The complex of PAMAM-OH dendrimer with Angiotensin (1-7) prevented the disuse-induced skeletal muscle atrophy in mice.
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.
Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago; Fundación Fraunhofer Chile Research, Las Condes.
Valeria
V
Márquez-Miranda
Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello; Millennium Institute on Immunology and Immunotherapy, Santiago.
Johanna
J
Abrigo
Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello; Millennium Institute on Immunology and Immunotherapy, Santiago.
Juan Carlos
JC
Rivera
Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago.
Ingrid
I
Araya-Durán
Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello; Millennium Institute on Immunology and Immunotherapy, Santiago.
Javier
J
Aravena
Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello; Millennium Institute on Immunology and Immunotherapy, Santiago.
Felipe
F
Simon
Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago.
Nicolás
N
Pacheco
Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago; Fundación Fraunhofer Chile Research, Las Condes; Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Fernando Danilo
FD
González-Nilo
Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello; Millennium Institute on Immunology and Immunotherapy, Santiago.
Claudio
C
Cabello-Verrugio
D000803:Angiotensin I / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D050091:Dendrimers / Q000737:chemistry*; D024202:Electrophoretic Mobility Shift Assay; D007103:Immobilization; D007274:Injections, Intraperitoneal; D008297:Male; D008810:Mice, Inbred C57BL; D056004:Molecular Dynamics Simulation; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000517:prevention & control*; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D018995:Myosin Heavy Chains / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D055672:Static Electricity; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D050091:Dendrimers; D009124:Muscle Proteins; C104700:PAMAM Starburst; D010446:Peptide Fragments; D010455:Peptides; D000070584:Tripartite Motif Proteins; D000803:Angiotensin I; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D018995:Myosin Heavy Chains; C118790:angiotensin I (1-7)
anti-atrophic peptide; carrier; muscle wasting; peptide delivery