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Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2015
Author Galimov Artur, Hartung Angelika, Trepp Roman, Mader Alexander, Flück Martin, Linke Axel, Blüher Matthias, Christ Emanuel, Krützfeldt Jan,
Project Role of microRNAs from myogenic progenitors in adult skeletal muscle function and the implications for type 2 diabetes
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Original article (peer-reviewed)

Journal J Mol Med
Volume (Issue) 93(12)
Page(s) 1369 - 1379
Title of proceedings J Mol Med
DOI 10.1007/s00109-015-1322-y

Open Access

URL https://www.ncbi.nlm.nih.gov/pubmed/26199111
Type of Open Access Website

Abstract

Replacement of growth hormone (GH) in patients suffering from GH deficiency (GHD) offers clinical benefits on body composition, exercise capacity, and skeletal integrity. However, GH replacement therapy (GHRT) is also associated with insulin resistance, but the mechanisms are incompletely understood. We demonstrate that in GH-deficient mice (growth hormone-releasing hormone receptor (Ghrhr)(lit/lit)), insulin resistance after GHRT involves the upregulation of the extracellular matrix (ECM) and the downregulation of microRNA miR-29a in skeletal muscle. Based on RNA deep sequencing of skeletal muscle from GH-treated Ghrhr(lit/lit) mice, we identified several upregulated genes as predicted miR-29a targets that are negative regulators of insulin signaling or profibrotic/proinflammatory components of the ECM. Using gain- and loss-of-function studies, five of these genes were confirmed as endogenous targets of miR-29a in human myotubes (PTEN, COL3A1, FSTL1, SERPINH1, SPARC). In addition, in human myotubes, IGF1, but not GH, downregulated miR-29a expression and upregulated COL3A1. These results were confirmed in a group of GH-deficient patients after 4 months of GHRT. Serum IGF1 increased, skeletal muscle miR-29a decreased, and miR-29a targets were upregulated in patients with a reduced insulin response (homeostatic model assessment of insulin resistance (HOMA-IR)) after GHRT. We conclude that miR-29a could contribute to the metabolic response of muscle tissue to GHRT by regulating ECM components and PTEN. miR-29a and its targets might be valuable biomarkers for muscle metabolism following GH replacement.
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