Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice
Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin‐(1‐7), respectively, is the primary process that counteracts activation of the canonical renin‐angiotensin system (RAS). Although inhibition of canonical RAS could delay the progress...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.021030 |
| _version_ | 1828046306726117376 |
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| author | Hikari Takeshita Koichi Yamamoto Masaki Mogi Yu Wang Yoichi Nozato Taku Fujimoto Serina Yokoyama Kazuhiro Hongyo Futoshi Nakagami Hiroshi Akasaka Yoichi Takami Yasushi Takeya Ken Sugimoto Masatsugu Horiuchi Hiromi Rakugi |
| author_facet | Hikari Takeshita Koichi Yamamoto Masaki Mogi Yu Wang Yoichi Nozato Taku Fujimoto Serina Yokoyama Kazuhiro Hongyo Futoshi Nakagami Hiroshi Akasaka Yoichi Takami Yasushi Takeya Ken Sugimoto Masatsugu Horiuchi Hiromi Rakugi |
| author_sort | Hikari Takeshita |
| collection | DOAJ |
| description | Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin‐(1‐7), respectively, is the primary process that counteracts activation of the canonical renin‐angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging‐related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild‐type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS‐associated genes, inflammation‐associated genes, and senescence‐associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging‐associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging‐associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging. |
| first_indexed | 2024-04-10T18:24:27Z |
| format | Article |
| id | doaj.art-553dd448b1d244648ed1c40ad46f723a |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-10T18:24:27Z |
| publishDate | 2021-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-553dd448b1d244648ed1c40ad46f723a2023-02-02T06:18:05ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802021-07-01101310.1161/JAHA.120.021030Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male MiceHikari Takeshita0Koichi Yamamoto1Masaki Mogi2Yu Wang3Yoichi Nozato4Taku Fujimoto5Serina Yokoyama6Kazuhiro Hongyo7Futoshi Nakagami8Hiroshi Akasaka9Yoichi Takami10Yasushi Takeya11Ken Sugimoto12Masatsugu Horiuchi13Hiromi Rakugi14Department of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Pharmacology Ehime University Graduate School of Medicine Ehime JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanDepartment of Molecular Cardiovascular Biology and Pharmacology Ehime University Graduate School of Medicine Ehime JapanDepartment of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita JapanBackground The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin‐(1‐7), respectively, is the primary process that counteracts activation of the canonical renin‐angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging‐related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild‐type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS‐associated genes, inflammation‐associated genes, and senescence‐associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging‐associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging‐associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.https://www.ahajournals.org/doi/10.1161/JAHA.120.021030agingangiotensin II type 2 receptorMas receptormusclerenin‐angiotensin system |
| spellingShingle | Hikari Takeshita Koichi Yamamoto Masaki Mogi Yu Wang Yoichi Nozato Taku Fujimoto Serina Yokoyama Kazuhiro Hongyo Futoshi Nakagami Hiroshi Akasaka Yoichi Takami Yasushi Takeya Ken Sugimoto Masatsugu Horiuchi Hiromi Rakugi Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease aging angiotensin II type 2 receptor Mas receptor muscle renin‐angiotensin system |
| title | Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice |
| title_full | Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice |
| title_fullStr | Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice |
| title_full_unstemmed | Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice |
| title_short | Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice |
| title_sort | double deletion of angiotensin ii type 2 and mas receptors accelerates aging related muscle weakness in male mice |
| topic | aging angiotensin II type 2 receptor Mas receptor muscle renin‐angiotensin system |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.021030 |
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