Injectable antifibrotic drug-loaded hydrogels reduce fibrosis and restore myogenesis by enhancing mitochondrial metabolism and cell mechanics in an in vitro coculture model

Treatment with pirfenidone-loaded hydrogels reduced fibrotic stiffness by ∼40% and increased myotube formation by 33%.

• Chronic low-grade inflammation is associated with changes in cellular mechanics and mitochondrial function, impacting muscle health.
• Paracrine signals from inflammation-stimulated macrophages decreased markers linked to muscle formation and increased markers related to fibrosis.
• Mitochondrial metabolism was impaired, as evidenced by decreased energy production indicators like maximal respiration and increased proton leak.
• Pirfenidone-loaded hydrogels improved mitochondrial function, restoring 20% of maximal respiration and reducing proton leak by 50%.
• The treatment also suppressed fibrotic markers while enhancing myogenic gene expression, suggesting a shift toward muscle regeneration.
• RNA transcriptomics supported the findings by showing upregulation of muscle development pathways and downregulation of fibrosis-related signaling.

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