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

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 Ghrhrlit/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.Key messagesGHRT most significantly affects the ECM cluster in skeletal muscle from mice.GHRT downregulates miR-29a and upregulates miR-29a targets in skeletal muscle from mice.PTEN, COL3A1, FSTL1, SERPINH1, and SPARC are endogenous miR-29a targets in human myotubes.IGF1 decreases miR-29a levels in human myotubes.miR-29a and its targets are regulated during GHRT in skeletal muscle from humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-015-1322-y) contains supplementary material, which is available to authorized users.

Plasma biomarker proteins for detection of human growth hormone administration in athletes

“…Lumican, an extracellular matrix protein (ECM), and ECM1 promote collagen fibril organisation and tissue repair, and play a key role in the control of growth factor signalling 46 . Abnormal ECM remodelling has been linked to obesity and insulin resistance, and animal studies provide now evidence that insulin resistance after GH administration in mice involves the upregulation of the extracellular matrix in muscle 47 . There are no studies investigating the effect of growth hormone administration on circulating lumican and ECM1 from the available literature.…”

Glucose Metabolism in Children With Growth Hormone Deficiency

“…Recently, Staverska et al demonstrated that GHD children are a heterogeneous group as regards the differences in the metabolic profile, probably due to the different IGF-1 bioavailability, and concluded that naïve GHD children have a worse metabolic profile when the IGF-1 bioavailability and the body mass were greater, although the authors do not fully explain this phenomenon ( 54 ). In addition, the role of microRNAs expression in skeletal muscles has been hypothesized as a mechanism that contributes to increased insulin resistance during GHT ( 86 ).…”

Mechanism of Astragalus polysaccharides in attenuating insulin resistance in Rats with type 2 diabetes mellitus via the regulation of liver microRNA‑203a‑3p

“…MiRNAs belong to a clan for non-coding RNAs with 20–24 nucleotides in length ( 14 ). The expression of multiple genes involving various pathways can be regulated coordinately by a singular miRNA, and therefore the gene regulation can be unraveled by discovering changed miRNA expression in complex diseases.…”