Modulation of SIRT1-Foxo1 Signaling axis by Resveratrol: Implications in Skeletal Muscle Aging and Insulin Resistance

Abstract

Aging individuals and diabetic patients often exhibit concomitant reductions of skeletal muscle mass/strength and insulin sensitivity, suggesting an intimate link between muscle aging and insulin resistance. Foxo1, a member of the FOXO transcription factor family, is an important player in insulin signaling due to its inhibitory role in glucose uptake and utilization in skeletal muscle. Phosphorylation of Foxo1 is thought to mitigate the transactivation of pyruvate dehydrogenase lipoamide kinase 4 (PDK4), which is a negative regulator of the glycolytic enzyme pyruvate dehydrogenase (PDH). In contrast, how aging would regulate acetylation/deacetylation machineries and glucose utilization in skeletal muscle through the Foxo1/PDH axis remains largely undetermined. Accumulating body of evidence have shown that resveratrol, a natural polyphenol in grapes and red wine, activates the longevity-related protein sirtuin 1 (SIRT1) and augments insulin sensitivity in addition to its well-documented effects on mitochondrial energetics. The present review summarizes the role of Foxo1/SIRT1 in insulin signaling in skeletal muscle and proposes the insight that activation of SIRT1 deacetylase activity to deacetylate and suppress the Foxo1-induced transactivation of PDK4 may represent an anti-hyperglycemic mechanism of resveratrol in aging skeletal muscle.

Post-translational modifications of FOXO family proteins

“…Resveratrol can increase the SIRT1 deacetylation activity, which reduces FOXO1 and FOXO3a acetylation and increases the nucleus localization, resulting stronger transcriptional activity. Resveratrol activates AMPK, which increases the deacetylase activity of SIRT1, and further increases the FOXO1 transcription activity (92,93). Studies have demonstrated that certain proteins form complexes with FOXO-SIRT1.…”

Schisandrae fructus enhances myogenic differentiation and inhibits atrophy through protein synthesis in human myotubes

“…[1][2][3][4][5] Search for the dietary supplements to ameliorate and maintain skeletal muscle function is becoming an important topic in antiaging research field. [49][50][51][52][53][54][55] Muscle growth starts by the activation of quiescent myoblasts (proliferation). These cells get committed to myogenic differentiation and fuse with existing muscle fibers.…”

Sirtuins and Aging: is there a Role for Resveratrol?

“…In fact heart performance decreases with age and Foxo1-related apoptotic signalling increases. A long term treatment with resveratrol improves cardiac function in senescent mice also by reducing age-induced deposition of collagen fibers [45].…”