Angelica dahurica alleviates peripheral nerve injury-induced muscle atrophy via the Phlpp2-Akt-FoxO3α axis independently of analgesia.

BACKGROUND

Peripheral nerve injury frequently causes refractory neuropathic pain and muscle atrophy. While clinical care focuses on analgesia, effective therapies for muscle wasting are lacking. Angelica dahurica (BZ) is known for its analgesic properties, but whether it also ameliorates muscle atrophy remains unclear.

PURPOSE: This study evaluates the dual analgesic and anti‑atrophic effects of BZ, with a focus on determining whether its muscle‑protective action is separable from pain relief and elucidating the underlying mechanism.

METHODS

Following sciatic nerve chronic constriction injury (CCI), rats were treated with BZ extract or Pregabalin (Pre), a positive analgesic control. Nociceptive behaviors and motor function were assessed via behavioral tests and gait analysis. Muscle atrophy was evaluated by wet weight, histology, and transmission electron microscopy. RNA‑seq was performed to profile transcriptomic changes in muscle. High‑resolution mass spectrometry was used to identify BZ‑derived components in plasma and muscle.

RESULTS

Post-CCI muscle atrophy and pain showed distinct temporal trajectories, with atrophy transitioning from an acute phase of rapid mass loss (days 1-10) to a later phase of progressive fibrosis (days 14-21). BZ administration significantly alleviated mechanical, cold, and thermal hypersensitivity, while concurrently increasing muscle mass and partially improving myofiber morphology and sarcomere ultrastructure. Notably, while Pre provided equivalent analgesia, it failed to mitigate muscle atrophy, demonstrating that the anti-atrophic effect of BZ is largely independent of its analgesic activity. Mechanistically, BZ-mediated recovery was associated with the modulation of the intramuscular Phlpp2‑Akt‑ FoxO3α signaling axis, as indicated by suppressed Phlpp2 expression and enhanced Akt phosphorylation. Seven muscle-distributed components were identified as potential contributors to these therapeutic effects.

CONCLUSIONS

BZ exerts potential anti-atrophic effects that correlated with modulation of the Phlpp2‑Akt‑FoxO3α axis, largely independent of its analgesic activity. These findings identify BZ as a promising dual-action therapeutic candidate for addressing both neuropathic pain and muscle wasting following peripheral nerve injury.