Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes.

Research paper by Carmelo C Milioto, Adriana A Malena, Eleonora E Maino, Maria J MJ Polanco, Caterina C Marchioretti, Doriana D Borgia, Marcelo Gomes MG Pereira, Bert B Blaauw, Andrew P AP Lieberman, Roberta R Venturini, Mario M Plebani, Fabio F Sambataro, Lodovica L Vergani, Elena E Pegoraro, Gianni G Sorarù, et al.

Indexed on: 25 Jan '17Published on: 25 Jan '17Published in: Scientific Reports


Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA.

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