Development of active compounds for the improvement of muscle function and metabolic syndrome

Abstract

The advantageous effects of exercise on overall health make it advisable to identify the orally active agents that improve the effects of exercise. Decreased aerobic capacity and mitochondrial oxidative phosphorylation are commonly associated with reduced longevity. We examined whether myricetin which is known to prolong lifespan in C. elegans, impacts mitochondrial function. Supplementation of mice with myricetin significantly improved their aerobic capacity, as evidenced by their enhanced running distance and time. Additionally, treatment of C. elegans with myricetin significantly improved healthspan and lifespan. These effects were associated with an induction of genes for mitochondrial biogenesis and oxidative phosphorylation and were mainly explained by an myricetin-mediated reduce in PGC-1α acetylation through enhancing SIRT1 activity. These results demonstrate that myricetin enhances mitochondrial activity, possibly by promoting SIRT1 and PGC-1α, and increases the endurance of mice, highly suggesting that myricetin is an excellent potential agent that mimics exercise. Peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) agonist as regulators of glucose and lipid metabolism has increased interest in the development of synthetic ligands as potential candidate drugs for therapeutic intervention in the metabolic syndrome and type 2 diabetes. However, some PPARα/γ dual agonists are accompanied with unwished adverse effects, including body weight gain, and tissue failure. We screened PPARα/γ dual agonists in Prestwick library, amodiaquine was shown to activate the PPARα/γ. This study examined the effects of a novel PPARα/γ dual agonist, amodiaquine, on metabolic syndromes. Amodiaquine selectively induced the transcriptional activities of PPARα and PPARγ. Amodiaquine enhanced fatty acid oxidation and glucose uptake in vitro. In high fat induced mice and genetically obese/diabetic models ob/ob and KKAy mice, amodiaquine greatly ameliorate insulin resistance, hyperlipidemia and hepatic steatosis, without body weight gain. In addition, amodiaquine would inhibit atherosclerosis in vitro by attenuating vascular smooth muscle cells (VSMC) proliferation. We demonstrate that amodiaquine shows advantageous effects on lipid and glucose metabolism by concurrent induction of both PPARα and PPARγ. Our data suggest that amodiaquine would be a new drug against obesity and related metabolic syndromes. Taken together, these studies suggest that the myricetin is a novel agent as mimics exercise and the amodiaquine can serve as a potential drug for metabolic disorders.