title: Androgen-dependent impairment of myogenesis in spinal and bulbar muscular atrophy.
abstract: Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). SBMA is triggered by the interaction between polyQ-AR and its natural ligands, testosterone and dihydrotestosterone (DHT). SBMA is characterized by the loss of lower motor neurons and skeletal muscle fasciculations, weakness, and atrophy. To test the hypothesis that the interaction between polyQ-AR and androgens exerts cell-autonomous toxicity in skeletal muscle, we characterized the process of myogenesis and polyQ-AR expression in DHT-treated satellite cells obtained from SBMA patients and age-matched healthy control subjects. Treatment with androgens increased the size and number of myonuclei in myotubes from control subjects, but not from SBMA patients. Myotubes from SBMA patients had a reduced number of nuclei, suggesting impaired myotube fusion and altered contractile structures. The lack of anabolic effects of androgens on myotubes from SBMA patients was not due to defects in myoblast proliferation, differentiation or apoptosis. DHT treatment of myotubes from SBMA patients increased nuclear accumulation of polyQ-AR and decreased the expression of interleukin-4 (IL-4) when compared to myotubes from control subjects. Following DHT treatment, exposure of myotubes from SBMA patients with IL-4 treatment rescued myonuclear number and size to control levels. This supports the hypothesis that androgens alter the fusion process in SBMA myogenesis. In conclusion, these results provide evidence of an androgen-dependent impairment of myogenesis in SBMA that could contribute to disease pathogenesis.
authors: Department of Neuroscience SNPSRR, University of Padova, 35128 Padova, Italy.
authors: Adriana
authors: A
authors: Malena
authors: Maria
authors: M
authors: Pennuto
authors: Caterina
authors: C
authors: Tezze
authors: Giorgia
authors: G
authors: Querin
authors: Carla
authors: C
authors: D'Ascenzo
authors: Vincenzo
authors: V
authors: Silani
authors: Giovanna
authors: G
authors: Cenacchi
authors: Annarita
authors: A
authors: Scaramozza
authors: Silvia
authors: S
authors: Romito
authors: Lucia
authors: L
authors: Morandi
authors: Elena
authors: E
authors: Pegoraro
authors: Aaron P
authors: AP
authors: Russell
authors: Gianni
authors: G
authors: Sorarù
authors: Lodovica
authors: L
authors: Vergani
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000728:Androgens / Q000494:pharmacology*; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006984:Hypertrophy / Q000139:chemically induced; D020287:In Situ Nick-End Labeling; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D024510:Muscle Development / Q000187:drug effects*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009218:Myosins / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D000728:Androgens; D010455:Peptides; D013196:Dihydrotestosterone; D015847:Interleukin-4; C097188:polyglutamine; D009218:Myosins