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Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging-Related Muscle Weakness in Male Mice
Hikari Takeshita1, Koichi Yamamoto1, Masaki Mogi2
1Department of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita Japan.
Abstract:
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.
Insights
Mice lacking both angiotensin II type 2 receptor (AT2) and Mas receptors showed accelerated muscle aging and weakness. These findings suggest AT2 and Mas receptors work together to counteract aging processes in muscles.
Area of Science:
- Physiology
- Aging Research
- Molecular Biology
Background:
- The renin-angiotensin system (RAS) plays a role in physiological aging.
- Angiotensin II type 2 receptor (AT2) and Mas receptor activation counteract the canonical RAS.
- Previous studies showed Mas receptor deletion did not impact aging in mice.
Purpose of the Study:
- To investigate the complementary roles of AT2 and Mas receptors in aging, specifically focusing on age-related muscle weakness.
- To determine if combined deletion of AT2 and Mas receptors exacerbates aging phenotypes compared to single deletions.
Main Methods:
- Utilized male mice with single AT2 receptor deletion or double deletion of AT2 and Mas receptors.
- Assessed serial changes in grip strength up to 24 months of age.
- Analyzed skeletal muscle fiber characteristics, gene expression (RAS-associated, inflammation, senescence), and muscle angiotensin II content.
Main Results:
- Mice with double AT2/Mas receptor deletion exhibited significantly weaker grip strength from 18 months of age compared to wild-type and AT2 knockout mice.
- AT2/Mas knockout mice showed aged muscle fiber characteristics, including larger size, fewer fibers, and increased central nucleation.
- Skeletal muscles of AT2/Mas knockout mice displayed heightened expression of RAS-associated, inflammation, and senescence genes, along with increased muscle angiotensin II content.
Conclusions:
- Combined deletion of AT2 and Mas receptors exacerbates aging-related muscle weakness in mice.
- This exacerbation is linked to activated RAS, inflammation, and senescence signatures in skeletal muscles.
- AT2 and Mas receptors appear to function complementarily in preventing local RAS activation during aging.
