Erythrocyte extravasation drives ferroptosis and inflammatory amplification in eccentric contraction-induced skeletal muscle injury via the heme-HO-1-iron axis
- 1Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
Abstract
Eccentric contraction-induced skeletal muscle injury is a common sports-related condition characterized by pain, impaired muscle function, slow recovery, and frequent recurrence, yet treatment remains symptomatic and mechanism-based targets are lacking. Although microvascular disruption and erythrocyte extravasation characterize severe muscle strain, the metabolic fate of extravasated erythrocytes has received little attention. In hemorrhagic and hemolytic conditions, erythrocyte-derived heme can activate heme oxygenase-1 (HO-1)-mediated iron release and ferroptosis, potentially amplifying inflammation; however, whether this pathway contributes to eccentric muscle injury remains unknown. To address this gap, we established a parameter-controlled rat model in which the gastrocnemius underwent 0, 50, 100, or 150 eccentric stretch repetitions. Muscle torque, gait, weight-bearing, endurance, pain threshold, histopathology, microcirculatory perfusion, macrophage polarization, and heme, ferrous iron, glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), and pro-inflammatory cytokine levels were assessed. Increasing repetitions produced graded functional impairment, myofiber damage, erythrocyte extravasation, inflammatory infiltration, and microcirculatory disturbance. Heme accumulation was accompanied by HO-1 upregulation in perivascular CD68-positive (CD68) macrophages, muscle iron accumulation, GSH and GPX4 depletion, elevated MDA, and increased M1 macrophage and cytokine levels. These findings suggest a potential heme-HO-1-iron-ferroptosis-associated inflammatory mechanism in eccentric muscle injury, providing a rationale for mechanistic validation and targeted therapeutic development. Keywords: Eccentric contraction-induced muscle injury; Erythrocyte extravasation; Heme oxygenase-1; Ferroptosis; Macrophage polarization
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BibTeX
@misc{liu2026erythrocyte,
title = {{Erythrocyte extravasation drives ferroptosis and inflammatory amplification in eccentric contraction-induced skeletal muscle injury via the heme-HO-1-iron axis}},
author = {M. Liu and X. Wang and Z. Liu and F. You and Q. Shen and M. Zhang and S. Chen and Y. Jing and J. Yang and Y. Wang},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.760722},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760722v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Erythrocyte extravasation drives ferroptosis and inflammatory amplification in eccentric contraction-induced skeletal muscle injury via the heme-HO-1-iron axis
AU - M. Liu
AU - X. Wang
AU - Z. Liu
AU - F. You
AU - Q. Shen
AU - M. Zhang
AU - S. Chen
AU - Y. Jing
AU - J. Yang
AU - Y. Wang
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.760722
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.760722v1
AB - Eccentric contraction-induced skeletal muscle injury is a common sports-related condition characterized by pain, impaired muscle function, slow recovery, and frequent recurrence, yet treatment remains symptomatic and mechanism-based targets are lacking. Although microvascular disruption and erythrocyte extravasation characterize severe muscle strain, the metabolic fate of extravasated erythrocytes has received little attention. In hemorrhagic and hemolytic conditions, erythrocyte-derived heme can activate heme oxygenase-1 (HO-1)-mediated iron release and ferroptosis, potentially amplifying inflammation; however, whether this pathway contributes to eccentric muscle injury remains unknown. To address this gap, we established a parameter-controlled rat model in which the gastrocnemius underwent 0, 50, 100, or 150 eccentric stretch repetitions. Muscle torque, gait, weight-bearing, endurance, pain threshold, histopathology, microcirculatory perfusion, macrophage polarization, and heme, ferrous iron, glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), and pro-inflammatory cytokine levels were assessed. Increasing repetitions produced graded functional impairment, myofiber damage, erythrocyte extravasation, inflammatory infiltration, and microcirculatory disturbance. Heme accumulation was accompanied by HO-1 upregulation in perivascular CD68-positive (CD68) macrophages, muscle iron accumulation, GSH and GPX4 depletion, elevated MDA, and increased M1 macrophage and cytokine levels. These findings suggest a potential heme-HO-1-iron-ferroptosis-associated inflammatory mechanism in eccentric muscle injury, providing a rationale for mechanistic validation and targeted therapeutic development. Keywords: Eccentric contraction-induced muscle injury; Erythrocyte extravasation; Heme oxygenase-1; Ferroptosis; Macrophage polarization
ER -