Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling
Abstract 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 e...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-022-00225-w |
| _version_ | 1811315161620807680 |
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| author | Takehito Ono Ryosuke Denda Yuta Tsukahara Takashi Nakamura Kazuo Okamoto Hiroshi Takayanagi Tomoki Nakashima |
| author_facet | Takehito Ono Ryosuke Denda Yuta Tsukahara Takashi Nakamura Kazuo Okamoto Hiroshi Takayanagi Tomoki Nakashima |
| author_sort | Takehito Ono |
| collection | DOAJ |
| description | Abstract 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-1α in 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. |
| first_indexed | 2024-04-13T11:25:13Z |
| format | Article |
| id | doaj.art-6a423d0218e3443181205c2da744d03b |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-04-13T11:25:13Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-6a423d0218e3443181205c2da744d03b2022-12-22T02:48:43ZengNature Publishing GroupBone Research2095-62312022-08-0110111410.1038/s41413-022-00225-wSimultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signalingTakehito Ono0Ryosuke Denda1Yuta Tsukahara2Takashi Nakamura3Kazuo Okamoto4Hiroshi Takayanagi5Tomoki Nakashima6Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU)Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU)Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU)Department of Biochemistry, Tokyo Dental CollegeDepartment of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of TokyoDepartment of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of TokyoDepartment of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU)Abstract 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-1α in 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.https://doi.org/10.1038/s41413-022-00225-w |
| spellingShingle | Takehito Ono Ryosuke Denda Yuta Tsukahara Takashi Nakamura Kazuo Okamoto Hiroshi Takayanagi Tomoki Nakashima Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling Bone Research |
| title | Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling |
| title_full | Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling |
| title_fullStr | Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling |
| title_full_unstemmed | Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling |
| title_short | Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling |
| title_sort | simultaneous augmentation of muscle and bone by locomomimetism through calcium pgc 1α signaling |
| url | https://doi.org/10.1038/s41413-022-00225-w |
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