Abstract
<jats:p>Duchenne muscular dystrophy (DMD) is initiated by dystrophin loss but is accompanied by profound metabolic remodelling. Here, we identify suppression of the muscle-enriched adenylosuccinate synthetase ADSS1 and wider purine nucleotide cycle in mdx muscle. Integrated transcriptomic, metabolomic and lipidomic profiling revealed a compensated purine-stress state characterised by increased nucleotide salvage and quality control, preservation of basal adenine nucleotide abundance, and altered mitochondrial and lipid metabolism. Interventions targeting metabolism upstream, across and downstream of ADSS1 produced distinct responses. Ribose induced extensive transcriptional remodelling and dimethyl fumarate engaged fumarate/redox-responsive pathways, but only adenylosuccinic acid (ASA), which bypasses ADSS1, increased adenine nucleotide availability and remodelled CoA/acetyl-CoA metabolism. ADSS1-centred interventions also suppressed pro-adipogenic transcription, while dystrophic muscle accumulated triacylglycerols and acylcarnitines. Human ADSS1-myopathy and mdx muscle shared purine, inflammatory and adipogenic signatures. These findings identify ADSS1 as a metabolic control node coupling purine retention to lipid and inflammatory remodelling in dystrophic muscle.</jats:p>