Immobilzation-Induced Muscle Atrophy Exacerbates Vascular Calcification and Abdominal Aortic Aneurysms Through Irisin...

Sarcopenia is widely recognized that affects multiple organs, including the cardiovascular system. Clinical studies have consistently shown associations between sarcopenia and vascular aging phenotypes such as vascular calcification, atherosclerosis, and abdominal aortic aneurysms (AAA). However, the molecular mechanisms by which muscle deterioration contributes to vascular degeneration remain poorly understood.

To elucidate muscle-vascular crosstalk, we established a murine model combining inflammation-associated muscle atrophy induced by hindlimb immobilization with CaPO₄-induced AAA. Vascular degeneration was evaluated by Elastica van Gieson staining for elastic fiber integrity and von Kossa staining for calcification. The role of the muscle-derived myokine irisin was examined through recombinant irisin administration and pharmacological inhibition using the αVβ5 integrin antagonist cilengitide.

Muscle atrophy markedly accelerated vascular calcification and AAA formation in the combined model compared with AAA alone. This was accompanied by enhanced osteogenic phenotype, downregulation of the growth arrest-specific gene 6 (Gas6)/pAkt survival pathways, and pronounced inflammatory responses in the aortic wall. We found that muscle atrophy significantly reduced muscular and circulating irisin levels. Irisin administration attenuated vascular calcification and AAA progression, whereas irisin signaling inhibition exacerbated these vascular pathologies.

This study provides experimental evidence that muscle atrophy directly accelerates vascular calcification and AAA formation. We also identify irisin as a key molecular mediator linking muscle atrophy to vascular degeneration, highlighting muscle-derived signaling as a critical target for preventing vascular pathologies.