title: Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx(-/-)-SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1.
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Chitra C
authors.initials: CC
authors.lastname: Iyer
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Vicki L
authors.initials: VL
authors.lastname: McGovern
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Dawnne O
authors.initials: DO
authors.lastname: Wise
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA; Department of Neurology, The Ohio State University, Columbus, OH, USA; Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA. Electronic address: burghes.1@osu.edu.
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
mesh_terms: D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D044843:SKP Cullin F-Box Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: MAFbx (Atrogin1); MuRF1 (Trim63); Muscle RING Finger 1; Muscle atrophy F-box; Muscle ubiquitin ligases; Spinal muscular atrophy (SMA)