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Effects of SMN Deficiency on Muscle Development and Maintenance in Spinal Muscular Atrophy Open Access

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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by mutations in the survival of motor neuron 1 (SMN1) gene, resulting in reduced expression of the ubiquitously expressed SMN protein. SMA is characterized by motor neuron loss and severe muscle atrophy. It is unclear to what extent SMN deficiency in peripheral tissues may contribute to the pathophysiology of SMA. However, there is growing evidence from human tissue and model organisms that SMN deficiency can lead to intrinsic muscle defects. Here we investigate the role of SMN in muscle development and maintenance using pharmacological and cell biological approaches. We first show that atrophy markers are induced in SMA model mice and SMA patient muscle in association with increased myogenin and histone deacetylase-4 (HDAC4) expression. These results indicate that myogenin-dependent induction of pro-atrophy genes is a mechanism for atrophy in SMN-deficient muscle. The activation of this atrophy pathway is suppressed by treatment with histone deacetylase inhibitors, suggesting that muscle atrophy in SMA is amenable to pharmacological intervention.SMA model mice have small, weak muscles before induction of atrophy, indicating that SMN may have an intrinsic role in muscle development. Using muscle cell lines we derived from wild-type and SMN-deficient mice, we found that the SMN-deficient muscle cells had reduced capacity to fuse into multinucleate myotubes compared to the wild-type cells. Expression of key muscle development factors such as myogenin and MyoD was increased and induction upon differentiation was reduced in SMN-deficient compared to wild-type cells. In addition, SMN-deficient muscle cells had impaired cell migration and altered organization of focal adhesions and the actin cytoskeleton. Restoring SMN increased expression of muscle differentiation markers and improved myoblast fusion. These data are consistent with a role for SMN in myotube maturation through changes in gene expression and effects on focal adhesions and the actin cytoskeleton. Overall, this dissertation shows a role for SMN in the formation of myotubes and delineates a pathway for muscle atrophy in SMN-deficient muscle.

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