Muscle spatial lipidomics identifies early ALS signatures in presymptomatic SOD1G93A mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose diagnosis often remains delayed. Skeletal muscle is increasingly recognized as an early contributor to ALS pathology. Using lipid imaging mass spectrometry (LIMS) in Tibialis anterior muscle from hSOD1G93A mice across disease stages, we identified fiber-type-specific and sex-dependent lipid remodeling. Lipid alterations were detected at the presymptomatic stage, preceding motor neuron loss and clinical symptoms. LIMS distinguished fast-twitch oxidative-glycolytic (type IIA) and glycolytic (type IIB/IIX) fibers and revealed their differential vulnerability to disease. Presymptomatic mutant muscles showed loss of physiological lipid signatures alongside disease-specific lipid changes. Although lipid profiles differed between sexes, ALS-associated alterations enabled accurate discrimination of mutant mice before symptom onset. Importantly, similar disease-related lipid changes were detected in serum, enabling accurate classification of presymptomatic animals. These findings establish lipid remodeling as an early ALS event and highlight novel biomarkers with potential for diagnosis and disease monitoring.