Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice

Takashi Yokota, Shintaro Kinugawa, Kagami Hirabayashi, Shouji Matsushima, Naoki Inoue, Yukihiro Ohta, Sanae Hamaguchi, Mochamad A. Sobirin, Taisuke Ono, Tadashi Suga, Satoshi Kuroda, Shinya Tanaka, Fumio Terasaki, Koichi Okita, Hiroyuki Tsutsui

Research output: Contribution to journalArticlepeer-review

110 Citations (Scopus)


Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (V̇O 2). The work (vertical distance X body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak V̇O 2. Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.

Original languageEnglish
Pages (from-to)H1069-H1077
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3
Publication statusPublished - Sept 2009

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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