Attenuation of Diabetic Cardiomyopathy by Caloric Restriction Through PGC-1α Activation

Introduction: Insulin resistance negatively impacts the diabetic heart in various ways, including impaired insulin-mediated glucose uptake and a reduction in intracellular signaling. Diabetic cardiomyopathy is independent of coronary artery disease and is characterized by extensive fibrotic changes, leading to increased myocardial stiffness and the development of diastolic dysfunction. Caloric restriction (CR) is cardioprotective mainly through its catabolic activity and increased insulin sensitivity. Peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) is a co-transcription factor that modulates thermogenesis, mitochondrial biogenesis and oxidative metabolism.

We aimed to assess biochemical, histological and functional markers of diabetic cardiomyopathy and the effect of CR on the development of diabetic cardiomyopathy.

Methods: Leptin resistant (db/db) mice suffer from obesity and diabetes. Mice were treated for 1 month with angiotensin II (ANGII) to induce severe cardiomyopathy. Mice under CR were fed 90% of their normal food intake for 2 week and 65% for additional 2 weeks. Each group consisted of 5-6 animals.

Results: CR in diabetic mice attenuated obesity and the cardiomyopathy phenotype. CR reduced body weight and heart weight in diabetic mice (33.7±7.9g vs.44 ±5.9g; 0.137±0.023g vs. 0.17±0.02g, p<0.05); and lowered blood glucose (576±167mg/dL vs 702.5±309 mg/dL, p<0.05) and reduced metabolic syndrome markers.

Echocardiography results indicated that CR attenuated the hypertrophic phenotype in the diabetic mice (LV internal diameter 3.34±0.46mm vs. 4.06±0.36mm, p=0.01).

Diabetes led to ERK1/2 activation compared to WT mice independently of ANGII (p<0.05) which was reduced under CR (p<0.05). PGC-1α expression mRNA levels were reduced by 60% in ANGII treated diabetic mice compare to non-treated diabetic mice (p=0.02) and were elevated by 240% (p=0.0008) in calorically restricted diabetic mice. The transcription factor PGC-1α protein is localized mainly in the nuclear and its levels were increased CR.

Conclusion: These results reveal the association of PGC-1α in the attenuation of diabetic cardiomyopathy under CR regiment.