Impact of angiotensin II on skeletal muscle metabolism and function in mice: Contribution of IGF-1, Sirtuin-1 and PGC-1α

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

“…RAS and ANG II might be involved in skeletal muscle wasting and regeneration impairment, via ROS production, activation of ubiquitinmediated protein degradation, and interference with metabolism and insulin-like growth factor I signaling (41,43,50,63,73). Accordingly, a role of RAS in heart and skeletal muscle damage in muscular dystrophy has been proposed (13,14,70).…”

“…Importantly, ANG II via AT 1 receptor activates canonical G q protein PLC/PKC signaling, which also leads to activation of NADPH-oxidase (NOX) in most of the tissues where AT 1 receptors are expressed. This pathway accounts for production of reactive oxygen species (ROS) and activation of redoxsensitive cellular process, including the regulation of ionic homeostasis, as in renal podocytes (1,41,43,63). Activation of NOX in skeletal muscle by systemic ANG II has also been observed, and overexpression of NOX is responsible of oxidative stress occurring in dystrophic muscle (41,43,50,73,74).…”

“…ANG II is known for its actions in cardiovascular system and its involvement in heart disease; however, it has been claimed that ANG II exerts prooxidant, proinflammatory, and profibrotic action in several tissues, among which is skeletal muscle (13,69,73). Increasing evidence supports a key role of enhanced activation of systemic and local renin-angiotensin system (RAS) and ANG II in aberrant remodeling and wasting conditions of skeletal muscle, including muscular dystrophy (13,41,43,70). Other than in microvasculature, the presence of ANG II receptors type 1 (AT 1 ) and 2 (AT 2 ) in myofibers and muscle cell lines has been described, although controversy is still unresolved about the role of these tissue receptors in mediating the ANG II actions in mature skeletal muscle (41,43,45,69,78).…”

“…Increasing evidence supports a key role of enhanced activation of systemic and local renin-angiotensin system (RAS) and ANG II in aberrant remodeling and wasting conditions of skeletal muscle, including muscular dystrophy (13,41,43,70). Other than in microvasculature, the presence of ANG II receptors type 1 (AT 1 ) and 2 (AT 2 ) in myofibers and muscle cell lines has been described, although controversy is still unresolved about the role of these tissue receptors in mediating the ANG II actions in mature skeletal muscle (41,43,45,69,78). Importantly, ANG II via AT 1 receptor activates canonical G q protein PLC/PKC signaling, which also leads to activation of NADPH-oxidase (NOX) in most of the tissues where AT 1 receptors are expressed.…”

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…The relation between RAS and sirtuins was confirmed by later work showing that telmisartan, an ARB that functions as a partial agonist of PPAR-␥, improved insulin sensitivity in obese db/db mice fed a high-fat diet through a PPAR-␥-independent pathway, and at least in part by upregulating the skeletal muscle AMPK/SIRT1 pathway (375). Also, in ANG II-treated mice, cardiac insulin resistance and hypertrophy were mediated by ANG II-induced reduction in SIRT3 levels (291), the loss of skeletal muscle force by increases in NAD(P)H oxidase expression, and the subsequent ROS-induced downregulation of IGF-I, PGC-1␣, and SIRT1 (199). In ANG II-treated human umbilical vein endothelial cells, the ACE inhibitor zofenoprilat inhibited superoxide production, cell apoptosis, and NF-kB activation and reverted SIRT1 downregulation; importantly, zofenoprilat downregulated AT 1 R protein expression through SIRT1 (268).…”