Muscle ATP homeostasis and exercise: insights from ADSS1 myopathy.

Muscles use large amounts of ATP during exercise. Three processes are widely recognized as important for maintaining muscle ATP with exercise. They include the phosphagen system, glycolysis, and mitochondrial oxidative phosphorylation. The goal of the current study was to evaluate the role of new purine synthesis in maintaining muscle ATP in individuals with pathogenic variants in adenylosuccinate synthase type 1 (ADSS1), an enzyme involved in muscle ATP synthesis. Muscle energetics were compared in 5 healthy controls and in 3 individuals with ADSS1 myopathy using 31phosphorus-magnetic resonance spectroscopy (31P-MRS) before and after two exercise tasks, one short task that is widely used in muscle physiology and one longer task designed to push ATP use for a longer period. Compared to healthy controls, baseline resting muscle ATP measures were low in the ADSS1 myopathy group. Unlike healthy controls, muscle ATP dropped even with modest exercise in the disease group, and restoration of the energy state was abnormally slow. This rare disorder provides an experiment of nature that suggests synthesis of new purines is a critical fourth process required to maintain muscle ATP during exercise.