The Role of Immunity in Maintaining the Muscle Satellite Cell Niche Necessary for Satellite Cell Function in Health and in Duchenne Muscular Dystrophy

Carolina Orsi

Introduction Duchenne Muscular Dystrophy (DMD) is a genetic condition resulting from a mutation in dystrophin, which is an essential protein needed to anchor striated myofibrils to the extracellular matrix (ECM)1,3. With decreased structural stability, extensive damage results during myofibril contraction and induces vast immune and inflammatory responses within the muscle tissue1,3. Satellite cells within the ECM activate and produce dystrophin when injury occurs to begin muscle repair2,3. However, satellite cells must reside within a balanced microenvironment, or niche, in order to function properly1. Immune agents such as neutrophils, macrophages, proteasomes, and T lymphocytes infiltrate the satellite cell niche continuously in those with DMD, leading to chronic inflammation2-4. Additional research about the immune system’s influence on the satellite cell niche could aid in understanding why regeneration of muscle tissue is inefficient in dystrophic muscle. Methods Neutrophil and neutrophil-derived elastase counts were measured via immunofluorescense within mdx-mice over 3 and 7.5 month time periods to analyze their association with necrotic tissue formation in dystrophic muscle3. The mdx-mouse model was also utilized in measuring INF-γ and proteasome counts via FACS and PCR to observe their presence within dystrophic tissue versus normal tissue4. Additionally, studies used IL-10-knockout mice and IL-10-manipulated macrophages to analyze the effects of IL-10 on macrophage balance and muscle regeneration2,6. Lastly, a study utilized DMD patient blood samples to screen for the CD49d surface marker on T lymphocytes via cytofluorometry to test biomarker accuracy in predicting DMD prognosis5. Results Mdx-mice were found to have significantly higher levels of neutrophils, neutrophil-derived elastases, and necrotic tissue at 7.5 months in comparison to 3 months3. Furthermore, mdx-mice were found to have higher INF-γ and proteasome levels in comparison to wild-type mice4. Moreover, IL-10-knockout mice showed deficient ability to undergo the transition from M1 to M2 macrophages needed for tissue repair while IL-10-activated macrophages had significantly increased ability for myocyte growth2, 6. Finally, the blood samples of DMD individuals showed strong correlation between increased CD49d biomarker presence and greater muscular disability5. Conclusions Results illustrate the strong influence of immunity on the satellite cell niche and satellite cell functioning. This signifies the potential for innovative treatments in targeting immune mediators to help relieve symptoms and delay progression of DMD. In fact, there are already developments of elastase inhibitors3, proteasome inhibitors4, IL-10 therapy2,6, and specialized anti-inflammatories4 that aim to control the immune infiltrate within the satellite cell niche of striated muscle to reduce chronic inflammation in DMD.

 

  1. Zhang Y, Zhu Y, Li Y, et al. Long-term engraftment of myogenic progenitors from adipose-derived stem cells and muscle regeneration in dystrophic mice. Human Molecular Genetics. 2015; 24(21):6029-6040. doi:10.1093/hmg/ddv316.
  2. Perandini LA, Chimin P, Lutkemeyer DDS, et al. Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche? The FEBS Journal. 2018. doi:10.1111/febs.14417.
  3. Arecco N, Clarke CJ, Jones FK, et al. Elastase levels and activity are increased in dystrophic muscle and impair myoblast cell survival, proliferation, and differentiation. Scientific Reports. 2016;6(1). doi:10.1038/srep24708.
  4. Farini A, Sitzia C, Cassani B, et al. Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy. The American Society of Gene & Cell Therapy. 2016;24(11):1898-1912.
  5. Savino W, Pinto-Mariz F, Mouly V. Flow Cytometry-Defined CD49d Expression in Circulating T-Lymphocytes Is a Biomarker for Disease Progression in Duchenne Muscular Dystrophy. Methods in Molecular Biology Duchenne Muscular Dystrophy. 2017:219-227. doi:10.1007/978-1-4939-7374-3_16.
  6. Deng B, Wehling-Henricks M, Villalta SA, et al. Interleukin-10 Triggers Changes in Macrophage Phenotype that Promote Muscle Growth and Regeneration. National Institute of Health. 2012;189(7):3669-3680. doi:10.4049/jimmunol.1103180.