title: Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes.
abstract: 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.
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.|Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.|Dipartimento di Medicina Sperimentale, University of Genova, 16100 Genova, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Milioto
authors.affiliation: Department of Neurosciences, University of Padova, 35100 Padova, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Malena
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Maino
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Polanco
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchioretti
authors.affiliation: Department of Neurosciences, University of Padova, 35100 Padova, Italy.
authors.forename: Doriana
authors.initials: D
authors.lastname: Borgia
authors.affiliation: Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, 35100 Padova, Italy.
authors.forename: Marcelo Gomes
authors.initials: MG
authors.lastname: Pereira
authors.affiliation: Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, 35100 Padova, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.affiliation: Department of Laboratory Medicine, University Hospital of Padova, 35100 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Venturini
authors.affiliation: Department of Laboratory Medicine, University Hospital of Padova, 35100 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Plebani
authors.affiliation: Department of Experimental &Clinical Medical Sciences (DISM), University of Udine, 33100 Udine, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.affiliation: Department of Neurosciences, University of Padova, 35100 Padova, Italy.
authors.forename: Lodovica
authors.initials: L
authors.lastname: Vergani
authors.affiliation: Department of Neurosciences, University of Padova, 35100 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.affiliation: Department of Neurosciences, University of Padova, 35100 Padova, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sorarù
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pennuto
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002976:Clenbuterol / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D000318:Adrenergic beta-Agonists; D002976:Clenbuterol; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; D058570:TOR Serine-Threonine Kinases; C097188:polyglutamine