Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden.Physical exercise at times can be an effective remedy for frailty,but exercise the...Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden.Physical exercise at times can be an effective remedy for frailty,but exercise therapy cannot be applied in all clinical cases.Medication is safer than exercise,but there are no drugs that reinforce both muscle and bone when administered alone.Multiple medications increase the risk of adverse events;thus,there is a need for individual drugs targeting both tissues.To this end,we established a novel sequential drug screening system and identified an aminoindazole derivative,locamidazole(LAMZ),which promotes both myogenesis and osteoblastogenesis while suppressing osteoclastogenesis.Administration of this drug enhanced locomotor function,with muscle and bone significantly strengthened.Mechanistically,LAMZ induced Mef2c and PGC-1αin a calcium signaling–dependent manner.As this signaling is activated upon physical exercise,LAMZ mimics physical exercise.Thus,LAMZ is a promising therapeutic drug for locomotor diseases,including sarcopenia and osteoporosis.展开更多
基金supported in part by the Japan Society for the Promotion of Science(JSPS)the Japan Science and Technology Agency+14 种基金Daiichi Sankyo CompanyDaiichi Sankyo Foundation of Life ScienceHisamitsu PharmaceuticalJapan Rheumatism Foundationthe Life Science Foundation of JapanLotte Research Promotion GrantMeiji Yasuda Life FoundationMitsui Life Social Welfare FoundationNaito FoundationSuzuken Memorial FoundationTakeda Science FoundationThe Asahi Glass FoundationThe Sumitomo FoundationThe Uehara Memorial FoundationSecom Science and Technology Foundation(SSTF).
文摘Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden.Physical exercise at times can be an effective remedy for frailty,but exercise therapy cannot be applied in all clinical cases.Medication is safer than exercise,but there are no drugs that reinforce both muscle and bone when administered alone.Multiple medications increase the risk of adverse events;thus,there is a need for individual drugs targeting both tissues.To this end,we established a novel sequential drug screening system and identified an aminoindazole derivative,locamidazole(LAMZ),which promotes both myogenesis and osteoblastogenesis while suppressing osteoclastogenesis.Administration of this drug enhanced locomotor function,with muscle and bone significantly strengthened.Mechanistically,LAMZ induced Mef2c and PGC-1αin a calcium signaling–dependent manner.As this signaling is activated upon physical exercise,LAMZ mimics physical exercise.Thus,LAMZ is a promising therapeutic drug for locomotor diseases,including sarcopenia and osteoporosis.
