ACE2 is augmented in dystrophic skeletal muscle and plays a role in decreasing associated fibrosis.
Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease and is characterized by absence of the cytoskeletal protein dystrophin, muscle wasting, and fibrosis. We previously demonstrated that systemic infusion or oral administration of angiotensin-(1-7) (Ang-(1-7)), a peptide with opposing effects to angiotensin II, normalized skeletal muscle architecture, decreased local fibrosis, and improved muscle function in mdx mice, a dystrophic model for DMD. In this study, we investigated the presence, activity, and localization of ACE2, the enzyme responsible for Ang-(1-7) production, in wild type (wt) and mdx skeletal muscle and in a model of induced chronic damage in wt mice. All dystrophic muscles studied showed higher ACE2 activity than wt muscle. Immunolocalization studies indicated that ACE2 was localized mainly at the sarcolemma and, to a lesser extent, associated with interstitial cells. Similar results were observed in the model of chronic damage in the tibialis anterior (TA) muscle. Furthermore, we evaluated the effect of ACE2 overexpression in mdx TA muscle using an adenovirus containing human ACE2 sequence and showed that expression of ACE2 reduced the fibrosis associated with TA dystrophic muscles. Moreover, we observed fewer inflammatory cells infiltrating the mdx muscle. Finally, mdx gastrocnemius muscles from mice infused with Ang-(1-7), which decreases fibrosis, contain less ACE2 associated with the muscle. This is the first evidence supporting ACE2 as an important therapeutic target to improve the dystrophic skeletal muscle phenotype.
Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile.
Cecilia
C
Riquelme
Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile.
María José
MJ
Acuña
Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile.
Javiera
J
Torrejón
Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile.
Daniela
D
Rebolledo
Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile.
Daniel
D
Cabrera
Department of Physiology and Biophysics, Biological Sciences Institute, INCT Nanobio-far, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Robson A
RA
Santos
Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile.
Enrique
E
Brandan
D000803:Angiotensin I / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D010446:Peptide Fragments; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)