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Activation of α7nAChR reduces inflammation and apoptosis, promoting muscle regeneration through the AKT-FOXO1 pathway

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Abstract

Denervation induces severe muscle atrophy characterized by inflammatory responses and tissue degradation, with limited effective therapeutic options. This study investigates the role of the α7 nicotinic acetylcholine receptor (α7nAChR) in denervation-induced muscle atrophy and evaluates electroacupuncture (EA) as a potential treatment strategy. Using a sciatic nerve transection mouse model, we observe that denervation decreases α7nAChR expression, activates proteolytic pathways. We find that α7nAChR degradation is associated with the activation of inflammatory cytokines and the caspase pathway. In α7nAChR knockout mice, we demonstrate that α7nAChR modulates mitochondrial metabolism and fiber-type composition. It exerts protective effects by activating the AKT-FOXO1 pathway, thereby reducing inflammation and apoptosis, processes that are critical for muscle regeneration. Additionally, treatment with PNU120596 or EA restores α7nAChR function and alleviates muscle atrophy. Our findings suggest that targeting α7nAChR offers a promising therapeutic approach for muscle wasting following denervation, with potential implications for clinical management and future intervention strategies.

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Fig. 1: The downregulation of α7nAChR in denervation-induced muscle atrophy.
Fig. 2: Denervation decreases α7nAchR expression through muscle inflammation.
Fig. 3: α7nAChR knockout induces muscle atrophy and impairs tissue repair.
Fig. 4: α7nAchR influences muscle growth by modulating the AKT/FOXO1 pathway.
Fig. 5: α7nAchR modulates fast and slow muscle fibers synthesis and mitochondrial metabolism.
Fig. 6: Activation of the Caspase pathway in myotubes triggers α7nAchR degradation.
Fig. 7: Electroacupuncture improves denervation atrophy through α7nAchR.

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Data availability

The RNA-seq data supporting this study have been deposited in the Gene Expression Omnibus (GEO) under accession numbers GSE315922, GSE253469 and GSE304280. The other data generated or analyzed during this study are available upon reasonable request from the corresponding author.

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Acknowledgements

We appreciate the contributions of all our lab members and the valuable insights provided by Prof. Muthu Periasamy in the scientific discussions. We thank BioRender for the drawing tools provided.

Funding

This research was funded by grants from the National Natural Science Foundation of China (No. 82571040, 82370899 and 82070912); State Key Laboratory of Analytical Chemistry for Life Science (5431ZZXM2404); Visiting Researcher Fund Program of State Key Laboratory of Metabolism and Regulation in Complex Organisms (Grant No.KF20250005); Medical Research Priority Project Establishment of Yancheng Municipal Health Commission (YK2023003); NUS-NJU Research Collaboration Fund; Jiangsu Province Leading Talents Cultivation Project for Traditional Chinese Medicine (SLJ0316) and Jiangsu Province Basic Research Funds (No. BK20251988, BK20251803). It was also supported by the Fundamental Research Funds for the Central Universities (No. 14380538, 14380550 to Z.H.) and by team building and scientific research start-up funds of Nanjing University (No. 14912217 to Z.H.). R.F. was supported by EFSD Novo Nordisk future leaders award, Swedish Research Council (2023-02311), Swedish Cancer Society (232891 Pj), and Karolinska Institute Strategic Research Program in Diabetes (SRP) Rolf Luft Grants.

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  1. These authors contributed equally: Xiaolu Jin, Ya Zhou, Luning Sun.

Authors and Affiliations

  1. Rehabilitation department, Affiliated Yancheng No.1 People’s Hospital, State Key Laboratory of Pharmaceutical Biotechnology, State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Yancheng, China

    Xiaolu Jin, Ya Zhou, Li Li, Chaozhu Zheng, Zhongliang Shan, Hongwei Wang & Zhiqiang Huang

  2. College of Acupuncture Moxibustion and Tuina, Nanjing University of Chinese Medicine, Nanjing, China

    Xiaolu Jin & Meihong Shen

  3. Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China

    Xiaolu Jin & Meihong Shen

  4. Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China

    Luning Sun

  5. Affiliated Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China

    Li Li, Chao Ding, Hongwei Wang & Zhiqiang Huang

  6. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China

    Dongdong Huang

  7. School of Life Sciences, 163 Xianlin Avenue, Nanjing University, Nanjing, China

    Qipeng Zhang

  8. Department of Medicine Huddinge, Unit for Gastroenterology and Nutrition, Karolinska Institute, Huddinge, Sweden

    Rongrong Fan

  9. Neurosurgery department, Affiliated Yancheng No.1 People’s Hospital, Medical School, Nanjing University, Yancheng, China

    Guan Sun

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Contributions

ZH, HW, MS, and GS supervised and designed the experiments and revised the manuscript. XJ, YZ, and LS performed the experiments, analyzed the data and wrote the manuscript. DH, QZ, and RF analyzed the data. LL, CZ, ZS, and CD provided essential technical instructions and intellectual support. HW and ZH provided funding support. XJ, YZ, and LS contributed equally as first authors.

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Correspondence to Guan Sun, Meihong Shen, Hongwei Wang or Zhiqiang Huang.

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All animal procedures were conducted at Nanjing University in accordance with the Law of the People’s Republic of China on Progress of Science and Technology and the Law of the People’s Republic of China on Animal Epidemic Prevention, concerning the protection of animals used for scientific purposes. All methods were carried out in compliance with the relevant guidelines and regulations.

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Jin, X., Zhou, Y., Sun, L. et al. Activation of α7nAChR reduces inflammation and apoptosis, promoting muscle regeneration through the AKT-FOXO1 pathway. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01738-1

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