Spinal muscular atrophy (SMA) is characterized by loss of motoneurons and muscular atrophy. While motoneurons are the primary cellular target of this disease, therapeutic strategies alleviating muscle pathology improve lifespan and/or phenotype of SMA mice. A combined therapeutic action at both neuironal and muscular sites can therefore be considered as the most pertinent approach towards SMA therapy. TWEAK is a cytokine of the TNF family that binds the Fn14 receptor. The TWEAK/Fn14 interaction plays a critical role in regulating denervation – induced muscle atrophy as well as muscle proliferation, differentiation, metabolism and atrophy. Seeing as neurodegeneration, muscle atrophy and metabolic perturbations typify SMA, we investigated their expression profiles in SMA mice. We thus uncover an aberrant expression of Tweak and Fn14 in pre-symptomatic muscle of SMA mice. Furthermore, TWEAK and Fn14 have been reported to interact with and regulate PGC-1α, Glut4, Mef2D and HK11, which all play key roles in muscle health and function. Interestingly, we show an abnormal expression of PGC-1α, Glut4, Mef2D and HK11 in SMA muscle, in agreement with the dysregulated expression of Tweak and Fn14. Finally, we demonstrate that Tweak, FN14 and PGC-1α are also misregulated in the heart of pre-symptomatic SMA mice, another muscle pathologically affected in severe SMA cases. We thus hypothesize that an abberant expression of the TWEAK/Fn14 pathway in SMA muscle promotes and exacerbates muscle pathology and that the modulation of this pathway may ameliorate disease pathogenesis. We propose herein to define the pathogenic role of TWEAK and Fn14 in muscle of SMA mice and patients as well as assess the therapeutic potential of manipulating TWEAK and Fn14 expression via genetic and pharmacological approaches. The aim of this project is to highlight TWEAK and Fn14 as novel muscle-specific molecular targets for SMA therapy that could be combined with strategies targeting the central nervous system.
