Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice.
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 (Vo(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 Vo(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.
Yokota
Takashi
T
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.
Kinugawa
Shintaro
S
Hirabayashi
Kagami
K
Matsushima
Shouji
S
Inoue
Naoki
N
Ohta
Yukihiro
Y
Hamaguchi
Sanae
S
Sobirin
Mochamad A
MA
Ono
Taisuke
T
Suga
Tadashi
T
Kuroda
Satoshi
S
Tanaka
Shinya
S
Terasaki
Fumio
F
Okita
Koichi
K
Tsutsui
Hiroyuki
H
D000818:Animals; D019069:Cell Respiration / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology*; D004041:Dietary Fats / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D006334:Heart Function Tests; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D005082:Physical Exertion / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism
D004041:Dietary Fats; D013481:Superoxides; D019255:NADPH Oxidases; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III