scholarly journals Myostatin regulates pituitary development and hepatic IGF1

2019 ◽  
Vol 316 (6) ◽  
pp. E1036-E1049 ◽  
Author(s):  
Wioletta Czaja ◽  
Yukiko K. Nakamura ◽  
Naisi Li ◽  
Jennifer A. Eldridge ◽  
David M. DeAvila ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Muscle Growth ◽  
Unintended Consequences ◽  
Pituitary Development ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Muscle Wasting Disease ◽  
And Function ◽  
Igf Binding Protein ◽  
Igf1 Expression

Circulating myostatin-attenuating agents are being developed to treat muscle-wasting disease despite their potential to produce serious off-target effects, as myostatin/activin receptors are widely distributed among many nonmuscle tissues. Our studies suggest that the myokine not only inhibits striated muscle growth but also regulates pituitary development and growth hormone (GH) action in the liver. Using a novel myostatin-null label-retaining model (Jekyll mice), we determined that the heterogeneous pool of pituitary stem, transit-amplifying, and progenitor cells in Jekyll mice depletes more rapidly after birth than the pool in wild-type mice. This correlated with increased levels of GH, prolactin, and the cells that secrete these hormones, somatotropes and lactotropes, respectively, in Jekyll pituitaries. Recombinant myostatin also stimulated GH release and gene expression in pituitary cell cultures although inhibiting prolactin release. In primary hepatocytes, recombinant myostatin blocked GH-stimulated expression of two key mediators of growth, insulin-like growth factor (IGF)1 and the acid labile subunit and increased expression of an inhibitor, IGF-binding protein-1. The significance of these findings was demonstrated by smaller muscle fiber size in a model lacking myostatin and liver IGF1 expression (LID-o-Mighty mice) compared with that in myostatin-null (Mighty) mice. These data together suggest that myostatin may regulate pituitary development and function and that its inhibitory actions in muscle may be partly mediated by attenuating GH action in the liver. They also suggest that circulating pharmacological inhibitors of myostatin could produce unintended consequences in these and possibly other tissues.

scholarly journals The effects of recombinant human IGF-I administration on concentrations of acid labile subunit, IGF binding protein-3, IGF-I, IGF-II and proteolysis of IGF binding protein-3 in adolescents with insulin-dependent diabetes mellitus

1998 ◽  
Vol 157 (1) ◽  
pp. 81-87 ◽  
Author(s):  
TD Cheetham ◽  
JM Holly ◽  
RC Baxter ◽  
K Meadows ◽  
J Jones ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Igf I ◽  
Igf Binding ◽  
Acid Labile Subunit ◽  
Insulin Dependent ◽  
Igf Binding Protein ◽  
Acid Labile ◽  
Igfbp 3

The long term therapeutic potential of recombinant human (rh) IGF-I administration in insulin-dependent diabetes mellitus (IDDM) may be determined by changes in the IGF binding proteins (IGFBPs) and thus the bioavailability of IGF-I. We have therefore studied the effects of a single subcutaneous dose of rhIGF-I (40 micrograms/kg at 1800 h), when compared with an untreated control night, in 17 subjects with IDDM, on serum concentrations of IGF-I, IGF-II, IGFBP-3, acid labile subunit (ALS), and IGFBP-3 proteolysis. Mean (+/- S.E.M.) IGF-I levels increased from 242 +/- 30 ng/ml to 399 +/- 26 ng/ml (P = 0.01) after rhIGF-I whereas IGF-II levels declined from 600 +/- 45 ng/ml to 533 +/- 30 ng/ml. There was a small overnight reduction in baseline ALS levels from 48 +/- 2.8 to 44.5 +/- 3.2 micrograms/ml (P = 0.04) after rhIGF-I administration. An early fall in IGFBP-3 concentrations on the control night was not seen after rhIGF-I and overall mean levels were increased (5.2 +/- 0.2 micrograms/ml vs 4.9 +/- 0.2 micrograms/ml, P = 0.04, on the control night). On the baseline night, IGFBP-3 levels correlated with the sum of IGF-I and IGF-II (r = 0.73, P = 0.02) and with levels of the ALS (r = 0.7, P = 0.002). However after rhIGF-I, the sum of IGF-I and IGF-II no longer correlated with IGFBP-3, whereas the relationship with ALS was maintained. Immunoblot studies in six subjects indicated that 60%-70% of the IGFBP-3 was detected as a low molecular weight fragment at 1900 h on both study nights, but the amount of fragment declined to approximately 50% at 0100 h and 45% at 0700 h. In conclusion, despite a slight but significant fall in ALS, IGFBP-3 levels rise after rhIGF-I administration in IDDM. This cannot be explained by alterations in IGFBP-3 proteolysis, and may relate to the relative stability of ALS/IGFBP-3 when complexed principally with IGF-I rather than IGF-II.

scholarly journals IGFBP-1 forms associated with placental cell membranes

2009 ◽  
Vol 74 (7) ◽  
pp. 707-716 ◽  
Author(s):  
Romana Masnikosa ◽  
Bogovid Zivkovic ◽  
Olgica Nedic
Keyword(s):  
Molecular Mass ◽  
Cell Membranes ◽  
High Molecular Mass ◽  
Matrix Metalloproteases ◽  
Placental Development ◽  
Placental Cell ◽  
Igf Receptors ◽  
Igf Binding ◽  
And Function ◽  
Igf Binding Protein

Fetal growth in utero depends on the proper development and function of the placenta. Insulin-like growth factors (IGFs) are critically involved in placental development. During pregnancy, an IGF-binding protein, IGFBP-1, which is produced by maternal decidua, plays an important role in the control of the bioavailability of IGFs. It has recently been proposed that cleavage of decidual IGFBP-1 by matrix metalloproteases is a novel mechanism in the control of placental development. The presence of IGFBP-1 in solubilized placental cell membranes, i.e. its association with the membranes, was detected in an earlier work. Herein, it is shown that IGFBP-1 from the solubilized membranes forms dimers, as well as high molecular mass complexes. IGFBP-1 dimers preferably contain the non-phosphorylated form of IGFBP-1. The high molecular mass forms are polymers of IGFBP-1 or its complexes with other membrane proteins. Dimerization of IGFBP-1, together with its association with the placental cell membrane, could serve as an additional mechanism of the regulation of IGF availability to the type 1 IGF receptors.

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