Skeletal muscle acts as a major organ for systemic oxidized LDL clearance via a CD36-dependent mechanism enhanced by physical exercise

Background and Purpose

Oxidized low-density lipoprotein (oxLDL) is a key driver of atherosclerosis, possessing potent pro-atherogenic bioactivity. While oxLDL primarily forms within the arterial wall, measurable levels circulate in the blood and correlate with the risk of coronary artery disease. We previously demonstrated that accelerating the systemic clearance of oxLDL prevents the progression of atherosclerosis in mice. Although the liver was traditionally considered the primary site for oxLDL clearance, our recent functional imaging using nanoSPECT/CT in unanesthetized mice revealed significant oxLDL uptake in brown adipose tissue (BAT) via the scavenger receptor CD36. This study aimed to comprehensively re-evaluate systemic oxLDL clearance pathways to identify previously overlooked regulatory mechanisms.

Methods and Results

Unanesthetized wild-type (WT) and knockout mice were intravenously administered 125I-oxLDL. Ten minutes post-injection, mice were perfusion-fixed with 4% paraformaldehyde under isoflurane anesthesia. Organs were harvested, weighed, and radioactivity was measured via gamma counting to calculate the percentage of injected dose (%ID).

In WT mice, nanoSPECT imaging confirmed intense oxLDL accumulation in the liver and BAT. Notably, while the signal intensity per unit volume appeared lower in skeletal muscle, ex vivo tissue analysis revealed that the total uptake of oxLDL in skeletal muscle was comparable to that in the liver due to the large total muscle mass. Among four major oxLDL receptors (CD36, SR-BI, SR-AI, and LOX-1), CD36 showed the highest expression in skeletal muscle. In CD36-deficient mice, oxLDL accumulation in skeletal muscle was nearly abolished, as previously seen in BAT. Furthermore, we investigated the effect of physical activity using a treadmill (10 m/min, 10° incline, 30 min). Mice in the exercise group showed a significant increase in 125I-oxLDL uptake in the quadriceps, tibialis anterior, gastrocnemius, and soleus muscles compared to sedentary controls.

Conclusions

This study identifies skeletal muscle as a major physiological site for the clearance of circulating oxLDL, rivaling the liver in total capacity. This process is mediated by the scavenger receptor CD36 and is dynamically up-regulated by physical exercise. These findings provide a novel mechanistic explanation for the anti-atherosclerotic benefits of exercise, suggesting that muscle-mediated removal of modified lipoproteins is a critical component of vascular health.figure