Meijboom, KE, Sutton, ER, McCallion, E, McFall, E, Anthony, D, Edwards, B, Kubinski, S, Tapken, I, Bünermann, I, Hazell, G, Ahlskog, N, Claus, P, Davies, KE, Kothary, R, Wood, MJA and Bowerman, M (2022) Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice. Skeletal Muscle, 12 (18). pp. 1-25. ISSN 2044-5040

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Background: Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle.

Methods: We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-
;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations.

Results: Here, we report significantly dysregulated expression of Tweak, Fn14 and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/-and Fn14 -/- mice revealed dysregulated myopathy, myogenesis and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models.

Conclusions: Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

Item Type: Article
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Uncontrolled Keywords: spinal muscular atrophy, survival motor neuron, Smn, Tweak, Fn14, glucose metabolism, skeletal muscle, atrophy, denervation
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC925 Diseases of the musculoskeletal system
Divisions: Faculty of Medicine and Health Sciences > School of Medicine
Depositing User: Symplectic
Date Deposited: 25 Jul 2022 09:33
Last Modified: 01 Feb 2023 10:57

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