Duchenne muscular dystrophy (DMD) is a chronic muscle degenerative disease. Patients with DMD progressively lose their ability to ambulate and, later, to breathe, causing early death.
DMD is caused by a genetic defect that results in the disruption of the dystrophin-associated glycoprotein complex (DGC). This results in membrane instability, enhancing myofiber susceptibility to damage from mechanical stress and necrosis.
Recent studies reveal that muscle stem cells/satellite cells are also being affected in DMD. Muscle stem cells are adult stem cells that have the primary function of muscle repair.
Muscle stem cells have been studied in detail since they were discovered in 1961. There are 2 main types of studies of muscle stem cells: in vitro and in vivo. Scientists know now that muscle stem cells come from multipotent mesodermal progenitors of the embryonic dermamyotome. At later stages of embryogenesis, muscle stem cells become committed to myogenesis.
Read more about DMD etiology
Adult muscle stem cells continue to drive myogenesis in most environments. However, in aged or dystrophic muscle, there is a propensity of muscle stem cells to adopt fibrogenic phenotypes.
“Following injury to skeletal muscle, [muscle stem cells] activate and enter the cell cycle,” Wosczyna and Rando wrote in Developmental Cell. “Their rapid proliferation produces daughter cells that either self-renew to maintain the [muscle stem cell] pool or differentiate to become myoblasts for myofiber production and repair.”
There are various theories on how muscle stem cells impacted by dystrophin deficiency contribute to DMD pathology. An early theory suggests that repetitive cycles of degeneration and regeneration “exhausts” muscle stem cells, resulting in the progressive loss of their capacity to regenerate. However, a study revealed that muscle stem cells are elevated in dystrophin mouse models, seemingly contradicting this theory.
A later theory proposes that DMD muscle stem cells are not just “exhausted” but become dysfunctional and cease to contribute meaningfully to muscle repair. Studies have validated this theory; scientists have observed that DMD muscle stem cells demonstrate impaired asymmetric cell division, hallmarks of mitotic stress, and a heightened vulnerability to enter senescence. The observation that muscle stem cells express dystrophin themselves further strengthens the idea that dysfunctional muscle stem cells contribute to DMD pathology.
“DMD can therefore be described as a 2-pronged disease, wherein dystrophin deficiency-mediated satellite cell dysfunction exacerbates the disease phenotype alongside the weakening of the muscle fiber membrane,” Filippelli and Chang wrote in Cell Tissues Organs.
Restoring Muscle Stem Cell Function
The goal of current DMD treatment is to improve quality of life and extend survival by targeting all the muscles in the body. Corticosteroids such as prednisolone are typically offered to all patients with DMD since existing literature suggests they improve clinical outcomes.
However, there are 2 problems with corticosteroids. First, their exact mechanism of action in DMD patients is still unknown, although they probably play a key role in slowing the rate of muscle breakdown. Second, long-term use of corticosteroids is known to cause negative side effects such as hypertension, weight gain, and loss of bone density.
In other words, corticosteroids are not a cure, even if they are typically well-tolerated. The bigger problem is that there are no long-term treatment solutions for DMD that can substitute for existing treatment regimens.
Current research is focused on using adeno-associated vectors for gene delivery and antisense oligonucleotide for exon skipping. These genetic approaches are intended to reinstate dystrophin expression, but, crucially, they do not take muscle stem cells into account.
However, there are solutions involving muscle stem cells that are currently the subject of intense research, one of which is stem cell therapy. The goal of stem cell therapy is to regenerate damaged tissues or organs by replenishing specific stem cell populations.
“In the case of DMD, the main goal is to reconstitute the satellite cell pool with dystrophin competent cells, and thereby restore muscle function due to the presence of dystrophin expressing muscle fibers,” Sun and colleagues wrote in Experimental Neurology.
An Alternative Solution
Another proposed solution is to target muscle stem cell dysfunctions. Studies conducted using mouse models demonstrate that glycine supplementation can increase DMD satellite proliferation. It achieves this by activating the mammalian target of rapamycin complex 1 (mTORC1). In addition, glycine supplementation also enhances the efficiency of the transplantation of exogenous satellite cells in dystrophic muscles.
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A study using dystrophic mice revealed that the depletion of satellite cells might be beneficial, suggesting that they play a deleterious role in DMD pathology. Hence, eliminating dysfunctional satellite cells may improve the DMD phenotype.
“However, it is important to acknowledge that exclusively targeting satellite cells as a therapeutic strategy has limitations,” Filippelli and Chang wrote. “Disrupting the balance between satellite cell symmetric and asymmetric cell divisions has long-term consequences on the efficiency of muscle regeneration and muscle health and longevity.”
Nevertheless, it is crucial that muscle stem cell research continues because it holds great promise for DMD and a number of other muscle diseases. For example, dysfunctional muscle stem cells have been linked to muscle cancer, cachexia, and sarcopenia. A strategy to deal with dysfunctional muscle stem cells could improve clinical outcomes for patients with any of these disorders.
Sun C, Serra C, Lee G, Wagner KR. Stem cell-based therapies for Duchenne muscular dystrophy. Exp Neurol. 2020;323:113086. doi:10.1016/j.expneurol.2019.113086
Filippelli RL, Chang NC. Empowering muscle stem cells for the treatment of Duchenne muscular dystrophy. Cells Tissues Organs. 2021;1-14. doi:10.1159/000514305
Wosczyna MN, Rando TA. A muscle stem cell support group: coordinated cellular responses in muscle regeneration. Dev Cell. 2018;46(2):135-143. doi:10.1016/j.devcel.2018.06.018