In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
Abstract:
Background: Skeletal muscle abnormalities such as mitochondrial dysfunction, fiber type transition, and atrophy are the main cause of reduced exercise capacity observed in various diseases such as diabetes mellitus and heart failure. Renin-angiotensin system (RAS) was activated in the skeletal muscle in these conditions. We thus hypothesized that angiotensin II (Ang II) could directly induce skeletal muscle abnormalities. Methods and Results: Ang II (1000ng/kg/min, n=8) or vehicle (saline, n=8) was administrated into male C57BL/6J mice (10-12 week of age) via subcutaneously implanted osmotic minipumps for 4 weeks. Ang II significantly decreased body weight (26.6±0.3 vs. 27.6±0.3 g, p 〈 0.05) and hind limb skeletal muscle weight compared with vehicle at 4 weeks (159±2 vs. 166±2 mg, p 〈 0.05). It also decreased myocyte cross-sectional area in the skeletal muscle at 4 weeks (1869±29 vs. 2233±46 μm2, p 〈 0.05). Muscle RING finger-1 and atrogin-1, the markers of protein degradation, were significantly increased in the skeletal muscle tissue from Ang II at 4 weeks by 133% and 102%, respectively (p 〈 0.05). In addition, cleaved caspase-3 and TUNEL positive cells were significantly increased in Ang II at 4 weeks by 2.5 and 1.4-folds, respectively (p 〈 0.05). Citrate synthase (1 week, 121±4 vs. 162±9; 4 weeks, 117±7 vs. 152±4 nmol/min/mg protein), complex I (1 week, 264±27 vs. 396±30; 4 weeks, 281±21 vs. 400±30 nmol/min/mg protein) and complex III (1 week, 321±33 vs. 508±49; 4 weeks, 347±30 vs. 503±43 nmol/min/mg protein) activities were significantly decreased in mitochondria isolated from skeletal muscle from Ang II at 1 and 4 weeks (all p 〈 0.05). NADH staining revealed that type I fiber decreased by 31% and type IIb fiber increased by 38% in Ang II at 1 week. The work (16±1 vs. 27±3 J, p 〈 0.05) and run distance (359±18 vs. 589±59 m, p 〈 0.05) evaluated by treadmill test significantly decreased in Ang II at 4 weeks. An administration of Ang II for 1 week also induced mitochondrial dysfunction, fiber type shift, and protein degradation, but did not skeletal muscle atrophy. Conclusion: Ang II could directly induce the reduction of exercise tolerance in association with the abnormalities in skeletal muscle function and structure.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.130.suppl_2.16555
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
1466401-X
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