Abstract 17034: Deletion of NAD(P)H Oxidase 2 Attenuates Angiotensin II-induced Skeletal Muscle Atrophy
Introduction: Skeletal muscle atrophy is observed in aging and a variety of diseases including chronic obstructive pulmonary disease, chronic renal failure, and heart failure. It has been considered that it is associated with chronic inflammation in the skeletal muscle. We have previously reported that angiotensin II (Ang II) could directly induce skeletal muscle abnormalities including atrophy in mice.
Hypothesis: Here, we hypothesized that the activation of NAD(P)H oxidase by Ang II induced the skeletal muscle atrophy.
Methods: Either saline (vehicle) or Ang II (1000 ng/kg/min) was infused into male wild-type (WT) and Nox2 knock out (KO) mice via subcutaneously implanted osmotic minipumps for 4 weeks. Experiments were performed in following 4 groups; WT+vehicle (n=8), KO+vehicle (n=6), WT+Ang II (n=8), and KO+Ang II (n=6). Lower skeletal muscle limbs were removed and used for the analysis. Exercise capacity was measured by using treadmill test.
Results: Increased activation of NAD(P)H oxidase and production of superoxide in the skeletal muscle by Ang II were completely inhibited in KO mice. Body and skeletal muscle weight, and myocyte cross sectional area were significantly decreased in WT+Ang II compared to WT+vehicle (24±1 vs. 28±1 g, 356±3 vs. 390±4 mg, and 2351±84 vs. 3221±118 μm2, respectively). These changes were significantly attenuated in KO+Ang II (27±1 g, 392±9 mg, 3012±150 μm2, respectively) Phospho-Akt and phospho-p70S6K, key molecule of protein synthesis, were decreased in WT+Ang II compared to WT+vehicle, which was attenuated in KO+Ang II. On the other hand, protein expressions of Muscle RING Finger-1 and MAFbx/Atrogin-1, key molecule of protein degradation, were significantly increased in WT+Ang II compare to WT+vehicle, which was not affected in KO+Ang II. Mitochondrial electron transfer complex and citrate synthase activities were also impaired in WT+Ang II and were not improved in KO+Ang II. In agreements with these results, exercise, Ang II-induced reduction in exercise capacity was not improved in KO mice.
Conclusions: The deletion of Nox2 attenuated the skeletal muscle atrophy and decreased protein synthase induced by Ang II, suggesting that Nox2 plays an essential role in the development of skeletal muscle atrophy.
Author Disclosures: T. Kadoguchi: None. S. Kinugawa: None. S. Takada: None. A. Fukushima: None. T. Furihata: None. W. Mizushima: None. J. Matsumoto: None. M. Tsuda: None. T. Yokota: None. S. Matsushima: None. K. Okita: None. H. Tsutsui: None.
- © 2015 by American Heart Association, Inc.