Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1 G93A Mice.
Fast-twitch muscle shows far more lipid mediator changes than slow-twitch muscle in amyotrophic lateral sclerosis mice
Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1 G93A Mice.
Skeletal muscle atrophy in amyotrophic lateral sclerosis (amyotrophic lateral sclerosis) drives loss of muscle strength, function and quality of life in amyotrophic lateral sclerosis patients.
This study investigated temporal and muscle type-specific endocannabinoid system changes in amyotrophic lateral sclerosis.
Female hSOD1 G93A transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56-138 days of age; n = 7-8/group).
63% of fast-twitch lipid mediators shifted, versus 22% in slow-twitch muscle
Amyotrophic lateral sclerosis caused severe atrophy in the predominantly fast-twitch tibialis anterior muscle (-76.5%; p < 0.01), while the slow-twitch soleus was largely preserved (-14.4%; p < 0.01).
In contrast, the soleus showed modest or opposite changes, consistent with its relative resistance to atrophy.
Notably, endocannabinoid system remodelling in the tibialis anterior was already evident at presymptomatic age (e.g., CB1: +76%; p = 0.01) and the same endocannabinoid system enzymes were affected in human amyotrophic lateral sclerosis skeletal muscle transcriptomes (e.g., twofold decrease in fatty acid amide hydrolase; p FDR = 0.010).
Muscle type-specific endocannabinoid system remodelling in amyotrophic lateral sclerosis precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation.
Although peripheral fatty acid amide hydrolase inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of amyotrophic lateral sclerosis muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.