Elevated extracellular adenosine under diabetic conditions impairs adult muscle stem cells.

What is it about?

Both diabetic patients and diabetic mice are known to have impaired tissue regeneration. Elevated levels of extracellular adenosine (eAdo) were detected in both blood and tissues of diabetic patients and diabetic mice. Here, we showed that elevated eAdo potently inhibits cell cycle re-entry of quiescent adult muscle stem cells (MuSCs) upon activation and injury-induced muscle regeneration. Mechanistically, eAdo engages the equilibrative Ado transporters (ENTs)-Ado kinase (ADK)-AMPK signaling axis in MuSCs to inhibit an mTORC1-dependent cell growth checkpoint during early activation of quiescent MuSCs. eAdo also inhibits cell cycle re-entry of quiescent fibroadipogenic progenitors (FAPs) and human MuSCs by the same mechanism. Treatment of freshly-isolated quiescent MuSCs or FAPs in culture with inhibitors for ENT or ADK largely restores the ability of these cells to re-enter the cell cycle even in the presence of eAdo. Moreover, treatment of db/db diabetic mice with an ADK inhibitor also partially rescues the activation defects of MuSCs in vivo. Thus, both ADK and ENTs represent potential therapeutic targets for restoring the defective regenerative functions of tissue stem cells in patients with diabetes.

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Photo by David Moruzzi on Unsplash

Photo by David Moruzzi on Unsplash

Why is it important?

The levels of extracellular purine nucleotides including adenosine (eAdo) are elevated under conditions that involve chronic inflammation and tissue damage. The impact of eAdo on adult muscle stem cells (MuSCs) has never been addressed. We show in this study that eAdo impairs the regenerative functions of adult quiescent MuSCs in both mouse and human by preventing them from re-entering the cell cycle upon activation. We identified key cellular proteins including the equilibrative Ado transporters (ENTs) and Ado kinase (ADK) in MuSCs that mediate the pathogenic effect of eAdo. Pharmacological inhibition of ENTs or ADK restores the ability of adult MuSCs to undergo activation and cell cycle re-entry in response to injury even in the presence of high levels of eAdo, which makes ENTs and ADK promising cellular targets to restore the defective functions of adult stem cells under pathological conditions like diabetes.