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Frontiers in Endocrinology 2020Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although... (Review)
Review
Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although the specific hormonal influence must be considered within the context of the entire endocrine system and its relationship with other physiological systems, three key hormones are considered the "anabolic giants" in cellular growth and repair: testosterone, the growth hormone superfamily, and the insulin-like growth factor (IGF) superfamily. In addition to these anabolic hormones, glucocorticoids, mainly cortisol must also be considered because of their profound opposing influence on human skeletal muscle anabolism in many instances. This review presents emerging research on: (1) Testosterone signaling pathways, responses, and adaptations to resistance training; (2) Growth hormone: presents new complexity with exercise stress; (3) Current perspectives on IGF-I and physiological adaptations and complexity these hormones as related to training; and (4) Glucocorticoid roles in integrated communication for anabolic/catabolic signaling. Specifically, the review describes (1) Testosterone as the primary anabolic hormone, with an anabolic influence largely dictated primarily by genomic and possible non-genomic signaling, satellite cell activation, interaction with other anabolic signaling pathways, upregulation or downregulation of the androgen receptor, and potential roles in co-activators and transcriptional activity; (2) Differential influences of growth hormones depending on the "type" of the hormone being assayed and the magnitude of the physiological stress; (3) The exquisite regulation of IGF-1 by a family of binding proteins (IGFBPs 1-6), which can either stimulate or inhibit biological action depending on binding; and (4) Circadian patterning and newly discovered variants of glucocorticoid isoforms largely dictating glucocorticoid sensitivity and catabolic, muscle sparing, or pathological influence. The downstream integrated anabolic and catabolic mechanisms of these hormones not only affect the ability of skeletal muscle to generate force; they also have implications for pharmaceutical treatments, aging, and prevalent chronic conditions such as metabolic syndrome, insulin resistance, and hypertension. Thus, advances in our understanding of hormones that impact anabolic: catabolic processes have relevance for athletes and the general population, alike.
Topics: Adaptation, Physiological; Animals; Exercise; Growth Hormone; Growth and Development; Humans; Hydrocortisone; Muscle, Skeletal; Somatomedins; Testosterone
PubMed: 32158429
DOI: 10.3389/fendo.2020.00033 -
Cells Jun 2022In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 () knockout mouse models, we have learnt much about the structure of this... (Review)
Review
In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 () knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver-Russell and Beckwith-Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of -linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of defects in these patients.
Topics: Animals; Beckwith-Wiedemann Syndrome; Epigenomics; Genomic Imprinting; Humans; Insulin-Like Growth Factor II; Mice; Silver-Russell Syndrome
PubMed: 35741015
DOI: 10.3390/cells11121886 -
Cells Jun 2021Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body... (Review)
Review
Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF-I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, and treatment of GH/IGF-I deficiency or excess during life.
Topics: Caloric Restriction; Carbohydrate Metabolism; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Lipolysis; Micronutrients; Signal Transduction
PubMed: 34199514
DOI: 10.3390/cells10061376 -
Endocrine Reviews Nov 2023Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the... (Review)
Review
Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface-associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.
Topics: Pregnancy; Humans; Female; Pregnancy-Associated Plasma Protein-A; Placenta; Metalloproteases; Cell Differentiation; Insulin-Like Growth Factor I
PubMed: 37267421
DOI: 10.1210/endrev/bnad017 -
Molecular and Cellular Endocrinology Dec 2020The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development,... (Review)
Review
The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through the type 1 IGF receptor (IGF-1R). The growth hormone (GH)-IGF-I axis is the major regulator of longitudinal growth. IGF-II is expressed in many tissues, notably the placenta, to regulate human pre- and post-natal growth and development. This review provides a brief introduction to the IGF system and summarizes findings from reports arising from recent larger genomic sequencing studies of human genetic mutations in IGF1 and IGF2 and genes of proteins regulating IGF action, namely the IGF-1R, IGF-1R signaling pathway components and the IGF binding proteins (IGFBPs). A perspective on the effect of homozygous mutations on structure and function of the IGFs and IGF-1R is also given and this is related to the effects on growth.
Topics: Animals; Female; Genetic Diseases, Inborn; Growth Disorders; Humans; Metabolic Diseases; Mutation; Pregnancy; Receptor, IGF Type 1; Receptors, Somatomedin; Signal Transduction; Somatomedins
PubMed: 32941924
DOI: 10.1016/j.mce.2020.111035 -
Cytokine & Growth Factor Reviews Apr 2022Platelets produce platelet growth factors such as PDGF, IGF-1, EGF-, HGF, TGFβ, bFGF, and VEGF, which are crucial in regulating all stages of the wound healing process.... (Review)
Review
Platelets produce platelet growth factors such as PDGF, IGF-1, EGF-, HGF, TGFβ, bFGF, and VEGF, which are crucial in regulating all stages of the wound healing process. The source of these substances is platelet-rich plasma (PRP). Over the past five decades, the interest and use of the regenerative properties of platelets have increased significantly in many different fields of medicine around the world. PRP and PRF plate preparations are used in: 1. Dentistry (they reduce bleeding, facilitate and accelerate soft tissue healing and bone regeneration - FGF 2, IGF-1, IGF-2, TGF-β1, and PDGF); 2. Sports medicine - IGF-1, IGF-2, TGF-β, VEGF, PDGF and bFGF, EGF); 3. dermatology and cosmetology (treatment of alopecia, hair reconstruction - FGF-7, HGF, acne scars, skin rejuvenation and regeneration, treatment of chronic and poorly healing wounds, burns, and acquired vitiligo); 4. Gynecology and reproductive medicine (treatment of infertility, erectile dysfunction - PDGF-β, TGF-β, IGF-1, in sexual dysfunction - PDGF, in vaginal atrophy); 5 Ophthalmology (in the healing of corneal epithelial wounds, in the treatment of dormant corneal ulcers, dry eye syndrome and the reconstruction of the corneal surface; 6. Neurology (regeneration of neurons, pain alleviation, and clinical symptoms - TGF-β 1, IGF-1, PDGF, VEGF) and FGF). Platelet-rich plasma therapy is a very interesting alternative and complement to traditional methods of treatment. However, the potential for using platelets is still not fully understood. The composition of platelet-rich plasma depends on many factors that may affect its use's efficacy and clinical benefits. Further research is necessary to standardize PRP delivery's preparation procedures and methods for a specific disease entity or clinical case.
Topics: Blood Platelets; Epidermal Growth Factor; Female; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Vascular Endothelial Growth Factor A
PubMed: 34924312
DOI: 10.1016/j.cytogfr.2021.11.003 -
The Lancet. Diabetes & Endocrinology Apr 2023Tackling the mechanisms underlying ageing is desirable to help to extend the duration and improve the quality of life. Life extension has been achieved in animal models... (Review)
Review
Tackling the mechanisms underlying ageing is desirable to help to extend the duration and improve the quality of life. Life extension has been achieved in animal models by suppressing the growth hormone-insulin-like growth factor 1 (IGF-1) axis and also via dietary restriction. Metformin has become the focus of increased interest as a possible anti-ageing drug. There is some overlap in the postulated mechanisms of how these three approaches could produce anti-ageing effects, with convergence on common downstream pathways. In this Review, we draw on evidence from both animal models and human studies to assess the effects of suppression of the growth hormone-IGF-1 axis, dietary restriction, and metformin on ageing.
Topics: Animals; Humans; Growth Hormone; Insulin-Like Growth Factor I; Metformin; Quality of Life; Aging; Human Growth Hormone
PubMed: 36848915
DOI: 10.1016/S2213-8587(23)00001-3 -
European Heart Journal Dec 2022Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study.... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.
METHODS AND RESULTS
Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.
CONCLUSIONS
Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.
Topics: Humans; Diabetes Mellitus, Type 2; Heart Failure; Inflammation; Proteomics; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Somatomedins
PubMed: 36017745
DOI: 10.1093/eurheartj/ehac495 -
The Journal of Clinical Endocrinology... Jun 2023The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF)... (Review)
Review
The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF) signaling. The only known pappalysin substrates are a subset of the IGF binding proteins (IGFBPs), which bind IGF-I or IGF-II with high affinity to antagonize receptor binding. Thus, by cleaving IGFBPs, the pappalysins have the potential to increase IGF bioactivity and hence promote IGF signaling. This is relevant both in systemic and local IGF regulation, in normal and several pathophysiological conditions. Stanniocalcin-1 and -2 were recently found to be potent pappalysin inhibitors, thus comprising the missing components of a complete proteolytic system, the stanniocalcin-PAPP-A-IGFBP-IGF axis. Here, we provide the biological context necessary for understanding the properties of this molecular network, and we review biochemical data, animal experiments, clinical data, and genetic data supporting the physiological operation of this branch as an important part of the IGF system. However, although in vivo data clearly illustrate its power, it is a challenge to understand its subtle operation, for example, multiple equilibria and inhibitory kinetics may determine how, where, and when the IGF receptor is stimulated. In addition, literally all of the regulatory proteins have suspected or known activities that are not directly related to IGF signaling. How such activities may integrate with IGF signaling is also important to address in the future.
Topics: Animals; Humans; Pregnancy-Associated Plasma Protein-A; Insulin-Like Growth Factor I; Glycoproteins; Insulin-Like Growth Factor Binding Proteins; Receptors, Somatomedin; Insulin-Like Growth Factor Binding Protein 4
PubMed: 36718521
DOI: 10.1210/clinem/dgad053 -
Current Osteoporosis Reports Aug 2020The purpose of this review is to describe the current state of our thinking regarding bone-muscle interactions beyond the mechanical perspective. (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to describe the current state of our thinking regarding bone-muscle interactions beyond the mechanical perspective.
RECENT FINDINGS
Recent and prior evidence has begun to dissect many of the molecular mechanisms that bone and muscle use to communicate with each other and to modify each other's function. Several signaling factors produced by muscle and bone have emerged as potential mediators of these biochemical/molecular interactions. These include muscle factors such as myostatin, Irisin, BAIBA, IL-6, and the IGF family and the bone factors FGF-23, Wnt1 and Wnt3a, PGE2, FGF9, RANKL, osteocalcin, and sclerostin. The identification of these signaling molecules and their underlying mechanisms offers the very real and exciting possibility that new pharmaceutical approaches can be developed that will permit the simultaneous treatments of diseases that often occur in combination, such as osteoporosis and sarcopenia.
Topics: Adaptor Proteins, Signal Transducing; Aminoisobutyric Acids; Bone and Bones; Dinoprostone; Fibroblast Growth Factor 9; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibronectins; Humans; Interleukin-6; Muscle, Skeletal; Myostatin; Osteocalcin; Paracrine Communication; RANK Ligand; Somatomedins; Wnt1 Protein; Wnt3A Protein
PubMed: 32519283
DOI: 10.1007/s11914-020-00602-6