Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun;74(6):1048-1058.
doi: 10.1002/art.42071. Epub 2022 May 13.

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

Qing-Lin Peng  1 , Ya-Mei Zhang  1 , Yan-Chun Liu  2 , Lin Liang  1 , Wen-Li Li  1 , Xiao-Lan Tian  1 , Lu Zhang  1 , Hong-Xia Yang  1 , Xin Lu  1 , Guo-Chun Wang  1
Affiliations

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

Qing-Lin Peng et al. Arthritis Rheumatol. 2022 Jun.

Abstract

Objective: Myofiber necrosis is a significant pathologic characteristic of idiopathic inflammatory myopathies (IIMs), and its molecular mechanism is largely unknown. Necroptosis is a recently identified form of regulated necrotic cell death, and its activation might have crucial biologic consequences. The aim of the present study was to investigate the role of necroptosis in IIM muscle damage.

Methods: Western blot and immunohistochemistry analyses were performed to examine the expression of receptor-interacting protein 3 (RIP-3) and mixed-lineage kinase domain-like (MLKL) proteins in 26 IIM patients and 4 healthy controls, as well as necroptosis-related damage-associated molecular pattern molecules. Tumor necrosis factor (TNF) was used to stimulate cultured C2C12 myoblasts, and the involvement of necroptosis in cell death of C2C12 cells was studied in vitro.

Results: The expression of RIP-3 and MLKL proteins and their phosphorylated forms was significantly increased in the muscle tissue of IIM patients compared to that of healthy controls. The expression levels of RIP-3 and MLKL proteins were associated with the severity of muscle damage in patients with IIM. Significant colocalization of MLKL with high mobility group box chromosomal protein 1 in necrotizing myofibers was observed in muscle biopsy tissue from patients with IIM. Stimulation of C2C12 myoblasts with TNF and a pan-caspase inhibitor, Z-VAD, resulted in the overactivation of necroptosis and significantly increased necrotic cell death. Strategies involving either inhibition of necroptosis with necrostatin-1 or knockdown of MLKL expression successfully prevented necroptosis-induced cell death of C2C12 cells.

Conclusion: These findings demonstrate that overactivated necroptosis contributes to muscle damage in IIMs and suggest that necroptosis inhibitors could represent a new therapeutic target in the treatment of IIMs.

PubMed Disclaimer

Comment in

References

REFERENCES

    1. Dalakas MC. Inflammatory muscle diseases. N Engl J Med 2015;372:1734-47.
    1. Nagaraju K, Casciola-Rosen L, Rosen A, Thompson C, Loeffler L, Parker T, et al. The inhibition of apoptosis in myositis and in normal muscle cells. J Immunol 2000;164:5459-65.
    1. Nagaraju K, Casciola-Rosen L, Lundberg I, Rawat R, Cutting S, Thapliyal R, et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 2005;52:1824-35.
    1. Alger HM, Raben N, Pistilli E, Francia DL, Rawat R, Getnet D, et al. The role of TRAIL in mediating autophagy in myositis skeletal muscle: a potential nonimmune mechanism of muscle damage. Arthritis Rheum 2011;63:3448-57.
    1. Pandya JM, Venalis P, Al-Khalili L, Shahadat Hossain M, Stache V, Lundberg IE, et al. CD4+ and CD8+ CD28null T cells are cytotoxic to autologous muscle cells in patients with polymyositis. Arthritis Rheumatol 2016;68:2016-26.

Publication types

Substances