title: The anabolic/androgenic steroid nandrolone exacerbates gene expression modifications induced by mutant SOD1 in muscles of mice models of amyotrophic lateral sclerosis.
abstract: Anabolic/androgenic steroids (AAS) are drugs that enhance muscle mass, and are often illegally utilized in athletes to improve their performances. Recent data suggest that the increased risk for amyotrophic lateral sclerosis (ALS) in male soccer and football players could be linked to AAS abuse. ALS is a motor neuron disease mainly occurring in sporadic (sALS) forms, but some familial forms (fALS) exist and have been linked to mutations in different genes. Some of these, in their wild type (wt) form, have been proposed as risk factors for sALS, i.e. superoxide dismutase 1 (SOD1) gene, whose mutations are causative of about 20% of fALS. Notably, SOD1 toxicity might occur both in motor neurons and in muscle cells. Using gastrocnemius muscles of mice overexpressing human mutant SOD1 (mutSOD1) at different disease stages, we found that the expression of a selected set of genes associated to muscle atrophy, MyoD, myogenin, atrogin-1, and transforming growth factor (TGF)β1, is up-regulated already at the presymptomatic stage. Atrogin-1 gene expression was increased also in mice overexpressing human wtSOD1. Similar alterations were found in axotomized mouse muscles and in cultured ALS myoblast models. In these ALS models, we then evaluated the pharmacological effects of the synthetic AAS nandrolone on the expression of the genes modified in ALS muscle. Nandrolone administration had no effects on MyoD, myogenin, and atrogin-1 expression, but it significantly increased TGFβ1 expression at disease onset. Altogether, these data suggest that, in fALS, muscle gene expression is altered at early stages, and AAS may exacerbate some of the alterations induced by SOD1 possibly acting as a contributing factor also in sALS.
authors.affiliation: Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.forename: Elisa
authors.initials: E
authors.lastname: Onesto
authors.forename: Arianna
authors.initials: A
authors.lastname: Zito
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mariotti
authors.forename: Marina
authors.initials: M
authors.lastname: Bentivoglio
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D045930:Anabolic Agents / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017570:MyoD Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D018008:Myogenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009277:Nandrolone / Q000494:pharmacology*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D009124:Muscle Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; D018008:Myogenin; C000606290:SOD1 protein, human; D016212:Transforming Growth Factor beta; D009277:Nandrolone; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases