A ketogenic diet and voluntary exercise modify the sciatic nerve and gastrocnemius transcriptome in diet-induced obese mice

The metabolic syndrome (MetS), an increasingly prevalent condition, causes peripheral nerve and skeletal muscle damage. Lifestyle interventions, such as a ketogenic diet (KD) and exercise (EX), are recommended to improve MetS and prevent peripheral nerve and skeletal muscle injury. However, a comprehensive understanding of the underlying protective effects of diet and EX on peripheral nerve and skeletal muscle health and a direct comparison of the two is currently lacking. Here, we measured peripheral nerve and skeletal muscle outcomes and examined transcriptomic profiles in the sciatic nerve (SCN) and gastrocnemius muscle (GASTROC) from mice fed standard (SD), 60% high-fat (HFD), or KD. We also evaluated the effect of switching HFD mice to SD, KD, and/or exercise (EX) on SCN and GASTROC. Long-term KD preserved peripheral nerve function while dietary and/or EX interventions improved HFD-induced peripheral neuropathy. Differentially expressed gene analyses followed by mFuzz and pathway enrichment analyses identified alterations in biological processes related to cytoskeletal dynamics, lipid metabolism, and amino acid metabolism by diet or interventions in the SCN and GASTROC. Additionally, diet and interventions led to cell-specific changes within the SCN and GASTROC. Collectively, our findings highlight the importance of a healthy diet and regular EX in promoting peripheral nerve and muscle health. We also highlight new and clinically relevant avenues for therapy.