title: Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1-7) through a p38 MAPK-dependent mechanism.
abstract: Skeletal muscle atrophy induced during sepsis syndrome produced by endotoxin in the form of LPS (lipopolysaccharide), is a pathological condition characterized by the loss of strength and muscle mass, an increase in MHC (myosin heavy chain) degradation, and an increase in the expression of atrogin-1 and MuRF-1 (muscle-specific RING-finger protein 1), two ubiquitin E3 ligases belonging to the ubiquitin-proteasome system. Ang-(1-7) [Angiotensin-(1-7)], through its Mas receptor, has beneficial effects in skeletal muscle. We evaluated in vivo the role of Ang-(1-7) and Mas receptor on the muscle wasting induced by LPS injection into C57BL/10J mice. In vitro studies were performed in murine C2C12 myotubes and isolated myofibres from EDL (extensor digitorum longus) muscle. In addition, the participation of p38 MAPK (mitogen-activated protein kinase) in the Ang-(1-7) effect on the LPS-induced muscle atrophy was evaluated. Our results show that Ang-(1-7) prevents the decrease in the diameter of myofibres and myotubes, the decrease in muscle strength, the diminution in MHC levels and the induction of atrogin-1 and MuRF-1 expression, all of which are induced by LPS. These effects were reversed by using A779, a Mas antagonist. Ang-(1-7) exerts these anti-atrophic effects at least in part by inhibiting the LPS-dependent activation of p38 MAPK both in vitro and in vivo. We have demonstrated for the first time that Ang-(1-7) counteracts the skeletal muscle atrophy induced by endotoxin through a mechanism dependent on the Mas receptor that involves a decrease in p38 MAPK phosphorylation. The present study indicates that Ang-(1-7) is a novel molecule with a potential therapeutic use to improve muscle wasting during endotoxin-induced sepsis syndrome.
authors.affiliation: Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Morales
authors.affiliation: Laboratorio de Reparación Tisular y Células Troncales Adultas, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Hugo
authors.initials: H
authors.lastname: Olguín
authors.affiliation: Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Di Capua
authors.affiliation: Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFAB, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
authors.affiliation: Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile and Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Simon
authors.affiliation: Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile claudio.cabello@unab.cl.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cabello-Verrugio
mesh_terms: D000704:Analysis of Variance; D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009210:Myofibrils / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D011897:Random Allocation; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000150:complications; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014665:Vasodilator Agents; D000803:Angiotensin I; C559132:March8 protein, mouse; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; C118790:angiotensin I (1-7)
keywords: Mas receptor; angiotensin-(1–7); lipopolysaccharide; renin–angiotensin system; sepsis syndrome; skeletal muscle atrophy