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ERβ-mediated estrogen signaling promotes the alleviation of inflammation and myofiber repair in cardiotoxin-induced acute skeletal myositis in mice

XIE Jun-Yi¹, CAI Qi-Hui¹, NIU Xiao-Lu¹, WANG Nan¹, HU Xin-Yu¹, HUANG Xiao-Lei¹, WANG Rui-Xue², CHEN Zhe³, LIAO Zhao-Hong^1,4,*

¹Department of Laboratory Medicine, School of Medicine, Foshan University, Foshan 528225, China；²Department of Basic Medicine, School of Medicine, Foshan University, Foshan 528225, China；³Department of Nursing Science, School of Medicine, Foshan University, Foshan 528225, China；⁴Guangdong Provincial Key Laboratory of Tissue Construction and Testing, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China

Abstract

Traumatic stress often leads to abnormalities in sex hormone levels, among which elevated estrogen levels are associated with improved patient prognosis. However, the mechanism by which estrogen affects the inflammatory response and repair process in acute skeletal myositis remains unclear. This study aimed to investigate the effects of estradiol (E2) signaling on the resolution of acute skeletal myositis and muscle fiber repair in mice induced by cardiotoxin (CTX). An acute skeletal myositis model was established in C57BL/6 mice. Endogenous E2 levels were reduced by ovariectomy (OVX) in female mice, and interventions were performed with β-Estradiol or the estrogen receptor β (ERβ)-specific antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP). Differentiated C2C12 myotubes were treated with interferon γ (IFN-γ) in combination with β-Estradiol or PHTPP. Serum E2 levels were measured by ELISA. Inflammatory cell infiltration in injured muscle was assessed by HE staining. Immunofluorescence staining was used to detect the expression levels of ERβ, embryonic myosin heavy chain (eMHC), CD45, myogenic determining factor (MyoD) and myogenin. Proportion of CD45+ inflammatory cells in injured muscle was detected by flow cytometry. Western blot was used to detect protein expression levels of mouse major histocompatibility complex class I molecules (MHC-I) H-2Kb, major histocompatibility complex class II molecules (MHC-II) H2-Eα, Toll-like receptor 3 (TLR3), and ERβ in differentiated myotubes. RT-qPCR was used to measure mRNA expression levels of ERα, ERβ, G protein-coupled receptor 30 (GPR30), interleukin-1β (IL-1β), IL-6, IL-10, and monocyte chemoattractant protein-1 (MCP-1) in injured muscle and differentiated myotubes. The results showed that, in acute skeletal myositis, injured muscle of female mice exhibited milder inflammation compared to male mice, and serum E2 levels were significantly higher in the female mice. Meanwhile, expression of ERβ was significantly up-regulated in injured muscle and inflammatory myotubes, whereas no significant changes were observed in ERα and GPR30. OVX decreased serum E2 level, exacerbated inflammation, and increased infiltration of CD45+ inflammatory cells in injured muscle, whereas these effects were reversed by β-Estradiol treatment. The effects of PHTPP were the same as those of OVX, except that it didn't affect serum E2 levels. In inflammatory myotubes, β-Estradiol up-regulated the protein expression level of ERβ, down-regulated the expression levels of immune molecules H-2Kb, H2-Eα, TLR3, and pro-inflammatory factors IL-1β, IL-6, MCP-1, up-regulated the expression of anti-inflammatory factor IL-10, and up-regulated the expression of MyoD and myogenin. The effects of PHTPP were opposite to those of β-Estradiol. The expression of eMHC in the injured muscle of OVX mice was down-regulated, while β-Estradiol restored its expression. These results suggest that in acute skeletal myositis, E2 inhibits the accumulation of inflammatory cells in the injured muscle by binding to ERβ in muscle fibers, regulates the intrinsic immune behavior of inflammatory myofibers, thereby promoting inflammation resolution and muscle fiber regeneration and repair, providing new insights for the clinical treatment of acute skeletal myositis.

Key words: estrogen signaling; estrogen receptor β; acute skeletal myositis; immune behavior; myofiber repair

Received: 　　Accepted:

Corresponding author: 廖钊宏　　E-mail:

DOI: 10.13294/j.aps.2026.0049

Citing This Article：

XIE Jun-Yi, CAI Qi-Hui, NIU Xiao-Lu, WANG Nan, HU Xin-Yu, HUANG Xiao-Lei, WANG Rui-Xue, CHEN Zhe, LIAO Zhao-Hong. ERβ-mediated estrogen signaling promotes the alleviation of inflammation and myofiber repair in cardiotoxin-induced acute skeletal myositis in mice. Acta Physiol Sin 2026; 78 (3): 631-641 (in Chinese with English abstract).