Caloric Restriction Attenuates Cardiomyopathy in Diabetic Mice through the Activation of SIRT1, PGC-1α HO-1 axis

Diabetes mellitus (DM) leads to cardiomyopathy, aggravated in the presence of hypertension. Caloric restriction (CR) is cardioprotective through increased insulin sensitivity, activation of autophagy and antiinflammtory activity. PGC-1α is a transcriptional coactivator that modulates mitochondrial biogenesis and oxidative metabolism. We aimed to assess the effect of CR on the development of cardiomyopathy in DM as related to activation of SIRT1, PGC-1α and HO-1 signalling pathway.

Obese diabetic db/db mice, 14-16 week old were treated with, angiotensin II (AT) for 4 weeks to induce cardiomyopathy. Mice were concomitantly treated with CR (65% of calories) or fed ad libitum.

Only AT treated db/db mice developed cardiomyopathy along with elevated serum glucose, FFA, and cholesterol and oxidative stress marker (MDA). Hearts developed left ventricular hypertrophy with preserved fractional shortening. Leukocytes infiltration, fibrosis and an increase in inflammatory markers (TNFα) and ANP gene expression was observed in AT treated db/db mice hearts. MDA elevation was associated with reduction in SIRT1, HO-1 and PGC-1α levels. Signaling pathways investigation demonstrated that DM led to ERK1/2 activation compared to WT mice, which was independent of AT (p<0.05). CR attenuated all these markers and prevented the development of cardiomyopathy. ERK1/2 phosphorylation and PARP-1 activity were reduced in CR treated mice (p=0.008). CR normalized the reduction in SIRT activity, PGC-1α mRNA and HO-1 protein level (p<0.04). Cardiomyocytes, exposed to different concentration of glucose, treated with HO-1 inhibitor (SnMP) exhibited a marked reduction of SIRT1 and PGC-1α (p<0.03) indicating a cross-talk between these mediatotors. Contrary, induction of HO-1 by CoPP augmented these proteins.

CR attenuated the development of cardiomyopathy in diabetic mice. The results of this study reveal the link between SIRT1, PGC-1α and HO-1 signalling in diabetic cardiomyopathy. CR or pharmacological targeting of PGC-1α and HO-1 may facilitate the development of novel therapies for cardiomyopathy in diabetes.