Ketogenic diet mitigates sepsis-related acquired weakness in conjunction with SIRT3 upregulation and macrophage M2 polarization

The therapeutic effect of the ketogenic diet (KD) on sepsis-related acquired weakness (SAW) has recently been revealed. However, the precise molecular mechanisms remain unclear. Based on emerging links between immunometabolism and muscle pathology, we hypothesized that KD might exert its effects by modulating the SIRT3 pathway and macrophage polarization in skeletal muscle. In a murine model of SAW, KD intervention robustly improved key disease metrics: it reversed the decline in grip strength, body weight, and muscle mass, enhanced 7-day survival, and attenuated muscle atrophy. At the molecular level, SAW was characterized by a downregulation of SIRT3 and M2 macrophage markers (CD206, ARG-1) alongside an upregulation of M1 markers (CD86, iNOS) in skeletal muscle. Notably, these SAW-induced alterations were counteracted by KD treatment. The functional relevance of SIRT3 was substantiated by pharmacological manipulation: the SIRT3 agonist Honokiol mimicked the therapeutic effects of KD, whereas the SIRT3 inhibitor 3-TYP abolished them. Our findings establish that KD ameliorates SAW in mice. The protection conferred by KD correlates with the restoration of SIRT3 expression and a concomitant shift in the skeletal muscle macrophage landscape from a pro-inflammatory M1 toward a reparative M2 phenotype. The fact that SIRT3 activation or inhibition could recapitulate or block the benefits of KD, respectively, positions SIRT3 as a critical nodal point linking KD to improved macrophage polarization and SAW outcomes. These data unveil a previously unrecognized association between KD, SIRT3, and immunomodulation in SAW, offering a novel conceptual framework for therapeutic development.