Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1

backgroundSkeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type-specific ECS changes in ALS.

methodsFemale hSOD1

resultsALS caused severe atrophy in the predominantly fast-twitch TA muscle (-76.5%; p < 0.01), while the slow-twitch soleus was largely preserved (-14.4%; p < 0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy- and epoxy-fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; p = 0.03) and multiple N-acyl-ethanolamine congeners (+76-102%; p < 0.05), reduced 2-arachidonoylglycerol (-28%; p = 0.06), increased CB1 receptor expression (+93%; p < 0.01) and dynamic, age-dependent regulation of FAAH (presymptomatic: -68%; p = 0.04, symptomatic: +21%; p = 0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; p = 0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; p

conclusionsMuscle type-specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.