Elevated Extracellular Purine Nucleotides Impair Muscle Regeneration in Diabetic Mice by Suppressing Early Activation of Muscle Satellite Cells

ABSTRACT: Chronic diabetic patients often exhibit defective tissue repair. Similarly, injury-induced muscle regeneration was also found to be defective in diabetic mice. However, the underlying mechanisms remain obscure. Here, we found that quiescent muscle satellite cells (MuSC) from db/db diabetic mice, a mouse model for obesity-induced type 2 diabetes, failed to re-enter the cell cycle upon activation in vivo but not in culture, suggesting the involvement of certain niche factors. Elevated extracellular AMP (eAMP) and adenosine (eAdo) were detected in both muscle tissues and blood of diabetic patients and mice. Unexpectedly, we found that eAMP and eAdo potently inhibited cell cycle re-entry of MuSC, and consequently impaired injury-induced muscle regeneration. Mechanistically, we demonstrated that eAMP and eAdo impaired the functions of MuSC via a signaling axis of equilibrative Ado transporter (ENT)-Ado kinase (ADK)-AMPK, which in turn inhibited an mTORC1-dependent cell growth checkpoint and subsequent cell cycle re-entry. Moreover, eAdo also inhibited early activation of quiescent fibroadipogenic progenitors and human MuSC by the same mechanism. Importantly, treatment of db/db diabetic mice with an ADK inhibitor not only reduced plasma glucose level but also partially restored the regenerative functions of MuSC in vivo. Collectively, our study suggests that both ENT and ADK are promising therapeutic targets for the treatment of diabetes and for restoring the regenerative functions of tissue stem cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE175786 | GEO | 2022/05/28

REPOSITORIES: GEO