Muscle satellite cells are impaired in type 2 diabetic mice by elevated extracellular adenosine

Area of Science:

• Biomedical Science
• Stem Cell Biology
• Metabolic Disease Research

Background:

• Muscle regeneration is impaired in diabetic conditions, but the specific molecular mechanisms are not fully understood.
• Adult quiescent muscle stem cells (MuSCs) from diabetic mice show defective in vivo activation, suggesting extrinsic niche factors are involved.
• Elevated extracellular adenosine (eAdo) and extracellular AMP (eAMP) are observed in diabetes and impact cellular functions.

Purpose of the Study:

• To elucidate the mechanisms by which diabetic conditions impair muscle stem cell activation and regeneration.
• To investigate the role of extracellular adenosine and AMP in inhibiting MuSC activation and muscle repair.
• To identify potential therapeutic targets for restoring muscle regeneration in diabetes.

Main Methods:

• Utilized leptin-receptor-deficient (db/db) diabetic mice to study muscle stem cell behavior in vivo and in vitro.
• Measured extracellular adenosine and AMP levels in diabetic conditions.
• Investigated the signaling pathways involved, including equilibrative nucleoside transporters (ENTs), adenosine kinase (ADK), AMPK, and mTORC1.
• Administered an ADK inhibitor to diabetic mice to assess rescue of MuSC activation defects.

Main Results:

• Quiescent MuSCs from db/db diabetic mice exhibited impaired early activation in vivo, but not in culture.
• Elevated eAdo and eAMP were detected in diabetic conditions and were found to inhibit MuSC cell cycle re-entry and muscle regeneration.
• eAdo and eAMP activate the ENTs-ADK-AMPK signaling axis in MuSCs, inhibiting the mTORC1-dependent cell growth checkpoint.
• This mechanism also inhibited the activation of fibroadipogenic progenitors and human MuSCs.
• Treatment with an ADK inhibitor partially restored MuSC activation in db/db mice.

Conclusions:

• Extracellular adenosine and AMP are key inhibitory factors contributing to defective muscle regeneration in diabetes.
• The ENTs-ADK-AMPK-mTORC1 signaling axis is a critical pathway mediating these inhibitory effects on muscle stem cells.
• Adenosine kinase (ADK) and equilibrative nucleoside transporters (ENTs) are promising therapeutic targets for enhancing muscle stem cell regenerative capacity in diabetic patients.