scholarly journals Inherent Growth Hormone Resistance in the Skeletal Muscle of the Fine Flounder Is Modulated by Nutritional Status and Is Characterized by High Contents of Truncated GHR, Impairment in the JAK2/STAT5 Signaling Pathway, and Low IGF-I Expression

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 283-294 ◽  
Author(s):  
Eduardo N. Fuentes ◽  
Ingibjörg Eir Einarsdottir ◽  
Juan Antonio Valdes ◽  
Marco Alvarez ◽  
Alfredo Molina ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathway ◽  
Growth Regulation ◽  
Slow Growth ◽  
Muscle Growth ◽  
Janus Kinase ◽  
Signal Transducers ◽  
Igf I ◽  
Plasma Gh ◽  
Gh Resistance

A detailed understanding of how the GH and IGF-I regulate muscle growth, especially in early vertebrates, is still lacking. The fine flounder is a flatfish species exhibiting remarkably slow growth, representing an intriguing model for elucidating growth regulatory mechanisms. Key components of the GH system were examined in groups of fish during periods of feeding, fasting, and refeeding. Under feeding conditions, there is an inherent systemic and local (muscle) GH resistance, characterized by higher levels of plasma GH than of IGF-I, skeletal muscle with a greater content of the truncated GH receptor (GHRt) than of full-length GHR (GHRfl), an impaired activation of the Janus kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) signaling pathway, and low IGF-I expression. Fasting leads to further elevation of plasma GH levels concomitant with suppressed IGF-I levels. The ratio of GHRfl to GHRt in muscle decreases during fasting, causing an inactivation of the JAK2/STAT5 signaling pathway and suppressed IGF-I expression, further impairing growth. When fish are returned to nutritionally favorable conditions, plasma GH levels decrease, and the ratio of GHRfl to GHRt in muscle increases, triggering JAK2/STAT5 reactivation and local IGF-I expression, concomitant with increased growth. The study suggests that systemic IGF-I is supporting basal slow growth in this species, without ruling out that local IGF-I is participating in muscle growth. These results reveal for the first time a unique model of inherent GH resistance in the skeletal muscle of a nonmammalian species and contribute to novel insights of the endocrine and molecular basis of growth regulation in earlier vertebrates.

Mechanical signal transduction in skeletal muscle growth and adaptation

2005 ◽  
Vol 98 (5) ◽  
pp. 1900-1908 ◽  
Author(s):  
James G. Tidball
Keyword(s):  
Skeletal Muscle ◽  
Signal Transduction ◽  
Mechanical Activation ◽  
Signaling Pathways ◽  
Mechanical Stimulation ◽  
Muscle Growth ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Mechanical Signal ◽  
Igf I

The adaptability of skeletal muscle to changes in the mechanical environment has been well characterized at the tissue and system levels, but the mechanisms through which mechanical signals are transduced to chemical signals that influence muscle growth and metabolism remain largely unidentified. However, several findings have suggested that mechanical signal transduction in muscle may occur through signaling pathways that are shared with insulin-like growth factor (IGF)-I. The involvement of IGF-I-mediated signaling for mechanical signal transduction in muscle was originally suggested by the observations that muscle releases IGF-I on mechanical stimulation, that IGF-I is a potent agent for promoting muscle growth and affecting phenotype, and that IGF-I can function as an autocrine hormone in muscle. Accumulating evidence shows that at least two signaling pathways downstream of IGF-I binding can influence muscle growth and adaptation. Signaling via the calcineurin/nuclear factor of activated T-cell pathway has been shown to have a powerful influence on promoting the slow/type I phenotype in muscle but can also increase muscle mass. Neural stimulation of muscle can activate this pathway, although whether neural activation of the pathway can occur independent of mechanical activation or independent of IGF-I-mediated signaling remains to be explored. Signaling via the Akt/mammalian target of rapamycin pathway can also increase muscle growth, and recent findings show that activation of this pathway can occur as a response to mechanical stimulation applied directly to muscle cells, independent of signals derived from other cells. In addition, mechanical activation of mammalian target of rapamycin, Akt, and other downstream signals is apparently independent of autocrine factors, which suggests that activation of the mechanical pathway occurs independent of muscle-mediated IGF-I release.

Postpartum Fatigue and Inhibited Lactation

2021 ◽  
pp. 109980042110500
Author(s):  
Feng Zhang ◽  
Qin Xue ◽  
Ting Bai ◽  
Fan Wu ◽  
Shuhan Yan
Keyword(s):  
Mammary Gland ◽  
Signaling Pathway ◽  
Light And Electron Microscopy ◽  
Chronic Fatigue ◽  
Janus Kinase ◽  
Inhibition Mechanism ◽  
Signal Transducers ◽  
Downstream Signaling ◽  
Transmission Electron ◽  
Postpartum Fatigue

Background: Postpartum fatigue is a common disorder worldwide and affects both physical and mental functioning. In breastfeeding women, Prolactin (PRL) is not only involved in immunoregulation, but also responsible for lactation. Prolactin levels in women with chronic fatigue are higher than normal, but a chronic fatigue state inhibits postpartum lactation in humans. Objectives: This paper explored the inhibition mechanism of lactation by postpartum fatigue in rats. Methods: Postpartum fatigue models were built by forcing mother rats to stand in water and divided into 3-hour, 9-hour and 15-hour per day fatigue groups according to the underwater time. Mother rats and their offspring were reunited in a dry cage for 90 minutes every 3 hours for feeding. The expression of PRL, PRL receptor (PRLR), Janus Kinase 2 (JAK 2), and Signal transducers and activators of transcription 5 (STAT5) mRNA were analyzed and the microstructure of mammary gland were observed under light and electron microscopy. Results: The expression of pituitary PRL mRNA and its downstream signaling pathway JAK2 and STAT5 mRNA were down-regulated in the severe postpartum fatigue rats. PRL mRNA responses were dose-related to duration of fatigue. The expression of PRLR mRNA increased. Postpartum fatigue led to functional degeneration of mammary gland. The breast lobules were shrunk and the number of alveoli were decreased. Few milk protein granules and fat droplets were observed in the cytoplasm under transmission electron microscope. Conclusion: Postpartum fatigue inhibits the lactation by down-regulating the expression of PRL and PRL-dependent signaling pathway in rats.

scholarly journals Protective Effect of Pyropia yezoensis Peptide on Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 284 ◽  
Author(s):  
Min-Kyeong Lee ◽  
Jeong-Wook Choi ◽  
Youn Hee Choi ◽  
Taek-Jeong Nam
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Protective Effects ◽  
Factor I ◽  
Igf I ◽  
Foxo Signaling Pathway

Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 μM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal muscle atrophy.

Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth

1990 ◽  
Vol 259 (1) ◽  
pp. E89-E95 ◽  
Author(s):  
D. L. DeVol ◽  
P. Rotwein ◽  
J. L. Sadow ◽  
J. Novakofski ◽  
P. J. Bechtel
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Growth ◽  
Experimental Period ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Muscle Weight ◽  
Skeletal Muscle Growth ◽  
Igf I

We have investigated the hypothesis that there is local regulation of insulin-like growth factor (IGF) gene expression during skeletal muscle growth. Compensatory hypertrophy was induced in the soleus, a predominantly slow-twitch muscle, and plantaris, a fast-twitch muscle, in 11- to 12-wk-old female Wistar rats by unilateral cutting of the distal gastrocnemius tendon. Animals were killed 2, 4, or 8 days later, and muscles of the nonoperated leg served as controls. Muscle weight increased throughout the experimental period, reaching 127% (soleus) or 122% (plantaris) of control values by day 8. In both growing muscles, IGF-I mRNA, quantitated by a solution-hybridization nuclease-protection assay, rose by nearly threefold on day 2 and remained elevated throughout the experimental period. IGF-II mRNA levels also increased over controls. A more dramatic response was seen in hypophysectomized rats, where IGF-I mRNA levels rose by 8- to 13-fold, IGF-II values by 3- to 7-fold, and muscle mass increased on day 8 to 149% (soleus) or 133% (plantaris) of the control contralateral limb. These results indicate that signals propagated during muscle hypertrophy enhance the expression of both IGF genes, that modulation of IGF-I mRNA levels can occur in the absence of growth hormone, and that locally produced IGF-I and IGF-II may play a role in skeletal muscle growth.

scholarly journals The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

2013 ◽  
Vol 203 (2) ◽  
pp. 345-357 ◽  
Author(s):  
Catherine E. Winbanks ◽  
Justin L. Chen ◽  
Hongwei Qian ◽  
Yingying Liu ◽  
Bianca C. Bernardo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Bmp Signaling ◽  
Positive Regulator ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.

Induction of mRNA for IGF-I and -II during growth hormone-stimulated muscle hypertrophy

1988 ◽  
Vol 255 (4) ◽  
pp. E513-E517 ◽  
Author(s):  
J. D. Turner ◽  
P. Rotwein ◽  
J. Novakofski ◽  
P. J. Bechtel
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
Growth Factors ◽  
Cardiac Muscle ◽  
Muscle Hypertrophy ◽  
Muscle Growth ◽  
Gh3 Cells ◽  
Autocrine Factors ◽  
Igf I ◽  
Steady State Levels

The expression of insulin-like growth factor (IGF) genes during skeletal and cardiac muscle hypertrophy was examined using skeletal and cardiac muscle hypertrophy was examined using adult 5-mo-old female Wistar-Furth rats implanted with growth hormone-secreting GH3 cells. Control and treated animals were killed at 40, 60, and 80 days after initiation of the experiment. From the time of injection to day 80, body, heart, skeletal muscle, and liver weights increased 112, 93, 55, and 314%, respectively. RNA was extracted and steady-state levels of IGF-I and IGF-II mRNAs were quantitated using a solution-hybridization nuclease-protection assay. Low levels of mRNA for both growth factors were detected in control tissues. By day 80 IGF-I mRNA had increased eightfold and IGF-II mRNA sixfold in skeletal muscle from treated rats. In cardiac muscle the levels of mRNA for both growth factors rose three- to fourfold. Although growth hormone induced an increase in hepatic IGF-I mRNA, IGF-II mRNA remained nearly undetectable. This study shows that during growth hormone-stimulated muscle growth mRNAs for both IGF-I and IGF-II accumulate, supporting other observations implicating the IGFs as paracrine or autocrine factors involved in skeletal muscle growth.

Inhibition of glycogen synthase kinase-3β activity is sufficient to stimulate myogenic differentiation

2006 ◽  
Vol 290 (2) ◽  
pp. C453-C462 ◽  
Author(s):  
Jos L. J. van der Velden ◽  
Ramon C. J. Langen ◽  
Marco C. J. M. Kelders ◽  
Emiel F. M. Wouters ◽  
Yvonne M. W. Janssen-Heininger ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Glycogen Synthase ◽  
Muscle Growth ◽  
Glycogen Synthase Kinase ◽  
Skeletal Muscle Atrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Igf I ◽  
Gsk 3Β ◽  
Stimulation Of

Skeletal muscle atrophy is a prominent and disabling feature of chronic wasting diseases. Prevention or reversal of muscle atrophy by administration of skeletal muscle growth (hypertrophy)-stimulating agents such as insulin-like growth factor I (IGF-I) could be an important therapeutic strategy in these diseases. To elucidate the IGF-I signal transduction responsible for muscle formation (myogenesis) during muscle growth and regeneration, we applied IGF-I to differentiating C2C12 myoblasts and evaluated the effects on phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK-3β) signaling and myogenesis. IGF-I caused phosphorylation and inactivation of GSK-3β activity via signaling through the PI3K/Akt pathway. We assessed whether pharmacological inhibition of GSK-3β with lithium chloride (LiCl) was sufficient to stimulate myogenesis. Addition of IGF-I or LiCl stimulated myogenesis, evidenced by increased myotube formation, muscle creatine kinase (MCK) activity, and troponin I (TnI) promoter transactivation during differentiation. Moreover, mRNAs encoding MyoD, Myf-5, myogenin, TnI-slow, TnI-fast, MCK, and myoglobin were upregulated in myoblasts differentiated in the presence of IGF-I or LiCl. Importantly, blockade of GSK-3β inhibition abrogated IGF-I- but not LiCl-dependent stimulation of myogenic mRNA accumulation, suggesting that the promyogenic effects of IGF-I require GSK-3β inactivation and revealing an important negative regulatory role for GSK-3β in myogenesis. Therefore, this study identifies GSK-3β as a potential target for pharmacological stimulation of muscle growth.

scholarly journals Idiopathic short stature: will genetics influence the choice between GH and IGF-I therapy?

2007 ◽  
Vol 157 (suppl_1) ◽  
pp. S33-S37 ◽  
Author(s):  
Martin O Savage ◽  
Cecilia Camacho-Hübner ◽  
Alessia David ◽  
Louise A Metherell ◽  
Vivian Hwa ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Regulation ◽  
Single Gene ◽  
Idiopathic Short Stature ◽  
Dominant Negative ◽  
Growth Responses ◽  
Igf I ◽  
The Usa ◽  
Gene Defects ◽  
Gh Resistance

Background: Idiopathic short stature (ISS) includes a range of conditions. Some are caused by defects in the GH–IGF-I axis. ISS is an approved indication for GH therapy in the USA and a similar approval in Europe may be imminent. Genetic analysis for single-gene defects has made enormous contributions to understanding the physiology of growth regulation. Can this type of investigation help in predicting growth responses to GH or IGF-I therapy? Methods: The rationale for choice of GH or IGF-I therapy in ISS is reviewed. Many ISS patients have low IGF-I, but most can generate IGF-I levels in response to short-term GH administration. Some GH resistance seems to be present. Mutation analysis in several cohorts of GHIS and ISS patients is reviewed. Results: Low IGF-I levels suggest either unrecognised GH deficiency or GH resistance. In classical GHIS patients, there was a positive relationship between IGFBP-3 levels and height SDS. No relationship exists between mutations and phenotype. There is a wide variability of phenotype in patients carrying identical mutations. Heterozygous GH receptor (GHR) mutations were present in <5% of ISS patients and their role in causing growth defects is questionable. Exceptions are dominant negative mutations that have been shown to disturb growth. Conclusions: Analysis for single-gene defects does not give sensitive predictions of phenotype and cannot predict responses to GH or IGF-I therapy. Endocrine abnormalities have closer correlations with phenotype and may thus be a better guide to therapeutic responsiveness.

scholarly journals Metabolic hormones modulate the effect of growth hormone (GH) on insulin-like growth factor-I (IGF-I) mRNA level in primary culture of salmon hepatocytes

2005 ◽  
Vol 184 (2) ◽  
pp. 341-349 ◽  
Author(s):  
A L Pierce ◽  
H Fukada ◽  
W W Dickhoff
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Primary Culture ◽  
Growth Regulation ◽  
Mrna Level ◽  
Insulin Like Growth Factor ◽  
Metabolic Hormones ◽  
Factor I ◽  
Igf I ◽  
Gh Resistance

Liver production of insulin-like growth factor-I (IGF-I) is a major point of control in the growth hormone (GH)/IGF axis, the endocrine system regulating body growth in fishes and other vertebrates. Pituitary GH stimulates hepatocyte production of IGF-I; however, in catabolic states, hepatocyte GH resistance results in decreases in liver IGF-I production. To investigate endocrine mechanisms leading to the development of hepatocyte GH resistance, we examined the regulation of IGF-I mRNA level by GH and metabolic hormones in primary culture of salmon hepatocytes. Cells were cultured in RPMI medium, and exposed to insulin (Ins, 10−6 M), glucagon (Glu, 10−6 M), triiodothyronine (T3, 10−7 M), dexamethasone (Dex, 10−6 M) and glucagon-like peptide (GLP, 10−6 M), in the presence and absence of GH (5×10−9 M). GH always increased IGF-I mRNA. None of the other hormones tested alone affected IGF-I mRNA. However, Dex, Ins and Glu reduced the response to GH. The response to GH was inhibited by Dex at concentrations of 10−12 M and above, by Ins at 10−9 M and above, and by Glu only at 10−6 M. Inhibition of GH response by glucocorticoids is found in other vertebrates. Salmon hepatocytes were very sensitive to Dex, suggesting that glucocorticoids may play an important role in salmon growth regulation even in unstressed conditions. Inhibition of GH response by Ins is the opposite of what is found in mammals and chickens, suggesting that the role of Ins in growth regulation may differ between fishes and tetrapods. To examine mechanisms for modulation of GH sensitivity, we measured hepatocyte GH receptor (GHR) mRNA levels. Ins inhibited and Dex stimulated GHR mRNA, suggesting that different mechanisms mediate the inhibition of GH response by these hormones. This study shows that glucocorticoids, Ins, and Glu induce GH resistance in cultured salmon hepatocytes.

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