Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK

Abstract

The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Inhibiting the cAMP effector protein Epac prevents SRT1720 from activating AMPK or Sirt1 in myotubes. Moreover, SRT1720 does not increase mitochondrial function or improve glucose tolerance in AMPKα2 knockout mice. Interestingly, weight loss induced by SRT1720 is not sufficient to improve glucose tolerance. Therefore, contrary to current belief, the metabolic effects produced by SRT1720 require AMPK, which can be activated independently of Sirt1.

Sirt1 inhibits HG-induced endothelial injury: Role of Mff-based mitochondrial fission and F‑actin homeostasis-mediated cellular migration

“…The results showed that the expression of Sirt1 was significantly reduced at the protein and mRNA levels in the diabetic mice. A previous study showed that the loss of Sirt1 contributed to glucose metabolic abnormalities in diabetics (35). To examine the role of Sirt1 in the glucose metabolic activities observed in diabetic mice, SRT1720, an activator of Sirt1, was used to reactivate Sirt1 in the diabetic mice.…”

Sirtuin activators and inhibitors: Promises, achievements, and challenges

“…Several Sirtuin isoforms appear to bear potential for being used as therapeutic targets, but to date only modulators of SIRT1 have entered into the clinic. The natural STAC resveratrol suffered from low bioavailability and potency, and - like early synthetic STACs such as SRT1720 – from limited target specificity (Pirola and Frojdo, 2008; Huber et al, 2010; Nguyen et al, 2013b; Park et al, 2017). This review will concentrate on a SIRT1 inhibitor and novel synthetic SIRT1 activators with superior properties that have advanced into the clinic.…”

In vitro experimental models for examining the skeletal muscle cell biology of exercise: the possibilities, challenges and future developments

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