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Here, we used cytokine antibody arrays to identify humoral factors involved in sarcopenia and found a significant increase in levels of milk fat globule epidermal growth factor 8 (MFG\u2010E8) in skeletal muscle of aged mice, compared with young mice. We found that the increase in MFG\u2010E8 protein at arterial walls and neuromuscular junctions (NMJs) in muscles of aged mice. High levels of MFG\u2010E8 at NMJs and an age\u2010related increase in arterial MFG\u2010E8 have also been identified in human skeletal muscle. In NMJs, MFG\u2010E8 is localized on the surface of terminal Schwann cells, which are important accessory cells for the maintenance of NMJs. We found that increased MFG\u2010E8 at NMJs precedes age\u2010related denervation and is more prominent in sarcopenia\u2010susceptible fast\u2010twitch than in sarcopenia\u2010resistant slow\u2010twitch muscle. Comparison between fast and slow muscles further revealed that arterial MFG\u2010E8 can be uncoupled from sarcopenic phenotype. A genetic deficiency in MFG\u2010E8 attenuated age\u2010related denervation of NMJs and muscle weakness, providing evidence of a pathogenic role of increased MFG\u2010E8. Thus, our study revealed a mechanism by which increased MFG\u2010E8 at NMJs leads to age\u2010related NMJ degeneration and suggests that targeting MFG\u2010E8 could be a promising therapeutic approach to prevent sarcopenia.<\/jats:p>","DOI":"10.1111\/acel.13536","type":"journal-article","created":{"date-parts":[[2021,12,25]],"date-time":"2021-12-25T07:06:33Z","timestamp":1640415993000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Increased MFG\u2010E8 at neuromuscular junctions is an exacerbating factor for sarcopenia\u2010associated denervation"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2771-9851","authenticated-orcid":false,"given":"Madoka","family":"Ikemoto\u2010Uezumi","sequence":"first","affiliation":[{"name":"Muscle Aging and Regenerative Medicine Tokyo Metropolitan Institute of Gerontology (TMIG)  Tokyo 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