Erythrocyte extravasation drives ferroptosis and inflammatory amplification in eccentric contraction-induced skeletal muscle injury via the heme-HO-1-iron axis
This study highlights a potential inflammatory mechanism in muscle injury related to erythrocyte extravasation and heme metabolism, warranting further investigation for therapeutic development.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study investigated the role of erythrocyte extravasation and associated pathways in eccentric contraction-induced skeletal muscle injury in a rat model. The researchers assessed various parameters including muscle torque, endurance, and levels of glutathione (GSH) following different repetitions of eccentric contractions. Findings indicated that increasing repetitions led to functional impairment and biochemical changes associated with inflammation and oxidative stress.
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. <h4>Keywords:</h4> Eccentric contraction-induced muscle injury; Erythrocyte extravasation; Heme oxygenase-1; Ferroptosis; Macrophage polarization
Background
Eccentric contraction-induced skeletal muscle injury is prevalent in sports, leading to pain and impaired function. Previous research has focused on symptomatic treatments, with limited understanding of underlying mechanisms. This study aims to explore the metabolic fate of extravasated erythrocytes and their potential role in muscle injury through the heme-HO-1-iron axis.
Methods
A parameter-controlled rat model was established to assess the effects of 0, 50, 100, or 150 eccentric stretch repetitions on muscle injury. Various outcomes were measured, including muscle torque, pain threshold, and levels of GSH, MDA, and pro-inflammatory cytokines. The study does not specify the exact n or duration of the experiment.
Results
Increasing eccentric stretch repetitions resulted in graded functional impairment and myofiber damage. Heme accumulation was associated with HO-1 upregulation in macrophages, depletion of GSH and GPX4, and elevated MDA levels. Specific numeric results for these findings are not provided in the abstract.
Interpretation
The findings suggest a potential inflammatory mechanism involving heme and ferroptosis in muscle injury, aligning with previous literature on muscle strain. However, the clinical significance of these findings remains uncertain due to the lack of detailed numeric outcomes and the use of a rodent model, which may limit applicability to human conditions.
Key findings
- Muscle torque decreased with increasing eccentric stretch repetitions, exact values not reported.
- GSH levels were depleted, exact values not reported.
- Heme accumulation was observed, exact values not reported.
- Increased MDA levels were noted, exact values not reported.
- Elevated M1 macrophage levels and pro-inflammatory cytokines were reported, exact values not reported.
Limitations
- Rodent model may not fully translate to humans.
- Specific numeric values for key outcomes are not reported.
- Potential confounding factors not addressed in the abstract.