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  3. Intrinsic muscle stem cell dysfunction underlies functional deficits in models of type 1 diabetes

Intrinsic muscle stem cell dysfunction underlies functional deficits in models of type 1 diabetes

  • NPJ Regen Med. 2026 Jan 6;11(1):8. doi: 10.1038/s41536-025-00452-9.
Jin D Chung 1 2 3 4,  Jennifer Trieu 1 2,  Benjamin L Parker 1 2,  John H Nguyen 1 2,  Annabel Chee 1 2,  Audrey S Chan 1 2,  Abhirup Jayasimhan 2,  Devy Deliyanti 2,  Peter J Houweling 3 5,  Holly K Voges 3 4,  Karly C Sourris 6 7,  Richard J Mills 3 4,  Melinda T Coughlan 6 7 8,  Jennifer L Wilkinson-Berka 2,  Enzo R Porrello 9 10 11 12 13,  Gordon S Lynch 14 15
Affiliations

Affiliations

  • 1 Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia.
  • 2 Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia.
  • 3 Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.
  • 4 Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • 5 Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.
  • 6 Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, VIC, Australia.
  • 7 Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.
  • 8 Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University Parkville Campus, Parkville, VIC, Australia.
  • 9 Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia. [email protected].
  • 10 Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia. [email protected].
  • 11 Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia. [email protected].
  • 12 Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, VIC, Australia. [email protected].
  • 13 Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia. [email protected].
  • 14 Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia. [email protected].
  • 15 Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia. [email protected].
PMID: 41495072 DOI: 10.1038/s41536-025-00452-9
Abstract

Muscle function and regeneration are impaired in type 1 diabetes, but whether this arises directly from muscle stem cell (MuSC) dysfunction has not been addressed. Here, we utilized three-dimensional MuSC cultures (micromuscles) to demonstrate that hyperglycemia drives deficits in muscle stem cell function, leading to impaired force production in differentiated myotubes. The functional capacity of skeletal muscle was shown to decline after repeated bouts of injury in mouse models of type 1 diabetes, and this was replicated in micromuscles derived from MuSCs isolated from diabetic mice, indicating MuSC dysfunction was linked to poor muscle regeneration and function. The loss of force producing capacity was associated with impaired myotube hypertrophy in vitro and in vivo after injury. Furthermore, poor muscle regeneration was exacerbated by a loss of MuSC number due to aberrant activation, even in the absence of injury. Deficits in MuSC function and number could be rescued by early treatment with the glucose-lowering drug dapagliflozin, indicating that MuSC defects were driven by exposure to a hyperglycemic environment. The findings reveal that MuSC dysfunction contributes to muscle functional deficits in models of type 1 diabetes.

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