Exercise and disease state influence the beneficial effects of Fn14-depletion on survival and muscle pathology in theSOD1G93Aamyotrophic lateral sclerosis (ALS) mouse model

Abstract

ABSTRACTBackgroundAmyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of theSOD1G93AALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in theSOD1G93AALS mice could lead to differential and potentially improved benefits.MethodsWe thus investigated the contribution of Fn14 to disease phenotypes in theSOD1G93AALS mice. To do so, Fn14 knockout mice (Fn14-/-) were crossed onto theSOD1G93Abackground to generateSOD1G93A;Fn14-/-mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT),Fn14-/-,SOD1G93AandSOD1G93A;Fn14-/-).ResultsHere, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle ofSOD1G93Amice. We then show that Fn14-depletedSOD1G93Amice display an increased lifespan and decreased muscle pathology, without an impact on motor function, and that this is dependent on exposure to exercise. Indeed, we observe that endurance (rotarod) and resistance (grid test) exercises influence the positive effects of Fn14 deletion on survival and muscle phenotypes inSOD1G93Amice, which may be further influenced by genotype and disease state.ConclusionsOur study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease and metabolic state. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism and exercise will be of importance in future studies.