humans, there is one IGF-1 gene and one IGF-2 gene. Here we report the identification and functional characterization of 4 distinct IGF genes (termed as igf-1a, -1b, -2a, and -2b) in zebrafish. These genes encode 4 structurally distinct and functional IGF peptides. IGF-1a and IGF-2a mRNAs were detected in multiple tissues in adult fish. IGF-1b mRNA was detected only in the gonad and IGF-2b mRNA only in the liver. Functional analysis showed that all 4 IGFs caused similar developmental defects but with different potencies. Many of these embryos had fully or partially duplicated notochords, suggesting that an excess of IGF signaling causes defects in the midline formation and an expansion of the notochord. IGF-2a, the most potent IGF, was analyzed in depth. IGF-2a expression caused defects in the midline formation and expansion of the notochord but it did not alter the anterior neural patterning. These results not only provide new insights into the functional conservation and divergence of the multiple igf genes but also reveal a novel role of IGF signaling in midline formation and notochord development in a vertebrate model.
Article
Full-text available
Insulin-like growth factor binding proteins (IGFBPs) are high-affinity binding partners for IGFs and play important roles in modulating IGF activities. In this study, we have identified and characterized two functional IGFBP-6 genes in zebrafish. Structural, phylogenetic, and comparative genomic analyses indicate that they are co-orthologs of the human IGFBP-6 gene. To gain insight into how the duplicated genes may have evolved through partitioning of ancestral functions, gene expression and functional studies were carried out. In adult fish, IGFBP-6a mRNA was most abundantly expressed in the muscle. The levels of IGFBP-6a mRNA in nonmuscle tissues were very low or barely detectable. In comparison, the levels of IGFBP-6b mRNA were high in the brain, heart, and muscle, but very low or undetectable in other adult tissues. During embryogenesis, the IGFBP-6a mRNA levels were relatively low. The IGFBP-6b mRNA levels were low during the initial 48 h. They became significantly higher at 72 and 96 h postfertilization. Overexpression of zebrafish IGFBP-6a and IGFBP-6b caused a similar degree of reduction in body size and developmental rate. No notable effects were observed on cell fate or patterning in these transgenic fish. These data suggest that the duplicated igfbp-6 genes encode two functionally similar proteins, but they have evolved distinct spatial and temporal expression patterns. These findings are consistent with the notion of an additional gene duplication event in teleost fish and have provided novel insight into the structural and functional evolution of the IGFBP gene family.
Article
Full-text available
Insulin-like growth factor (IGF) binding protein (IGFBP)-3 has traditionally been defined by its role as a binding protein and its association with IGF delivery and availability. Development of non-IGF binding IGFBP-3 analogs and the use of cell lines devoid of type 1 IGF receptors (IGF-R) have led to critical advances in the field of IGFBP-3 biology. These studies show that IGFBP-3 has IGF-independent roles in inhibiting cell proliferation in cancer cell lines. Nuclear transcription factor, retinoid X receptor (RXR)-alpha, and IGFBP-3 functionally interact to reduce prostate tumor growth and prostate-specific antigen in vivo. Moreover, IGFBP-3 inhibits insulin-stimulated glucose uptake into adipocytes independent of IGF. The purpose of this review is to highlight IGFBP-3 as a novel effector molecule and not just another "binding protein" by discussing its IGF-independent actions on metabolism and cell growth. Although this review presents studies that assume the role of IGFBP-3 as either an endocrine or autocrine/paracrine molecule, these systems may not exist as distinct entities, justifying the examination of IGFBP-3 in an integrated model. Also, we provide an overview of factors that regulate IGFBP-3 availability, including its production, methylation, and ubiquitination. We conclude with the role of IGFBP-3 in whole body systems and possible future applications of IGFBP-3 in physiology.
Article
Full-text available
Insulin-like growth factor binding protein-2 (IGFBP-2) is a secreted protein that binds and regulates IGF actions in controlling growth, development, reproduction, and aging. Elevated expression of IGFBP-2 is often associated with progression of many types of cancers. We report the identification and characterization of two IGFBP-2 genes in zebrafish and four other teleost fish. Comparative genomics and structural analyses suggest that they are co-orthologs of the human IGFBP-2 gene. Biochemical assays show that both zebrafish igfbp-2a and -2b encode secreted proteins that bind IGFs. These two genes exhibit distinct spatiotemporal expression patterns. During embryogenesis, IGFBP-2a mRNA is initially detected in the lens, then in the brain boundary vasculature, and subsequently becomes highly expressed in the liver. In the adult stage, liver has the highest levels of IGFBP-2a mRNA, followed by the brain. Low levels of IGFBP-2a mRNA were detected in muscle and in the gonad in male adults only. IGFBP-2b mRNA is detected initially in all tissues at low levels, but later becomes abundant in the liver. In adult males, IGFBP-2b mRNA is only detected in the liver. In adult females, it is also found in the gut, kidney, ovary, and muscle. To gain insights into how the IGFBP-2 genes may have evolved through partitioning of ancestral functions, functional and mechanistic studies were carried out. Expression of zebrafish IGFBP-2a and -2b caused significant decreases in the growth and developmental rates and their effects are comparable to that of human IGFBP-2. IGFBP-2 mutants with altered IGF binding-, RGD-, and heparin-binding sites were generated and their actions examined. While mutating the RGD and heparin binding sites had little effect, altering the IGF binding site abolished its biological activity. These results suggest that IGFBP-2 is a conserved regulatory protein and it inhibits growth and development primarily by binding to and inhibiting IGF actions in vivo. The duplicated IGFBP-2 genes may provide additional flexibility in the regulation of IGF activities.
Article
Full-text available
Gene duplication is the primary force of new gene evolution. Deciphering whether a pair of duplicated genes has evolved divergent functions is often challenging. The zebrafish is uniquely positioned to provide insight into the process of functional gene evolution due to its amenability to genetic and experimental manipulation and because it possess a large number of duplicated genes. We report the identification and characterization of two hypoxia-inducible genes in zebrafish that are co-ortholgs of human IGF binding protein-1 (IGFBP-1). IGFBP-1 is a secreted protein that binds to IGF and modulates IGF actions in somatic growth, development, and aging. Like their human and mouse counterparts, in adult zebrafish igfbp-1a and igfbp-1b are exclusively expressed in the liver. During embryogenesis, the two genes are expressed in overlapping spatial domains but with distinct temporal patterns. While zebrafish IGFBP-1a mRNA was easily detected throughout embryogenesis, IGFBP-1b mRNA was detectable only in advanced stages. Hypoxia induces igfbp-1a expression in early embryogenesis, but induces the igfbp-1b expression later in embryogenesis. Both IGFBP-1a and -b are capable of IGF binding, but IGFBP-1b has much lower affinities for IGF-I and -II because of greater dissociation rates. Overexpression of IGFBP-1a and -1b in zebrafish embryos caused significant decreases in growth and developmental rates. When tested in cultured zebrafish embryonic cells, IGFBP-1a and -1b both inhibited IGF-1-induced cell proliferation but the activity of IGFBP-1b was significantly weaker. These results indicate subfunction partitioning of the duplicated IGFBP-1 genes at the levels of gene expression, physiological regulation, protein structure, and biological actions. The duplicated IGFBP-1 may provide additional flexibility in fine-tuning IGF signaling activities under hypoxia and other catabolic conditions.
Article
Full-text available
IGF-II stimulates both mitogenesis and myogenesis through its binding and activation of the IGF-I receptor (IGF-IR). How this growth factor pathway promotes these two opposite cellular responses is not well understood. We investigate whether local IGF binding protein-5 (IGFBP-5) promotes the myogenic action of IGF-II. IGFBP-5 is induced before the elevation of IGF-II expression during myogenesis. Knockdown of IGFBP-5 impairs myogenesis and suppresses IGF-II gene expression. IGF-II up-regulates its own gene expression via the PI3K-Akt signaling pathway. Adding IGF-II or constitutively activating Akt rescues the IGFBP-5 knockdown-caused defects. However, an IGF analogue that binds to the IGF-IR but not IGFBP has only a limited effect. When added with low concentrations of IGF-II, IGFBP-5 restores IGF-II expression and myogenic differentiation, whereas an IGF binding-deficient IGFBP-5 mutant has no effect. These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop.