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Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy

Iyer, CC and McGovern, VL and Wise, DO and Glass, DJ and Burghes, AHM (2014) Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy. Neuromuscular Disorders. pp. 436-444.

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 7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx<sup>-/-</sup>-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 7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a 7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. 2014 Elsevier B.V

Item Type: Article
Additional Information: NIBR author: Glass, DJ institute: NIBR contributor address: (Iyer, McGovern, Wise, Burghes) Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, United States (Glass) Novartis Institutes for Biomedical Research, Cambridge, MA, United States (Burghes) Department of Neurology, The Ohio State University, Columbus, OH, United States (Burghes) Department of Molecular Genetics, The Ohio State University, Columbus, OH, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22625

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