Seung-Min Lee¹, Seol Hee Lee^1,2, Youngae Jung³, Younglang Lee⁴, Jong Hyun Yoon^1,5, Jeong Yi Choi¹, Chae Young Hwang¹, Young Hoon Son¹, Sung Sup Park^1,2, Geum-Sook Hwang³, Kwang-Pyo Lee^1,2,4,* & Ki-Sun Kwon^1,4,5,*

¹Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea. ²Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Republic of Korea. ³Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea. ⁴Aventi Inc., Daejeon 34141, Republic of Korea. ⁵Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.

^*Corresponding author

Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.