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Here, we found that microgravity might induce mitochondrial protein buildup in skeletal muscle, alongside reduced levels of LONP1 protein. We revealed that disruptions in mitochondrial proteolysis, induced by the targeted skeletal muscle-specific deletion of the essential mitochondrial protease LONP1 or by the acute inducible deletion of muscle LONP1 in adult mice, cause reduced bone mass and compromised mechanical function. Moreover, the bone loss and weakness phenotypes were recapitulated in skeletal muscle-specific overexpressing \u0394OTC mice, a known protein degraded by LONP1. Mechanistically, mitochondrial proteostasis imbalance triggered the mitochondrial unfolded protein response (UPR\n                    <jats:sup>mt<\/jats:sup>\n                    ) in muscle, leading to an up-regulation of multiple myokines, including FGF21, which acts as a pro-osteoclastogenic factor. Surprisingly, this mitochondrial proteostasis stress influenced muscle\u2013bone crosstalk independently of ATF4 in skeletal muscle. Furthermore, we established a marked association between serum FGF21 levels and bone health in humans. These findings emphasize the pivotal role of skeletal muscle mitochondrial proteostasis in responding to alterations in loading conditions and in coordinating UPR\n                    <jats:sup>mt<\/jats:sup>\n                    to modulate bone metabolism.\n                  <\/jats:p>","DOI":"10.34133\/research.0465","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T08:45:47Z","timestamp":1723538747000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":11,"title":["Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss"],"prefix":"10.34133","volume":"7","author":[{"given":"Zhen","family":"Jin","sequence":"first","affiliation":[{"name":"Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital \rof Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing University, Nanjing, China."},{"name":"Division of Spine Surgery, Department of Orthopedic Surgery, \rNanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Mao","sequence":"additional","affiliation":[{"name":"Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital \rof Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital \rof Nanjing University Medical School, MOE Key Laboratory of Model Animal 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