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

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.

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

“…In line with this, we found that muscle Mas was 3.7-fold up-regulated in 15-month-old Tsukuba hypertensive mice carrying human renin and angiotensinogen, suggesting that Mas could increase as a compensation for the chronic overload of Ang II [4]. Ang 1-7 infusion alleviated muscle dysfunction in multiple pathological conditions, including Ang II infusion [69][70][71], muscular dystrophy [72,73], disuse-induced atrophy [74,75], chronic liver disease [76], exhaustive swimming exercise [77] and cancer cachexia [78] in rodents. Most of these studies used genetic deletion [72,75] or pharmacological inhibition [69][70][71][72] of Mas to show the dependency of Mas in the Ang 1-7-induced effects on pathological muscle remodelling, while Murphy et al used muscle-specific Mas overexpression mice or a Mas agonist to show the protective effects of Mas in cancer-induced muscle wasting [78].…”

Dendrimers: Amazing Platforms for Bioactive Molecule Delivery Systems

“…Molecular dynamics simulation analysis revealed that the ability of neutral PAMAM-OH to protect Ang-(1-7) and form stable complexes. In short, the complex Ang-(1-7)/PAMAM-OH is an efficient administration method for Ang-(1-7), since it improves the anti-atrophic activity of this peptide in skeletal [123].…”

New Advances in General Biomedical Applications of PAMAM Dendrimers

“…PAMAM has also been used as an anti-atrophic agent. Márquez-Miranda and colleagues [ 58 ] have reported the application of PAMAM-G4-OH conjugated to angiotensin (1-7) (Ang-(1-7)) ( Figure 5 ) in rats to prevent skeletal atrophy associated to disuse by immobilization. The results demonstrated that PAMAM-Ang (1-7) almost fully recovered muscular fiber diameters and regulated proteins, which in an atrophic state, would be differentially regulated.…”