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Denervated muscle promotes nerve regeneration via retrograde metabolic signaling, revising the neural-dominated view of neuromuscular interactions

ABSTRACT: Peripheral nerve injury causes muscle atrophy due to slow axonal regeneration, highlighting an unmet therapeutic need. Although neuromuscular interactions are classically viewed as unidirectionally nerve-dominated, we show that acutely denervated muscle (adMu) regulates nerve regeneration via a retrograde signaling pathway. adMu initiates a trans-tissue regulatory mechanism through extracellular vesicles (EVsadMu) that orchestrate neural energy homeostasis to accelerate regeneration. Functional profiling identifies IDH2 and CS as key metabolic enzymes within EVsadMu. Neurons treated with EVsadMu exhibit a 1.39-fold increase in NADPH/NADP+ ratio via IDH2, along with a 1.18- and 1.27-fold increase in NADH/NAD+ and FADH2/FAD ratios via CS, fueling the TCA cycle to enhance mitochondrial bioenergetics. This restores redox balance and energy supply, driving axonal regeneration. In sciatic nerve injury models, EVadMu-microneedle conduits significantly promote energy metabolism and functional recovery. Together, our findings position adMu as a metabolic signaling center enabling retrograde regulation for nerve regeneration, offering potential for clinical translation.

ORGANISM(S): Mus Musculus

SUBMITTER: Bing Xia

PROVIDER: PXD071459 | iProX | Tue Dec 02 00:00:00 GMT 2025

REPOSITORIES: iProX

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