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The complex of PAMAM-OH dendrimer with Angiotensin (1–7) prevented the disuse-induced skeletal muscle atrophy in mice

Authors Márquez-Miranda V, Abrigo J, Rivera JC, Araya-Durán I, Aravena J, Simon F, Pacheco N, González-Nilo FD, Cabello-Verrugio C

Received 23 October 2016

Accepted for publication 1 February 2017

Published 13 March 2017 Volume 2017:12 Pages 1985—1999

DOI https://doi.org/10.2147/IJN.S125521

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Alexander Kharlamov

Peer reviewer comments 2

Editor who approved publication: Dr Thomas Webster


Valeria Márquez-Miranda,1,2,* Johanna Abrigo,3,4,* Juan Carlos Rivera,3,4 Ingrid Araya-Durán,1 Javier Aravena,3,4 Felipe Simon,3,4 Nicolás Pacheco,1 Fernando Danilo González-Nilo,1,2,5 Claudio Cabello-Verrugio3,4

1Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, 2Fundación Fraunhofer Chile Research, Las Condes, 3Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello, 4Millennium Institute on Immunology and Immunotherapy, Santiago, 5Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

*These authors contributed equally to this work

Abstract: Angiotensin (1–7) (Ang-(1–7)) is a bioactive heptapeptide with a short half-life and has beneficial effects in several tissues – among them, skeletal muscle – by preventing muscle atrophy. Dendrimers are promising vehicles for the protection and transport of numerous bioactive molecules. This work explored the use of a neutral, non-cytotoxic hydroxyl-terminated poly(amidoamine) (PAMAM-OH) dendrimer as an Ang-(1–7) carrier. Bioinformatics analysis showed that the Ang-(1–7)-binding capacity of the dendrimer presented a 2:1 molar ratio. Molecular dynamics simulation analysis revealed the capacity of neutral PAMAM-OH to protect Ang-(1–7) and form stable complexes. The peptide coverage ability of the dendrimer was between ~50% and 65%. Furthermore, an electrophoretic mobility shift assay demonstrated that neutral PAMAM-OH effectively bonded peptides. Experimental results showed that the Ang-(1–7)/PAMAM-OH complex, but not Ang-(1–7) alone, had an anti-atrophic effect when administered intraperitoneally, as evaluated by muscle strength, fiber diameter, myofibrillar protein levels, and atrogin-1 and MuRF-1 expressions. The results of the Ang-(1–7)/PAMAM-OH complex being intraperitoneally injected were similar to the results obtained when Ang-(1–7) was systemically administered through mini-osmotic pumps. Together, the results suggest that Ang-(1–7) can be protected for PAMAM-OH when this complex is intraperitoneally injected. Therefore, the Ang-(1–7)/PAMAM-OH complex is an efficient delivery method for Ang-(1–7), since it improves the anti-atrophic activity of this peptide in skeletal muscle.

Keywords: muscle wasting, peptide delivery, carrier, anti-atrophic peptide

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