Background/Purpose: Systematic sclerosis (SSc) is an autoimmune disease characteristic by fibroblast transition and overproduction of extracellular matrix, yet with limited treatment. Recent studies provided evidence that aberrant fibroblast activation is at least in part due to mitochondrial dysfunction and associated metabolic changes. Sodium pyruvate is the stable form of pyruvate acid that works as a central hub in several key metabolism pathways including glycolysis, tricarboxylic acid (TCA) cycle, and fatty acid metabolism. In this study, we tested the hypothesis that supplementation with pyruvate may compensate several of the metabolic defects in SSc to improve mitochondrial fitness and that this metabolic rebalancing may dampen fibroblast activation and fibrotic tissue remodeling in SSc.

Methods: The effect of sodium pyruvate on metabolism, mitochondrial fitness, collagen synthesis and fibroblast-to-myofibroblast transition was evaluated in cultured human dermal fibroblasts from SSc patients and controls, in mice with bleomycin-induced dermal fibrosis and precision cut human skin slices. Outcomes included metabolic flux assays, real-time PCR, IF and IHC stainings, cellomics, histomorphometry, hyodroxyproline assays, RNA-seq analysis and datamining of published transcriptomic data of SSc skin.

Results: Several key regulatory components of pyruvate metabolism such as MPC1, PC and PDK2, were found to be dysregulated in the skin of SSc patients compared to matched healthy individuals in the PRESS cohort. Treatment of SSc fibroblasts with sodium pyruvate improve OXPHOS metabolism and the mitochondrial potential. Of note, these metabolic changes upon pyruvate supplementation were associated with a reduced expression of fibrotic related genes including COL1A1 and ACTA2, of markers of myofibroblasts and decreased synthesis of extracellular matrix. Pyruvate supplementation also showed prominent antifibrotic effects at well tolerated doses in mice with bleomycin-induced dermal fibrosis with 55% change reduced dermal thickening, decreased hydroxyproline content of the skin and lower myofibroblast numbers. Moreover, treatment with pyruvate also reduced the expression of profibrotic genes including COL1A1 and ACTA2 in human skin as an ex vivo trial approach.

Conclusion: Sodium pyruvate, which as available as a nutrient supplementation, improves metabolic defects and improves mitochondrial fitness to inhibit fibroblast-to-myofibroblast transition and collagen in human dermal fibroblasts, in experimental murine models of fibrosis and directly in human skin. Pyruvate supplementation may thus by one of the first examples of a metabolically-directed, antifibrotic therapy and may offer potential for further evaluation in clinical studies in SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sodium-pyruvate-improves-mitochondrial-fitness-in-ssc-fibroblasts-to-prevent-fibroblast-to-myofibroblast-transition-and-fibrotic-remodeling/