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Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury

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

PROVIDER: GSE312514 | GEO | 2025/12/09

REPOSITORIES: GEO

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Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury

Project description: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.

2025-12-06 | GSE312113 | GEO

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

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Signaling to Transcription Networks in the Neuronal Retrograde Injury Response

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Timecourse expression data from sciatic nerve distal stump of C57BL/6 and C57BL/6 OlaHsd-Wlds mice.

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Transcription profiling of Xenopus dorsal root ganglia conditioned in vitro vs freshly dissected control

Project description:Axonal regeneration is enhanced by prior conditioning peripheral nerve lesions. Here we show that Xenopus dorsal root ganglia (DRGs) with attached peripheral nerves (PN-DRGs) can be conditioned in vitro, thereafter showing enhanced axonal growth in response to neurotrophins, similar to preparations conditioned by axotomy in vivo. In contrast to freshly dissected preparations, conditioned PN-DRGs show abundant neurotrophin-induced axonal growth in the presence of actinomycin D, suggesting synthesis of mRNA encoding proteins necessary for axonal elongation occurs during the conditioning period, and this was confirmed by oligonucleotide micro-array analysis.

2008-04-16 | E-MEXP-1297 | biostudies-arrayexpress

Timecourse expression data from sciatic nerve distal stump of C57BL/6 and C57BL/6 OlaHsd-Wlds mice.

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Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

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