Short-chain fatty acids alleviate sarcopenia in rats via modulation of the NF-κB signaling pathway.

Sarcopenia, characterized by progressive impairment of muscle quantity and performance, is closely linked to chronic inflammatory responses and cell death pathways. Short-chain fatty acids (SCFAs), metabolites originating from the gut microbial community, have shown immunomodulatory effects. This investigation evaluated the protective role and mechanistic basis of SCFAs in an induced sarcopenia rat model, focusing on the NF-κB signaling cascade. A pharmacologically induced sarcopenia model was established in adult female SD rats (6 months old) through bilateral ovariectomy followed by dexamethasone injections. Animals were grouped as follows: Sham, Model, and SCFAs (administered 150 mM SCFAs in drinking water for 4 weeks). Muscle function (forelimb grip strength, gastrocnemius muscle index), histological changes (H&E), reactive oxygen species, apoptosis (TUNEL), inflammatory cytokines (ELISA), gene expression (RT-qPCR), and protein expression (immunoblotting) were evaluated to assess the impact of SCFAs on sarcopenia and its underlying mechanistic basis. Relative to the Model group, SCFAs significantly increased circulating SCFA levels, improved grip strength and gastrocnemius index, restored muscle fiber structure, and reduced reactive oxygen species levels and apoptosis. SCFAs were associated with reduced NF-κB pathway activation (p-IKKβ and p-p65), downregulated NLRP3 inflammasome components (NLRP3, ASC, cleaved-Caspase-1), and reduced pyroptosis (GSDMD-N expression) and inflammatory cytokines (IL-1β and IL-18). SCFAs ameliorated sarcopenia in a pharmacologically induced rat model by suppressing NF-κB/NLRP3-mediated inflammation and pyroptosis, highlighting their potential as a candidate nutritional intervention for muscle atrophy associated with inflammation, hormonal imbalance, or metabolic stress.