A12839 Angiotensin 1-7 functionally recovers aging-induced locomotive dysfunction, but is not associated with accelerated aging phenotypes in angiotensin-converting-enzyme 2 knockout mice

Abstract

Objectives: The angiotensin-converting enzyme 2 (ACE2)-angitotensin 1-7 (A1-7)-A1-7 receptor (Mas) axis has been shown to have a protective role in the renin-angiotensin system (RAS). We recently found that ACE2 knockout (KO) mice exhibit earlier aging-associated muscle weakness, and A1-7 restores muscle weakness in aging mice. As ACE2 has a multifunctional role outside the RAS, we investigated the dependence on the A1-7-Mas pathway in the effect of ACE2 on physiological aging including locomotive dysfunction with muscle weakness and osteoporosis in mice. Methods: Wildtype (WT), ACE2KO, and MasKO mice were subjected to periodical grip strength measurement, followed by administration of A1–7 (100 ng/kg/min) or saline for 4 weeks with an osmotic pump in 24-month-old mice. Results: ACE2KO mice exhibited decreased grip strength compared with WT mice after 6 months of age, while MasKO mice had grip strength similar to WT mice during aging. A1-7 infusion at 24 months old improved grip strength with increased muscle size in WT and ACE2KO mice but not in MasKO mice. A1–7 significantly increased bone volume in WT and ACE2KO mice, but not in MasKO mice. Histological and gene expression analysis revealed that tissue aging including skin and adipose tissue was accelerated in aging ACE2KO mice, but not in MASKO mice, compared to WT mice. Conclusion: A1-7 improves muscle weakness and osteoporosis in aged mice via a Mas-dependent pathway. In contrast, the different aging phenotypes between ACEKO and MasKO mice suggest the A1-7-independent effect of ACE2 on senescence.