Deciphering the Role of IGFBP5 in Delaying Fibrosis and Sarcopenia in Aging Skeletal Muscle: Therapeutic Implications and Molecular Mechanisms

Luze Shi ^* Yaying Sun ^* Jiwu Chen ^*

• Shanghai First People's Hospital, Shanghai, China

The interplay between muscle atrophy and fibrosis is central to sarcopenia, a condition characterized by the loss of muscle fibers and excessive deposition of extracellular matrix proteins, particularly collagen. This study investigates the role of D-galactose (D-gal) in inducing cellular senescence and skeletal muscle fibrosis, both in cellular and animal models. We found that D-gal effectively induces cellular senescence and skeletal muscle fibrosis, with increased senescence markers and fibrosisrelated proteins, and a decline in muscle strength and mass. Sequencing analysis revealed substantial alterations in mRNA expression, with IGFBP5 identified as a potential regulator of skeletal muscle fibrosis. Overexpression of IGFBP5 in senescent skeletal muscle fibroblasts and its association with elevated fibrosis markers suggest its potential as a therapeutic target. Our in vivo experiments in SAMP8 mice with knockdown of IGFBP5 showed improved muscle strength and a reduction in fibrosis, indicating that IGFBP5 may regulate fibrosis through IGF-1. We also observed a balance between IGF-1 and TGF-β, suggesting that IGFBP5 could affect skeletal muscle aging and fibrosis by mediate these factors. These findings provide new insights into age-related skeletal muscle fibrosis and potential molecular targets for therapeutic strategies aimed at improving muscle function and quality of life in the elderly.