Cordycepin ameliorates lipopolysaccharide-challenged C2C12 myotube shrinkage by regulating sodium channel kinetics and inhibiting the protein degradation pathway.

BACKGROUND

Skeletal muscle contraction relies on action potentials mediated by voltage-gated sodium channels (Naᵥ), and dysfunction of Naᵥ is closely associated with muscle atrophy. Cordycepin(Cor), a bioactive metabolite of Cordyceps militaris, exhibits anti-inflammatory and anti-fatigue properties. These properties suggest its therapeutic potential at the intersection of functional food science and muscle physiology research.

OBJECTIVE

This study aimed to assess the effects of Cor on inflammatory myotube atrophy and Naᵥ kinetics, and to explore the potential correlation between these effects.

METHODS

The effects of Cor were evaluated using behavioural assays, immunofluorescence, immunoprobe assays, RT-qPCR, western blotting, and whole-cell patch clamp recording.

RESULTS

Lipopolysaccharide (LPS)-challenged C2C12 myotubes exhibited shrinkage, impaired fusion, loss of intracellular Na+ content, and upregulation of the atrophy driver FOXO3a. Cor reversed all of these changes; however, the Naᵥ-blocker tetrodotoxin (TTX) abolished this rescue. Patch-clamp analysis showed that LPS suppressed Naᵥ function: activation and current density decreased, inactivation shifted positively, recovery slowed, use-dependent decline accelerated, and channel availability decreased. Cor restored each parameter to control levels, whereas TTX nullified the benefit. In LPS-treated C57BL/6 mice(male, 8 weeks old), Cor increased muscle mass, fibre cross-sectional area, grip strength, and running distance, suggesting that the fungal metabolite may protect skeletal muscle by reactivating Naᵥ.

CONCLUSION

The attenuation of myotube atrophy by Cor via suppression of Foxo3a is likely associated with the restoration of sodium channel function and inhibition of proteolytic pathways. Our findings indicate that Cor may mitigates inflammatory responses in the context of muscle atrophy, providing new insights into its pharmacological effects on skeletal muscle atrophy.