Renin-Angiotensin System: An Old Player with Novel Functions in Skeletal Muscle Claudio Cabello-Verrugio, 1 Mar´ ıa Gabriela Morales, 1 Juan Carlos Rivera, 1 Daniel Cabrera, 2 and Felipe Simon 3,4 1 Laboratorio de Biolog´ ıa y Fisiopatolog´ ıa Molecular, Departamento de Ciencias Biol ´ ogicas, Facultad de Ciencias Biol ´ ogicas & Facultad de Medicina, Universidad Andres Bello, Santiago, Chile 2 Departamento de Ciencias Qu´ ımicas y Biol ´ ogicas, Universidad Bernardo O´Higgins, Santiago, Chile 3 Laboratorio de Fisiopatolog´ ıa Integrativa, Departamento de Ciencias Biol ´ ogicas, Facultad de Ciencias Biol ´ ogicas & Facultad de Medicina, Universidad Andres Bello, Santiago, Chile 4 Millennium Institute on Immunology and Immunotherapy, Santiago, Chile Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21343  Abstract: Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy- associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin- converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1–7 [Ang (1–7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. C  2015 Wiley Periodicals, Inc. Med. Res. Rev., 00, No. 00, 1–26, 2015 Key words: angiotensin II; angiotensin (1–7); skeletal muscle; insulin resistance; atrophy; fibrosis Contract grant sponsor: Association-Franc ¸ aise Contre Les Myopathies; Contract grant numbers: AFM 16670; Contract sponsor: FONDECYT; Contract grant numbers: 1120380, 3130593, 3140396, and 1121078; Contract grant sponsor: Millennium Institute on Immunology and Immunotherapy; Contract grant numbers: P09–016-F and UNAB-DI-281–13/R. Correspondence to: Claudio Cabello-Verrugio, Laboratorio de Biolog´ ıa y Fisiopatolog´ ıa Molecular, Departamento de Ciencias Biol ´ ogicas, Facultad de Ciencias Biol ´ ogicas & Facultad de Medicina, Universidad Andres Bello, Av. Republica 239, 8370146 Santiago, Chile. E-mail: claudio.cabello@unab.cl Medicinal Research Reviews, 00, No. 00, 1–26, 2015 C  2015 Wiley Periodicals, Inc.