Angiotensin II-induced reduction in exercise capacity is associated with increased oxidative stress in skeletal muscle

Abstract

giotensin II (ANG II)-induced oxidative stress has been known to be involved in the pathogenesis of cardiovascular diseases. We have reported that the oxidative stress in skeletal muscle can limit exercise capacity in mice (16). We thus hypothesized that ANG II could impair the skeletal muscle energy metabolism and limit exercise capacity via enhancing oxidative stress. ANG II (50 ng·kg Ϫ1 ·min Ϫ1 ) or vehicle was infused into male C57BL/6J mice for 7 days via subcutaneously implanted osmotic minipumps. ANG II did not alter body weight, skeletal muscle weight, blood pressure, cardiac structure, or function. Mice were treadmill tested, and expired gases were analyzed. The work to exhaustion (vertical distance ϫ body weight) and peak oxygen uptake were significantly decreased in ANG II compared with vehicle. In mitochondria isolated from skeletal muscle, ADP-dependent respiration was comparable between ANG II and vehicle, but ADP-independent respiration was significantly increased in ANG II. Furthermore, complex I and III activities were decreased in ANG II. NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence were significantly increased in skeletal muscle from ANG II mice. Treatment of ANG II mice with apocynin (10 mmol/l in drinking water), an inhibitor of NAD(P)H oxidase activation, completely inhibited NAD(P)H oxidase activity and improved exercise capacity, mitochondrial respiration, and complex activities in skeletal muscle. ANG II-induced oxidative stress can impair mitochondrial respiration in skeletal muscle and limit exercise capacity. mitochondria; reduced nicotinamide adenine dinucleotide phosphatase oxidase; oxygen uptake THE LIMITED EXERCISE CAPACITY represents a major symptom and an important prognostic factor in patients with cardiovascular disease and with risk factor for cardiovascular disease (19,24). The exercise capacity is generally believed to be limited in the presence of abnormalities in skeletal muscle, which include atrophy, transition of fiber type, and abnormal energy metabolism (6,26,30). The activation of renin-angiotensin system, particularly the increase in angiotensin II (ANG II), has been well established to play an important role in the pathogenesis and progression of various cardiovascular diseases (7, 15). Moreover, angiotensin-converting enzyme inhibitors have been shown to improve exercise capacity in patients with cardiovascular disease and in spontaneously hypertensive rats (5,22,34). These results suggest that ANG II may directly impair skeletal muscle function and reduce exercise capacity. However, the mechanisms by which ANG II induces skeletal muscle dysfunction remain unknown.ANG II leads to the production of superoxide (O 2 ·Ϫ ), the major reactive oxygen species (ROS), via NAD(P)H oxidase activation (2, 10). The production of O 2 ·Ϫ in skeletal muscle has been shown to be increased in the mouse model after myocardial infarction (31). In addition, our laboratory reported that the exercise capacity was decreased in heterozygous manganese ...

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

“…The observed plateau effect on gCl by ANG II is also in line with a physiological and reversible activation of a G protein-coupled phosphorylation pathway. In addition, the present results add clear evidence that the production of ROS via NOX works as fundamental part of the pathway leading to the observed reduction of gCl by ANG II in myofibers as in other experimental conditions (1,41,43,73). This is emphasized by the observation that effects of ANG II are completely antagonized by both the classical antioxidant NAC and by the NOX inhibitor apocynin, as well as by the PKC inhibitor, although the occurrence of a parallel ROSmediated signaling cannot be fully ruled out.…”

“…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).…”

“…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.…”

“…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).…”