Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice

Abstract

We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3 mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, FLED I vehicle, and HFD+pioglitazone (n=10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND I vehicle group. Pioglitazone normalized the insulin levels in RED fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP dependent mitochondrial respiration, complex l and Ill activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondria! function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus. (C) 2014 Elsevier B.V. All rights reserved

Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice

“…MI was established by ligating the left coronary artery as described previously (Fukushima et al, 2014;Kinugawa et al, 2000). Sham operation without ligation of the coronary artery was also performed.…”

“…The plasma renin activity level was determined using a SensoLyte 520 Renin Assay Kit (AnaSpec Inc., San Jose, CA). The plasma angiotensin (Ang) II level was measured by using an enzyme immunoassay (EIA) kit (Phoenix Pharmaceuticals Inc., Burlingame, CA) as previously described (Fukushima et al, 2014).…”

“…Blood glucose levels were determined using a glucometer (Glutest Ace R; Sanwa Kagaku Kenkyusho, Nagoya, Japan) (Takada et al, 2014). Data are shown as a percent change in blood glucose levels after insulin load.…”

“…GAPDH (Cell Signaling Technology) was used as an internal control to normalize the results and to control for blot-to-blot variation. Translocation of GLUT4 was also measured by the methods described previously (Fukushima et al, 2014;Mohammad et al, 2006). In short, subcellular membrane fractions were prepared by sequential differential centrifugation.…”

“…We previously reported that insulin resistance was induced in experimental HF in mice (Ohta et al, 2011), and a later study showed that this induction was accompanied by increased local angiotensin II (Ang II) in the skeletal muscle and subsequent NAD(P)H oxidase-derived oxidative stress (Fukushima et al, 2014). In addition, the recent discovery of a (pro)renin receptor for renin and its precursor, prorenin, raises the possibility that these components of RAS may play significant pathophysiological roles in the insulin resistance of rats with high fructose diet-induced diabetes or in post-infarct HF mice (Fukushima et al, 2014;Nagai et al, 2009). …”