Open Access

Denervation‑induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway

  • Authors:
    • Lin Ma
    • Xia Kang
    • Jindong Tan
    • Yunjiao Wang
    • Xiao Liu
    • Hong Tang
    • Lin Guo
    • Kanglai Tang
    • Xuting Bian
  • View Affiliations

  • Published online on: October 21, 2024     https://doi.org/10.3892/mmr.2024.13374
  • Article Number: 9
  • Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Peripheral nerve injury exacerbates progression of muscle heterotopic ossification (HO) and induces changes in expression of local cytokines in muscle tissue. The objective of the present study was to assess the impact of peripheral nerve injury on muscle HO development and the mechanism of cytokine modulation. A mouse model of gastrocnemius muscle HO was established and the sciatic nerve cut to simulate peripheral nerve injury. To evaluate the underlying factors contributing to the exacerbation of muscle HO resulting from denervation, fresh muscle tissue was collected and micro‑computed tomography, histochemical staining, RNA‑sequencing, reverse transcription‑quantitative PCR, Western blot, muscle tissue chip array were performed to analyze the molecular mechanisms. Sciatic nerve injury exacerbated HO in the gastrocnemius muscle of mice. Moreover the osteogenic differentiation of nerve‑injured muscle tissue‑derived fibro‑adipogenic progenitors (FAPs) increased in vitro. The expression of neuregulin 3 (NRG3) was demonstrated to be increased after nerve injury by muscle tissue chip array. Subsequent transcriptome sequencing analysis of muscle tissue revealed an enrichment of the PI3K/Akt pathway following nerve injury and an inhibitor of the PI3K/Akt pathway reduced the osteogenic differentiation of FAPs. Mechanistically, in vitro, peripheral nerve injury increased secretion of NRG3, which, following binding to ErbB4 on the cell surface of FAPs, promoted expression of osteogenesis‑associated genes via the PI3K/Akt signaling pathway, thus contributing to osteogenic differentiation of FAPs. In vivo, inhibition of the PI3K/Akt pathway effectively protected against muscle HO induced by peripheral nerve injury in mice. The present study demonstrated that the regulatory roles of NRG3 and the PI3K/Akt pathway in peripheral nerve injury exacerbated muscle HO and highlights a potential therapeutic intervention for treatment of peripheral nerve injury‑induced muscle HO.
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January-2025
Volume 31 Issue 1

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Spandidos Publications style
Ma L, Kang X, Tan J, Wang Y, Liu X, Tang H, Guo L, Tang K and Bian X: Denervation‑induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway. Mol Med Rep 31: 9, 2025.
APA
Ma, L., Kang, X., Tan, J., Wang, Y., Liu, X., Tang, H. ... Bian, X. (2025). Denervation‑induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway. Molecular Medicine Reports, 31, 9. https://doi.org/10.3892/mmr.2024.13374
MLA
Ma, L., Kang, X., Tan, J., Wang, Y., Liu, X., Tang, H., Guo, L., Tang, K., Bian, X."Denervation‑induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway". Molecular Medicine Reports 31.1 (2025): 9.
Chicago
Ma, L., Kang, X., Tan, J., Wang, Y., Liu, X., Tang, H., Guo, L., Tang, K., Bian, X."Denervation‑induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway". Molecular Medicine Reports 31, no. 1 (2025): 9. https://doi.org/10.3892/mmr.2024.13374