title: Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy.
abstract: Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn(2B/-) mice but not in the more severe Smn(-/-); SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn(2B/-) muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn(2B/-) and Smn(-/-); SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6 Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada.|Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Deguise
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6 Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Boyer
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6 Canada.
authors.forename: Emily R
authors.initials: ER
authors.lastname: McFall
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6 Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada.
authors.forename: Armin
authors.initials: A
authors.lastname: Yazdani
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6 Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6 Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada.|Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada.|Department of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5 Canada.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C508686:BNip3 protein, mouse; D018797:Cell Cycle Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D055540:Survival of Motor Neuron 2 Protein; C012589:trichostatin A