title: Genomic and lipidomic actions of nandrolone on detached rotator cuff muscle in sheep.
abstract: Reversal of fatty infiltration of pennate rotator cuff muscle after tendon release is hitherto impossible. The administration of nandrolone starting at the time of tendon release prevents the increase in fat content, but does not revert established fatty infiltration. We hypothesised that tendon release and myotendinous retraction cause alterations in lipid related gene expression leading to fatty muscle infiltration, which can be suppressed by nandrolone through its genomic actions if applied immediately after tendon release. The effects of infraspinatus tendon release and subsequent tendon repair at 16 weeks were studied in six Swiss Alpine sheep. In the interventional groups, 150mg nandrolone was administered weekly after tendon release until sacrifice (N22W, n=6) or starting at the time of repair (N6W, n=6). Infraspinatus volume, composition, expressed transcripts, lipids, and selected proteins were analyzed at baseline, 16 and 22 weeks. Tendon release reduced infraspinatus volume by 22% and increased fat content from 11% to 38%. These changes were not affected by repair. Fatty infiltration was associated with up-regulation of 227 lipid species, and increased levels of the adipocyte differentiation marker PPARG2 (peroxisome proliferator-activated receptor gamma 2). Nandrolone abrogated lipid accumulation, halved the loss in fiber area percentage, and up-regulated androgen receptor levels and transcript expression in the N22W but not the N6W group. The results document that nandrolone mitigates muscle-to-fat transformation after tendon release via a general down-regulation of lipid accumulation concomitantly with up-regulated expression of its nuclear receptor and downstream transcripts in skeletal muscle. Reduced responsiveness of retracted muscle to nandrolone as observed in the N6W group is reflected by a down-regulated transcript response.
authors: Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland. Electronic address: mflueck@research.balgrist.ch.
authors: Martin
authors: M
authors: Flück
authors: Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland.
authors: Severin
authors: S
authors: Ruoss
authors: Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland.
authors: Christoph B
authors: CB
authors: Möhl
authors: Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland.
authors: Paola
authors: P
authors: Valdivieso
authors: Musculoskeletal Research Unit, Center for Applied Biotechnology and Molecular Medicine, Equine Department, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors: Mario C
authors: MC
authors: Benn
authors: Musculoskeletal Research Unit, Center for Applied Biotechnology and Molecular Medicine, Equine Department, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors: Brigitte
authors: B
authors: von Rechenberg
authors: Functional Genomics Center Zurich (FGCZ), ETH and University of Zurich, Switzerland.
authors: Endre
authors: E
authors: Laczko
authors: Functional Genomics Center Zurich (FGCZ), ETH and University of Zurich, Switzerland.
authors: Junmin
authors: J
authors: Hu
authors: Balgrist University Hospital, Department of Orthopedics, Zurich, Switzerland.
authors: Karl
authors: K
authors: Wieser
authors: Balgrist University Hospital, Department of Orthopedics, Zurich, Switzerland.
authors: Dominik C
authors: DC
authors: Meyer
authors: Balgrist University Hospital, Department of Orthopedics, Zurich, Switzerland.
authors: Christian
authors: C
authors: Gerber
mesh_terms: D017667:Adipocytes / Q000166:cytology; D045930:Anabolic Agents / Q000494:pharmacology; D000818:Animals; D001284:Atrophy / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D023281:Genomics; D050356:Lipid Metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009277:Nandrolone / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D017006:Rotator Cuff / Q000473:pathology*; D012756:Sheep; D034561:Sheep, Domestic; D013256:Steroids / Q000737:chemistry / Q000627:therapeutic use; D013708:Tendon Injuries / Q000473:pathology*; D013710:Tendons / Q000473:pathology*; D058971:Tenotomy; D059467:Transcriptome
chemical_list: D045930:Anabolic Agents; D011944:Receptors, Androgen; D013256:Steroids; D009277:Nandrolone
keywords: Adipocyte; Anabolic steroids; Androgen receptor; Fat; Gene expression; Rotator cuff muscle; Tenotomy