Sirt1-Independent Rescue of Muscle Regeneration by Resveratrol in Type I Diabetes

The loss of insulin producing pancreatic beta-cells or peripheral resistance to insulin signaling causes diabetes mellitus, a terminal metabolic disorder that broadly affects organ systems ultimately leading to chronic wounds, blindness, muscle wasting and other disorders of abandoned tissue maintenance. We have recently demonstrated that in a mouse model of type I diabetes, there is a rapid decline in the regenerative capacity of muscle stem (satellite) cells due to elevated levels of myostatin; and that either insulin or inhibition of TGF-beta receptor signaling rescues muscle repair in the diabetic condition. Resveratrol (RSV) has been shown to improve energy metabolism in cases of type II diabetes, but its effects on stem cells and tissue regeneration are not well understood in a diabetic organism in general or in type I diabetes in particular. In this work, we studied the effect of RSV on the enhancement of muscle regeneration in type I diabetes. Our data demonstrate that systemic delivery of RSV to severely diabetic mice with ablated pancreatic beta-cells rescues muscle regeneration by boosting the myogenic capacity of muscle stem cells. Therefore, our results suggest that in our experimental system, RSV did not reduce the blood glucose levels (BGL) in diabetic animals and did not act through its key effector Sirt1 in the rescue of muscle regenerative capacity. Importantly, our data uncovers that muscle stem cells in diabetic animals have reduced mitochondrial membrane potential, which is restored to its healthy levels by RSV that does not act via Sirt1, based on the pharmacological and genetic data but that this boost of intracellular energy enables productive tissue repair, but RSV in an animal model of type I diabetes.