Studies of muscle metabolic alterations during amyotrophic lateral sclerosis: role in the development of the pathology.

Summary Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular degenerative disease. It is accompanied by metabolic alterations, which manifest themselves early in mouse models. The objective of this thesis was to identify the molecular targets involved in these changes. To do so, we studied the glycolytic muscle, the first one affected by denervation during the disease in an ALS model, the SOD1G86R mouse. We showed an imbalance between carbohydrate and lipid metabolic pathways at a presymptomatic stage, with a preference for the lipid catabolic pathway. This alteration may explain our observation on the change in exercise capacity of presymptomatic SOD1G86R mice. In this context, we showed that pharmacological inhibition of PDK4, a major glycolysis inhibitor, is beneficial, delaying the onset of symptoms. By taking into account the metabolic specificities of the different components of the neuromuscular axis, this work opens new therapeutic avenues for the treatment of ALS.