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. Researchers from the University of Zurich 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 LC Sciences’ RNA deep sequencing of skeletal muscle from GH-treated Ghrhrlit/lit mice, they 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. They 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.

LC Sciences

Regulation of miR-29a targets in human skeletal muscle after GHRT. Hypothetical model demonstrating the role of GHRT for ECM remodeling and its association with insulin resistance in skeletal muscle. Decreased miR-29a levels and upregulation of its targets during GHRT could contribute to this regulation

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Reference

A Galimov, A Hartung, R Trepp, A Mader, M Flück, A Linke, M Blüher, E Christ, J Krützfeldt. (2015) Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance J of Mol Med 93(12):1369-79. [article]