https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=38032735&retmode=xml&tool=Litmetric&email=readroberts32@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09 380327352024012420240303
2379-3708922024Jan23JCI insightJCI InsightUric acid formation is driven by crosstalk between skeletal muscle and other cell types.e17181510.1172/jci.insight.171815Hyperuricemia is implicated in numerous pathologies, but the mechanisms underlying uric acid production are poorly understood. Using a combination of mouse studies, cell culture studies, and human serum samples, we sought to determine the cellular source of uric acid. In mice, fasting and glucocorticoid treatment increased serum uric acid and uric acid release from ex vivo-incubated skeletal muscle. In vitro, glucocorticoids and the transcription factor FoxO3 increased purine nucleotide degradation and purine release from differentiated muscle cells, which coincided with the transcriptional upregulation of AMP deaminase 3, a rate-limiting enzyme in adenine nucleotide degradation. Heavy isotope tracing during coculture experiments revealed that oxidation of muscle purines to uric acid required their transfer from muscle cells to a cell type that expresses xanthine oxidoreductase, such as endothelial cells. Last, in healthy women, matched for age and body composition, serum uric acid was greater in individuals scoring below average on standard physical function assessments. Together, these studies reveal skeletal muscle purine degradation is an underlying driver of uric acid production, with the final step of uric acid production occurring primarily in a nonmuscle cell type. This suggests that skeletal muscle fiber purine degradation may represent a therapeutic target to reduce serum uric acid and treat numerous pathologies.MillerSpencer GSGIndiana Center for Musculoskeletal Health and.Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA.MatiasCatalinaCIndiana Center for Musculoskeletal Health and.Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.HafenPaul SPSIndiana Center for Musculoskeletal Health and.Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.LawAndrew SASIndiana Center for Musculoskeletal Health and.Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.WitczakCarol ACAIndiana Center for Musculoskeletal Health and.Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.BraultJeffrey JJJIndiana Center for Musculoskeletal Health and.Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.engP30 AR072581ARNIAMS NIH HHSUnited StatesR01 AR070200ARNIAMS NIH HHSUnited StatesR01 DK103562DKNIDDK NIH HHSUnited StatesJournal Article20240123
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