Muscle Fibers Secrete FGFBP1 to Slow Degeneration of Neuromuscular Synapses during Aging and Progression of ALS

• Published in: The Journal of neuroscience Vol. 37; no. 1; pp. 70 - 82
• Main Authors: Taetzsch, Thomas, Tenga, Milagros J, Valdez, Gregorio
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 04-01-2017
• Subjects: Aging - metabolism; Aging - pathology; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Axons - pathology; Carrier Proteins - metabolism; Mice; Mice, Knockout; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Nerve Degeneration - pathology; Nerve Regeneration; Neuromuscular Junction - pathology; Superoxide Dismutase-1 - genetics; Synapses - pathology; Transforming Growth Factor beta1 - metabolism; cytokine; synaptic elimination; axonal regeneration; geriatric; target-derived; Lou Gehrig's disease
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2992-16.2016

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 SOD1
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 SOD1
mice also accelerates NMJ degeneration and death. Based on these findings, we sought to identify the mechanism responsible for decreased FGFBP1 in stressed skeletal muscles. We show that FGFBP1 expression is inhibited by increased accumulation of the transforming growth factor-β1 (TGF-β1) in skeletal muscles and at their NMJs. These findings suggest that targeting the FGFBP1 and TGF-β1 signaling axis holds promise for slowing age- and disease-related degeneration of NMJs.
The neuromuscular junction (NMJ) is critical for all voluntary movement. Its malformation during development and degeneration in adulthood impairs motor function. Therefore, it is important to identify factors that function to maintain the structural integrity of NMJs. We show that muscle fibers secrete and concentrate the fibroblast growth factor binding protein 1 (FGFBP1) at NMJs. However, FGFBP1 expression decreases in skeletal muscles during aging and before NMJ degeneration in SOD1
mice, a mouse model for amyotrophic lateral sclerosis. We show that transforming growth factor-β1 is responsible for the decreased levels of FGFBP1. Importantly, we demonstrate critical roles for FGFBP1 at NMJs in developing, aging and SOD1
mice.