Depletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy

Review by Meriem Matouk

Satellite cell (SC) activation is deleterious in mouse models of muscular dystrophy through the activation of MyoD, which is responsible for the expression of genes known to weaken sarcolemmal stability.

Publication: Nature communication, 26 May 2022
https://pubmed.ncbi.nlm.nih.gov/35618700/

https://pubmed.ncbi.nlm.nih.gov/35618700/

Summary

Satellite cells (SC) are required for postnatal muscle growth and muscle regeneration, notably in the context of muscular dystrophies (MD), suggesting a pivotal role of SCs for disease mitigation. Contrary to this commonly held view on SC function in MDs, Boyer et al. reported the opposite effect in mouse models for delta-sarcoglycanopathy and Duchenne muscular dystrophy: depletion of SCs improved histopathological signs and muscle function.

The authors showed that depletion of SC led to a complete lack of muscle regeneration. Such lack in regeneration caused a loss in muscle mass, however, remaining fibers became hypertrophic. Strikingly, markers for fiber necrosis and muscle fibrosis decreased. Moreover, residual muscle improved its resistance to force drop following eccentric contractions, and mice increased their capacity for down-hill treadmill running. Boyer et al. explored the underlying molecular mechanism and showed that expression of the myogenic transcription factor MyoD increased in regenerating muscle. MyoD, in turn, upregulated expression of developmental genes and genes required for myoblast fusion that are known to weaken sarcolemmal stability. In consequence, overexpression of MyoD worsened, while MyoD inhibition improved the muscle dystrophic phenotype.

Taken together, these results suggest that presence of satellite cells and myofiber regeneration weakens sarcolemmal stability thereby causing vicious cycles of de- and regeneration that contribute to the dystrophic process.

About the first author: Justin G Boyer

During his PhD studies while working in the laboratory of Dr. Rashmi Kothary at the University of Ottawa, Dr. Boyer developed a passion for regenerative medicine related to neuromuscular diseases. His doctoral work focused on defining intrinsic muscle defects in the neurodegenerative disease Spinal Muscular atrophy. In 2013, Dr. Boyer joined the laboratory of Dr. Jeff Molkentin as a postdoctoral fellow at the Cincinnati Children’s Hospital Medical Center. There, he moved up the ranks becoming a junior Faculty member in the Department of Pediatrics in 2019 as well as a Muscular Dystrophy Association Fellow. Dr. Boyer’s research primarily focused on uncovering new skeletal muscle biology and disease mechanisms related to the muscular dystrophies using mouse genetics.  Currently, Dr. Boyer is Clinical Reviewer in the Office of Clinical Trials at Health Canada.

About the reviewer: Meriem Matouk

I obtained my first master's degree in biotechnology in 2019, in Algeria. In 2021, I earned a second master's degree in experimental therapies at the Sorbonne Paris Nord University in France. I first worked in immunology before becoming passionate about myology. I joined the team of Pr Helge Amthor at the University of Versailles Saint-Quentin-en-Yvelines as a PhD student. I study the role of dystrophin and the dystrophin-associated protein complex (DAPC) in fiber compartmentalization and in the satellite cell niche using different dystrophin and satellite cell reporter mouse lines.