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Am J Physiol Endocrinol Metab. 2019 Jun 1;316(6):E1036-E1049. doi: 10.1152/ajpendo.00001.2019. Epub 2019 Mar 19.

Myostatin regulates pituitary development and hepatic IGF1.

Author information

1
Washington Center for Muscle Biology, Department of Animal Sciences, Washington State University , Pullman, Washington.
2
Department of Biochemistry and Molecular Biology, University of Georgia , Athens, Georgia.
3
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati , Cincinnati, Ohio.
4
AAVogen, Incorporated, Rockville, Maryland.

Abstract

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.

KEYWORDS:

growth hormone; insulin-like growth factor 1; muscle; myostatin; prolactin

PMID:
30888862
PMCID:
PMC6620572
[Available on 2020-06-01]
DOI:
10.1152/ajpendo.00001.2019

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