Angiotensin 1-7 alleviates aging-associated muscle weakness and bone loss, but is not associated with accelerated aging in ACE2-knockout mice

Clin Sci (Lond). 2019 Sep 24;133(18):2005-2018. doi: 10.1042/CS20190573. Print 2019 Sep 30.

Abstract

The angiotensin-converting enzyme 2 (ACE2)-angiotensin 1-7 (A1-7)-A1-7 receptor (Mas) axis plays a protective role in the renin-angiotensin system (RAS). We recently found that ACE2 knockout (ACE2KO) mice exhibit earlier aging-associated muscle weakness, and that A1-7 alleviates muscle weakness in aging mice. In the present study, we investigated the role of the A1-7-Mas pathway in the effect of ACE2 on physiological aging. Male wild-type, ACE2KO, and Mas knockout (MasKO) mice were subjected to periodical grip strength measurement, followed by administration of A1-7 or vehicle for 4 weeks at 24 months of age. ACE2KO mice exhibited decreased grip strength after 6 months of age, while grip strength of MasKO mice was similar to that of wild-type mice. A1-7 improved grip strength in ACE2KO and wild-type mice, but not in MasKO mice. Muscle fibre size was smaller in ACE2KO mice than that in wild-type and MasKO mice, and increased with A1-7 in ACE2KO and WT mice, but not in MasKO mice. Centrally nucleated fibres (CNFs) and expression of the senescence-associated gene p16INK4a in skeletal muscles were enhanced only in ACE2KO mice and were not altered by A1-7. ACE2KO mice, but not MasKO mice, exhibited thinning of peripheral fat along with increased adipose expression of p16INK4a A1-7 significantly increased bone volume in wild-type and ACE2KO mice, but not in MasKO mice. Our findings suggest that the impact of ACE2 on physiological aging does not depend on the endogenous production of A1-7 by ACE2, while overactivation of the A1-7-Mas pathway could alleviate sarcopenia and osteoporosis in aged mice.

Keywords: Angiotensin 1-7; Angiotensin Converting Enzyme 2; Mas receptor; Muscle weakness; osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / pathology
  • Aging / pathology*
  • Angiotensin I / pharmacology
  • Angiotensin I / therapeutic use*
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Body Weight / drug effects
  • Bone Resorption / complications
  • Bone Resorption / drug therapy*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Forelimb / physiopathology
  • Gene Deletion
  • Hand Strength
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Weakness / complications
  • Muscle Weakness / diagnostic imaging
  • Muscle Weakness / drug therapy*
  • Muscles / diagnostic imaging
  • Muscles / drug effects
  • Muscles / pathology
  • Organ Size / drug effects
  • PAX3 Transcription Factor / metabolism
  • Peptide Fragments / pharmacology
  • Peptide Fragments / therapeutic use*
  • Peptidyl-Dipeptidase A / deficiency*
  • Peptidyl-Dipeptidase A / metabolism
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / metabolism
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / metabolism
  • Renin-Angiotensin System / drug effects
  • Time Factors

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • PAX3 Transcription Factor
  • Peptide Fragments
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)