Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by dysfunction of the upper and lower motor neurons resulting in muscle weakness and wasting. Recently, several studies on ALS patients and ALS animal models indicated that intramuscular toxicity played a role in ALS disease progression; however, the mechanisms driving this are unknown. In this study, we explored the possible dysfunction of lipid metabolism in myocytes associated with ALS. Initially, skeletal muscle from 41 ALS patients, as well as 53 non-ALS control subjects, was investigated, and we identified that lipid droplet accumulation in the muscle fibers of ALS patients was significantly increased, especially in patients with FUS mutations. A myoblast (C2C12) cell line expressing mutant FUS (FUS-K510Q) was able to induce lipid droplet accumulation and mitochondrial dysfunction. Consistently, transgenic flies expressing FUS-K510Q under a muscle-specific driver showed elevated triglyceride levels in the flight muscles, as well as locomotor defects. Biochemical analysis of C2C12 cells and fly muscle tissues showed upregulation of PLIN2, and downregulation of ATGL and CPT1A, indicating inhibition of lipolysis and fatty acid β-oxidation in muscle cells with FUS mutations. Our study provided a potential explanation for the pathogenesis associated with lipid droplets accumulating in skeletal muscle in ALS. Our data also suggested that disordered lipid metabolism and mitochondrial dysfunction play a crucial role in intramuscular toxicity in ALS.