TY - JOUR
T1 - Angiotensin-(1-7) prevents lipopolysaccharide-induced autophagy via the mas receptor in skeletal muscle
AU - Rivera, Juan Carlos
AU - Abrigo, Johanna
AU - Tacchi, Franco
AU - Simon, Felipe
AU - Brandan, Enrique
AU - Santos, Robson A.
AU - Bader, Michael
AU - Chiong, Mario
AU - Cabello-Verrugio, Claudio
N1 - Funding Information:
Funding: This research was funded by the National Fund for Science and Technological Development (FONDECYT 1200944 [C.C-V.], 1201039 [F.S.]; 1190144 [E.B.]), Millennium Institute on Immunology and Immunotherapy (P09-016-F [C.C-V., F.S.]), Programa de Cooperación Científica Ecos-ANID (C16S02 [C.C-V.]), Basal grant–CEDENNA from the National Research and Development Agency (ANID), Government of Chile (AFB180001 [C.C.-V.]), and Center for Aging and Regeneration (CONICYT, AFB170005 [E.B.]). The Millennium Nucleus of Ion Channel-associated Diseases (MiNICAD) is supported by the Iniciativa Científica Milenio (ANID, Chile). J.C.R. and J.A. thanks to Conicyt for providing a Ph.D. Scholarship [21141242 and 21161353, respectively]. The APC was funded by FONDECYT 1200944.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/2
Y1 - 2020/12/2
N2 - Skeletal muscle atrophy, which occurs in lipopolysaccharide (LPS)-induced sepsis, causes a severe muscle function reduction. The increased autophagy contributes to sepsis-induced skeletal muscle atrophy in a model of LPS injection, increasing LC3II/LC3I ratio, autophagy flux, and autophagosomes. Angiotensin-(1-7) (Ang-(1-7)) has anti-atrophic effects via the Mas receptor in skeletal muscle. However, the impact of Ang-(1-7) on LPS-induced autophagy is unknown. In this study, we determined the effect of Ang-(1-7) on sepsis-induced muscle autophagy. C57BL6 wild-type (WT) mice and mice lacking the Mas receptor (KO Mas) were injected with LPS together with the systemic administration of Ang-(1-7) to determine autophagy in skeletal muscle. We also evaluated autophagy and p38 and c-Jun N-terminal kinase (JNK)activation. Our results show that Ang-(1-7) prevents LPS-induced autophagy in the diaphragm, tibialis anterior, and gastrocnemius of WT mice, which is demonstrated by a decrease in the LC3II/LC3I ratio and mRNA levels of lc3b and ctsl. This effect was lost in KO Mas mice, suggesting the role of the Mas receptor. The results in C2C12 cells show that Ang-(1-7) reduces several LPS-dependent effects, such as autophagy (LC3II/LC3I ratio, autophagic flux, and autophagosomes), activation of p38 and JNK, B-cell lymphoma-2 (BCL2) phosphorylation, and disassembly of the Beclin1/BCL2 complex. In conclusion, Ang-(1-7)/Mas receptor reduces LPS-induced autophagy in skeletal muscle. In vitro assays indicate that Ang-(1-7) prevents LPS-induced autophagy and modifies the MAPK signaling and the disassembly of a complex involved at the beginning of autophagy.
AB - Skeletal muscle atrophy, which occurs in lipopolysaccharide (LPS)-induced sepsis, causes a severe muscle function reduction. The increased autophagy contributes to sepsis-induced skeletal muscle atrophy in a model of LPS injection, increasing LC3II/LC3I ratio, autophagy flux, and autophagosomes. Angiotensin-(1-7) (Ang-(1-7)) has anti-atrophic effects via the Mas receptor in skeletal muscle. However, the impact of Ang-(1-7) on LPS-induced autophagy is unknown. In this study, we determined the effect of Ang-(1-7) on sepsis-induced muscle autophagy. C57BL6 wild-type (WT) mice and mice lacking the Mas receptor (KO Mas) were injected with LPS together with the systemic administration of Ang-(1-7) to determine autophagy in skeletal muscle. We also evaluated autophagy and p38 and c-Jun N-terminal kinase (JNK)activation. Our results show that Ang-(1-7) prevents LPS-induced autophagy in the diaphragm, tibialis anterior, and gastrocnemius of WT mice, which is demonstrated by a decrease in the LC3II/LC3I ratio and mRNA levels of lc3b and ctsl. This effect was lost in KO Mas mice, suggesting the role of the Mas receptor. The results in C2C12 cells show that Ang-(1-7) reduces several LPS-dependent effects, such as autophagy (LC3II/LC3I ratio, autophagic flux, and autophagosomes), activation of p38 and JNK, B-cell lymphoma-2 (BCL2) phosphorylation, and disassembly of the Beclin1/BCL2 complex. In conclusion, Ang-(1-7)/Mas receptor reduces LPS-induced autophagy in skeletal muscle. In vitro assays indicate that Ang-(1-7) prevents LPS-induced autophagy and modifies the MAPK signaling and the disassembly of a complex involved at the beginning of autophagy.
KW - Autophagy
KW - LPS
KW - Muscle wasting
KW - Renin-angiotensin system
UR - http://www.scopus.com/inward/record.url?scp=85097566782&partnerID=8YFLogxK
U2 - 10.3390/ijms21249344
DO - 10.3390/ijms21249344
M3 - Article
C2 - 33302427
AN - SCOPUS:85097566782
SN - 1661-6596
VL - 21
SP - 1
EP - 18
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 24
M1 - 9344
ER -