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Effects of delayed repair of peripheral nerve injury on the spatial distribution of motor endplates in target muscle.

ABSTRACT: Motor endplates (MEPs) are important sites of information exchange between motor neurons and skeletal muscle, and are distributed in an organized pattern of lamellae in the muscle. Delayed repair of peripheral nerve injury typically results in unsatisfactory functional recovery because of MEP degeneration. In this study, the mouse tibial nerve was transected and repaired with a biodegradable chitin conduit, immediately following or 1 or 3 months after the injury. Fluorescent α-bungarotoxin was injected to label MEPs. Tissue optical clearing combined with light-sheet microscopy revealed that MEPs were distributed in an organized pattern of lamellae in skeletal muscle after delayed repair for 1 and 3 months. However, the total number of MEPs, the number of MEPs per lamellar cluster, and the maturation of single MEPs in gastrocnemius muscle gradually decreased with increasing denervation time. These findings suggest that delayed repair can restore the spatial distribution of MEPs, but it has an adverse effect on the homogeneity of MEPs in the lamellar clusters and the total number of MEPs in the target muscle. The study procedures were approved by the Animal Ethics Committee of the Peking University People's Hospital (approval No. 2019PHC015) on April 8, 2019.

SUBMITTER: Li DD

PROVIDER: S-EPMC8464005 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Effects of delayed repair of peripheral nerve injury on the spatial distribution of motor endplates in target muscle.

Li Dong-Dong DD Deng Jin J Jin Bo B Han Shuai S Gu Xin-Yi XY Zhou Xue-Feng XF Yin Xiao-Feng XF

Neural regeneration research 20220201 2

Motor endplates (MEPs) are important sites of information exchange between motor neurons and skeletal muscle, and are distributed in an organized pattern of lamellae in the muscle. Delayed repair of peripheral nerve injury typically results in unsatisfactory functional recovery because of MEP degeneration. In this study, the mouse tibial nerve was transected and repaired with a biodegradable chitin conduit, immediately following or 1 or 3 months after the injury. Fluorescent α-bungarotoxin was i ...[more]

PMID: 34269223

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Project description:Skeletal muscle-derived cells have strong secretory function, while skeletal muscle-derived stem cells, which are included in muscle-derived cells, can differentiate into Schwann cell-like cells and other cell types. However, the effect of muscle-derived cells on peripheral nerve defects has not been reported. In this study, 5-mm-long nerve defects were created in the right sciatic nerves of mice to construct a peripheral nerve defect model. Adult female C57BL/6 mice were randomly divided into four groups. For the muscle-derived cell group, muscle-derived cells were injected into the catheter after the cut nerve ends were bridged with a polyurethane catheter. For external oblique muscle-fabricated nerve conduit and polyurethane groups, an external oblique muscle-fabricated nerve conduit or polyurethane catheter was used to bridge the cut nerve ends, respectively. For the sham group, the sciatic nerves on the right side were separated but not excised. At 8 and 12 weeks post-surgery, distributions of axons and myelin sheaths were observed, and the nerve diameter was calculated using immunofluorescence staining. The number, diameter, and thickness of myelinated nerve fibers were detected by toluidine blue staining and transmission electron microscopy. Muscle fiber area ratios were calculated by Masson's trichrome staining of gastrocnemius muscle sections. Sciatic functional index was recorded using walking footprint analysis at 4, 8, and 12 weeks after operation. The results showed that, at 8 and 12 weeks after surgery, myelin sheaths and axons of regenerating nerves were evenly distributed in the muscle-derived cell group. The number, diameter, and myelin sheath thickness of myelinated nerve fibers, as well as gastrocnemius muscle wet weight and muscle area ratio, were significantly higher in the muscle-derived cell group compared with the polyurethane group. At 4, 8, and 12 weeks post-surgery, sciatic functional index was notably increased in the muscle-derived cell group compared with the polyurethane group. These criteria of the muscle-derived cell group were not significantly different from the external oblique muscle-fabricated nerve conduit group. Collectively, these data suggest that muscle-derived cells effectively accelerated peripheral nerve regeneration. This study was approved by the Animal Ethics Committee of Plastic Surgery Hospital, Chinese Academy of Medical Sciences (approval No. 040) on September 28, 2016.

Project description:Peripheral nerve injuries represent a significant clinical challenge due to their limited regenerative capacity. Surgical repair strategies include immediate nerve repair, performed shortly after injury, and delayed nerve repair, conducted after a prolonged period when primary intervention is not feasible. Understanding the molecular and genetic mechanisms underlying both strategies is essential for optimizing functional recovery. This study compares the transcriptional landscape of delayed and immediate nerve repair over time to elucidate key pathways involved in nerve regeneration. A rat model of sciatic nerve injury was used, where an 8-mm nerve gap was repaired using a chitosan conduit either immediately or after a 3-month delay. Regenerated nerves were collected at 7-, 14-, and 21-days post-repair. RNA sequencing was performed to analyze transcriptomic changes across time points, and differentially expressed genes were identified and subjected to Gene Ontology enrichment analysis to identify functional pathways and regulatory networks involved in nerve regeneration. Distinct transcriptional profiles were observed across time points after immediate and delayed repair when comparing regenerating nerves with a healthy nerve. At 7 days, both exhibited a robust inflammatory response with upregulation of genes related to cytokine signaling and myeloid cell activation. By 14 days, many pathways related to response to lipoprotein particles and phagocytosis were upregulated, with delayed repair showing downregulation of myelination-associated genes. At 21 days, immune response activation, phagocytosis and lipoprotein particle activated pathways remained upregulated in both conditions. These findings suggest that immediate repair induces a faster regenerative response, whereas delayed repair follows a slower trajectory but engages similar molecular pathways. Despite initial differences, both strategies eventually converge on key regenerative mechanisms. These insights emphasize the benefits of early intervention while highlighting the potential for delayed repair to achieve functional recovery. Future research will focus on enhancing delayed repair outcomes through targeted molecular approaches.

Dataset Information

Effects of delayed repair of peripheral nerve injury on the spatial distribution of motor endplates in target muscle.

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Effects of delayed repair of peripheral nerve injury on the spatial distribution of motor endplates in target muscle.

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