Muscle fibers secrete FGFBP1 to slow degeneration of neuromuscular synapses during aging and progression of ALS

Abstract

The identity of muscle secreted factors critical for the development and maintenance of neuromuscular junctions (NMJs) remains largely unknown. Here, we show that muscle fibers secrete and concentrate the fibroblast growth factor binding protein 1 (FGFBP1) at NMJs. Although FGFBP1 expression increases during development, its expression decreases before NMJ degeneration during aging and in SOD1G93A mice, a mouse model for amyotrophic lateral sclerosis (ALS). Based on these findings, we examined the impact of deleting FGFBP1 on NMJs. In the absence of FGFBP1, NMJs exhibit structural abnormalities in developing and middle age mice. Deletion of FGFBP1 from SOD1G93A mice also acceleratesNMJdegeneration and death. Based on these findings, we sought to identify the mechanism responsible for decreased FGFBP1 in stressed skeletal muscles.Weshow that FGFBP1 expression is inhibited by increased accumulation of the transforming growth factor-_1 (TGF-_1) in skeletal muscles and at their NMJs. These findings suggest that targeting the FGFBP1 and TGF-_1 signaling axis holds promise for slowing age- and disease-related degeneration of NMJs.