title: 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 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.
  
  
  CONCLUSIONS
  GHRT 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.
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University of Zurich and University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland.|Competence Center Personalized Medicine, ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Artur
authors.initials: A
authors.lastname: Galimov
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University of Zurich and University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Hartung
authors.affiliation: Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Bern Inselspital, Bern, Switzerland.
authors.forename: Roman
authors.initials: R
authors.lastname: Trepp
authors.affiliation: Division of Trauma Surgery, University Hospital, Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mader
authors.affiliation: Department of Orthopedics, University Hospital Balgrist, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Flück
authors.affiliation: Heart Center Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Linke
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Bern Inselspital, Bern, Switzerland.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Christ
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University of Zurich and University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland. jan.kruetzfeldt@usz.ch.|Competence Center Personalized Medicine, ETH Zurich and University of Zurich, Zurich, Switzerland. jan.kruetzfeldt@usz.ch.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. jan.kruetzfeldt@usz.ch.
authors.forename: Jan
authors.initials: J
authors.lastname: Krützfeldt
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers; D004393:Dwarfism, Pituitary / Q000188:drug therapy / Q000209:etiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D023421:Models, Animal; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D019382:Human Growth Hormone; C048250:somatotropin releasing hormone receptor
keywords: GH; IGF1; Insulin resistance; Skeletal muscle; microRNA