Abstract: FR-PO224

Unfolded Protein Responses Potentiated Uremic Sarcopenia through Perturbation of Myoblast Differentiation

Session Information

Category: Cell Biology

  • 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation

Authors

  • Jheng, Jia-Rong, National Taiwan University, College of Medicine, Taipei, Taiwan
  • Chen, Yuan-Siao, National Taiwan University, College of Medicine, Taipei, Taiwan
  • Chiang, Chih-Kang, National Taiwan University, College of Medicine, Taipei, Taiwan
  • Liu, Shing-Hwa, National Taiwan University, College of Medicine, Taipei, Taiwan
Background

Sarcopenia is the age-related degeneration characterized with the decline of skeletal muscle mass, strength, and mobility. The imbalance of protein synthesis and degradation which jeopardizes immune, hormone regulation, and muscle-motor neuron connection is the main cause of sarcopenia. There are limited knowledge regarding molecular mechanism of sarcopeia. As the endoplasmic reticulum (ER) is the control center of the protein syntheses and degradation, we hypothesized that ER stress and unfolded protein response (UPR) are important causes of sarcopenia. Understanding the sarcopenia molecular mechanisms may benefit the therapeutic diagnosis and treatment in the future.

Methods

Mouse myoblast C2C12 cells are exposed to designated time and concentration of indoxyl sulfate (IS). The proliferation, differentiation, and myotube atrophy are examined. The protein and mRNA expression of IS treated C2C12 cells are inspected to distinguish the role of ER stress and oxidative stress underlying the sarcopenia.

Results

IS inhibits myoblast differentiation. We demonstrate that number of multi-nuclei myotube decreased, the differentiation markers including myoD, myoG, and myosin heavy chain are also suppressed. IS inhibits myoblast proliferation and induces the myotubular atrophy marker atrogin 1 protein expression. IS stimulates eIF2α phosphorylation and XBP1 mRNA splicing in UPR. Interestingly, the oxidative stress is related to eIF2α phosphorylation but not XBP1 mRNA splicing. The eIF2α phosphorylation triggered by IS reduces myoD, myoG and myosin heavy chain protein expression, which is the antimyogenic modulation on the early differentiation event. The XBP1 mRNA splicing induced by IS, however, is considered the late differentiation event which is a promyogenic modulation— an adaptive response.

Conclusion

Our studies indicated that the ER stress and UPR modulation are critical both in sarcopenia and the CKD uremic toxin accumulation model. We believe that UPR-related molecules showed great potential in clinical application.

Funding

  • Government Support - Non-U.S.