In the present study, we aimed to evaluate the effect of
Sirt1,
Sirt3 and combined activation in high
fructose diet-induced
insulin resistance rat heart and assessed the cardiac function focusing on mitochondrial health and function. We administered the
Sirt1 activator;
SRT1720 (5 mg/kg, i.p.),
Sirt3 activator;
Oroxylin-A (10 mg/kg i.p.) and the combination;
SRT1720 +
Oroxylin-A (5 mg/kg and 10 mg/kg i.p.) daily from 12th week to 20th weeks of study. We observed significant perturbations of most of the cardiac structural and functional parameters in high
fructose diet-fed animals. Administration of
SRT1720 and
Oroxylin-A improved perturbed cardiac structural and functional parameters by decreasing
insulin resistance, oxidative stress, and improving mitochondrial function by enhancing mitochondrial biogenesis, OXPHOS expression and activity in high
fructose diet-induced
insulin-resistant rats. However, we could not observe the synergistic effect of
SRT1720 and
Oroxylin-A combination. Similar to in-vivo study, perturbed mitochondrial function and oxidative stress observed in
insulin-resistant H9c2 cells were improved after activation of
Sirt1 and
Sirt3. We observed that
Sirt1 activation enhances
Sirt3 expression and mitochondrial biogenesis, and the opposite effects were observed after
Sirt1 inhibition in cardiomyoblast cells. Taken together our results conclude that activation of
Sirt1 alone could be a potential therapeutic target for diabetes-associated cardiovascular complications.