title: Distinct Etiological Roles for Myocytes and Motor Neurons in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy.
abstract: Polyglutamine (polyQ) expansion of the androgen receptor (AR) causes Kennedy's disease/spinobulbar muscular atrophy (KD/SBMA) through poorly defined cellular mechanisms. Although KD/SBMA has been thought of as a motor neuron disease, recent evidence indicates a key role for skeletal muscle. To resolve which early aspects of the disease can be caused by neurogenic or myogenic mechanisms, we made use of the tet-On and Cre-loxP genetic systems to selectively and acutely express polyQ AR in either motor neurons (NeuroAR) or myocytes (MyoAR) of transgenic mice. After 4 weeks of transgene induction in adulthood, deficits in gross motor function were seen in NeuroAR mice, but not MyoAR mice. Conversely, reduced size of fast glycolytic fibers and alterations in expression of candidate genes were observed only in MyoAR mice. Both NeuroAR and MyoAR mice exhibited reduced oxidative capacity in skeletal muscles, as well as a shift in fast fibers from oxidative to glycolytic. Markers of oxidative stress were increased in the muscle of NeuroAR mice and were reduced in motor neurons of both NeuroAR and MyoAR mice. Despite secondary pathology in skeletal muscle and behavioral deficits, no pathological signs were observed in motor neurons of NeuroAR mice, possibly due to relatively low levels of polyQ AR expression. These results indicate that polyQ AR in motor neurons can produce secondary pathology in muscle. Results also support both neurogenic and myogenic contributions of polyQ AR to several acute aspects of pathology and provide further evidence for disordered cellular respiration in KD/SBMA skeletal muscle.
authors.affiliation: Department of Psychology.
authors.forename: Firyal
authors.initials: F
authors.lastname: Ramzan
authors.affiliation: Institute of Medical Sciences, University of Toronto, Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Mike
authors.initials: M
authors.lastname: McPhail
authors.affiliation: Department of Psychology.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Rao
authors.affiliation: Department of Psychology.
authors.forename: Kaiguo
authors.initials: K
authors.lastname: Mo
authors.affiliation: Department of Psychology.
authors.forename: Katherine
authors.initials: K
authors.lastname: Halievski
authors.affiliation: Department of Psychology.
authors.forename: Ashlyn
authors.initials: A
authors.lastname: Swift-Gallant
authors.affiliation: Department of Cell and Systems Biology, and.
authors.forename: Lucia
authors.identifier: http://orcid.org/0000-0001-9707-859X
authors.initials: L
authors.lastname: Mendoza-Viveros
authors.affiliation: Department of Cell and Systems Biology, and.
authors.forename: Hai-Ying M
authors.initials: HY
authors.lastname: Cheng
authors.affiliation: Department of Psychology, Department of Cell and Systems Biology, and Institute of Medical Sciences, University of Toronto, Mississauga, Ontario L5L 1C6, Canada ashley.monks@utoronto.ca.
authors.forename: D Ashley
authors.identifier: http://orcid.org/0000-0002-0972-4422
authors.initials: DA
authors.lastname: Monks
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009048:Motor Skills; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics
chemical_list: D011944:Receptors, Androgen
keywords: SBMA; androgen receptor; neuromuscular; polyglutamine; skeletal muscle; transgenic mice