title: Anabolic steroids activate calcineurin-NFAT signaling and thereby increase myotube size and reduce denervation atrophy.
abstract: Anabolic androgens have been shown to reduce muscle loss due to immobilization, paralysis and many other medical conditions, but the molecular basis for these actions is poorly understood. We have recently demonstrated that nandrolone, a synthetic androgen, slows muscle atrophy after nerve transection associated with down-regulation of regulator of calcineurin 2 (RCAN2), a calcineurin inhibitor, suggesting a possible role of calcineurin-NFAT signaling. To test this possibility, rat gastrocnemius muscle was analyzed at 56 days after denervation. In denervated muscle, calcineurin activity declined and NFATc4 was excluded from the nucleus and these effects were reversed by nandrolone. Similarly, nandrolone increased calcineurin activity and nuclear NFATc4 levels in cultured L6 myotubes. Nandrolone also induced cell hypertrophy that was blocked by cyclosporin A or overexpression of RCAN2. Finally protection against denervation atrophy by nandrolone in rats was blocked by cyclosporin A. These results demonstrate for the first time that nandrolone activates calcineurin-NFAT signaling, and that such signaling is important in nandrolone-induced cell hypertrophy and protection against paralysis-induced muscle atrophy.
authors.affiliation: Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York 10468, USA; Departments of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. Electronic address: weiping.qin@mssm.edu.
authors.forename: Weiping
authors.initials: W
authors.lastname: Qin
authors.affiliation: Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York 10468, USA.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Pan
authors.affiliation: Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York 10468, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York 10468, USA; Departments of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA; Rehabilitation Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Bauman
authors.affiliation: Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, New York 10468, USA; Departments of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA; Rehabilitation Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. Electronic address: Chris.cardozo@mssm.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cardozo
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009277:Nandrolone / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D045930:Anabolic Agents; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C477593:Nfatc4 protein, rat; D009277:Nandrolone; D016572:Cyclosporine; D019703:Calcineurin
keywords: Androgens; Calcineurin–NFAT signaling; Denervation; Muscle atrophy; Myotubes