Pharmacological Inhibition of the CXCR2 Protects Against Sepsis-Induced Myopathy in Mice

Background: Sepsis, a life-threatening organ dysfunction driven by a dysregulated host response to infection, causes profound muscle atrophy, weakness, and long-term morbidity in most survivors. Several chemokines (e.g., CXCL1, CXCL2, CXCL10, and CCL2) are elevated in septic mice and signal through CXCR2, CXCR3, and CCR2 receptors expressed on immune and skeletal muscle cells. We hypothesized that these chemokine pathways contribute to the sepsis-induced inflammation and muscle dysfunction, and that pharmacological inhibition of their receptors would attenuate skeletal muscle atrophy, weakness, and systemic inflammation during sepsis. Methods: Male C57BL/6 mice (n = 6/group) underwent cecal ligation and puncture (CLP) and received daily intraperitoneal injections of chemokine receptor antagonists (SB225002 for CXCR2, AMG487 for CXCR3, or BMSCCR2 for CCR2) or matched vehicles for 11 days. Body mass loss, and spleen weight were quantified as indices of disease severity and systemic inflammation. Tibialis anterior (TA) and soleus cross-sectional area (CSA) were assessed from OCT-embedded frozen sections. Soleus contractility was tested ex vivo. Group differences for morphological outcomes were analyzed using unpaired two-tailed Student’s t-tests (p < 0.05). Results: CXCR3 and CCR2 inhibition did not improve systemic outcomes or prevent muscle atrophy. In contrast, CXCR2 inhibition with SB225002 attenuated disease severity, reducing body mass loss (Vehicle: -7.3 ± 7.6%, SB225002: -1.2 ± 5.5%), preserving spleen weight (Vehicle: 325.8 ± 56.6 mg vs SB225002: 221.1 ± 53.7 mg), and increasing TA CSA (Vehicle: 1656.6 ± 144.8 μm 2 vs SB225002: 2004.8 ± 189.8 μm 2 ). Soleus muscle mass and contractile force were unchanged across groups. Conclusions: CXCR2 inhibition preserved skeletal muscle morphology and mitigates systemic inflammatory indicators in septic mice, identifying CXCR2 mediated signaling as a key contributor to sepsis-induced myopathy. These findings support CXCR2 inhibition as a promising therapeutic strategy to protect skeletal muscle during sepsis. Funding: This work was supported by the National Institutes of Health (NIH) under grant number R21AG072011 and R01AR085126 to OL. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.