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Post-translational Protein Modification Regulates Muscle Satellite Cell Function

Review of "O‐GlcNAc transferase is required to maintain satellite cell function" from STEM CELLS by Stuart P. Atkinson

The post-translational O‐GlcNAcylation of proteins serves as a nutrient sensor that guides cell functionality [1]; furthermore, O‐GlcNAcylation represents a critical regulator of skeletal muscle metabolic homeostasis. Interestingly, studies have linked high-level O‐GlcNAcylation to insulin resistance, while the complete loss of muscle O‐GlcNAcylation protects animals against high fat diet‐induced obesity and insulin resistance [2, 3]. Furthermore, increased O‐GlcNAcylation levels through the disruption of O‐GlcNAcase (OGA) expression impairs myogenesis in vitro [4] and induces muscle atrophy in vivo [5].

Given the established importance of O‐GlcNAcylation to muscle and whole‐body glucose and metabolic homeostasis, researchers from the laboratory of David E. Gerrard (Virginia Tech, Blacksburg, VA, USA) explored the potential links between adult skeletal muscle stem cells (or satellite cells) and O‐GlcNAcylation levels. Writing in a recent STEM CELLS article [6], Zumbaugh et al. report that O‐GlcNAcylation plays a critical role in maintaining satellite cell health and function in both normal and injured skeletal muscle.

The authors began their study by creating a mouse model that permitted the conditional ablation of O‐GlcNAc transferase (OGT) in satellite cells to abolish the O‐GlcNAcylation modification. Studies following chemically‐induced muscle injury in vivo revealed that satellite cells lacking OGT possessed an impaired ability to repair muscle damage, leading to reduced muscle weights, and displayed a lack of self-renewal capacity.

Further long-term in vivo lineage tracing studies under normal physiological conditions suggested that the loss of OGT inhibited satellite cell cycling, which prompts a reduction in the satellite cell pool over time. A combination of in vivo, in vitro, and ex vivo proliferation assays provided proof that satellite cells require OGT for activation and/or proliferation. The authors suggest that the loss of OGT may inhibit cell expansion via host‐cell factor 1 (HCF1)‐mediated cell cycle arrest, which would prompt the loss of the satellite cell pool.

Overall, these data provide the first proof that the O‐GlcNAcylation post-translational protein modification represents a critical regulator of the function of both quiescent and activated satellite cells, thereby compromising their ability to support homeostasis and repair adult muscle after injury. The authors hope to now extend their findings into additional adult stem cell types, which may aid the development of strategies to improve adult stem cell longevity and their ability to repair injured tissues.

For more on O‐GlcNAcylation, satellite cells, and muscle repair, stay tuned to the Stem Cells Portal!

References

  1. Butkinaree C, Park K, and Hart GW, O-linked β-N-acetylglucosamine (O-GlcNAc): Extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress. Biochimica et Biophysica Acta (BBA) - General Subjects 2010;1800:96-106.
  2. McClain DA, Lubas WA, Cooksey RC, et al., Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proceedings of the National Academy of Sciences 2002;99:10695.
  3. Shi H, Munk A, Nielsen TS, et al., Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity. Molecular Metabolism 2018;11:160-177.
  4. Ogawa M, Mizofuchi H, Kobayashi Y, et al., Terminal differentiation program of skeletal myogenesis is negatively regulated by O-GlcNAc glycosylation. Biochimica et Biophysica Acta (BBA) - General Subjects 2012;1820:24-32.
  5. Huang P, Ho S-R, Wang K, et al., Muscle-specific overexpression of NCOATGK, splice variant of O-GlcNAcase, induces skeletal muscle atrophy. American Journal of Physiology-Cell Physiology 2010;300:C456-C465.
  6. Zumbaugh MD, Geiger AE, Luo J, et al., O-GlcNAc transferase is required to maintain satellite cell function. STEM CELLS 2021;39:945-958.