Epigenetic Regulation of Muscle Regeneration in Duchenne Muscular Dystrophy

Colorized scanning electron micrograph (SEM) of muscle tissue affected by muscular dystrophy. Muscular dystrophy is a genetic disorder typified by muscle wasting and loss of function through a process called adipose metaplasia where muscle is being replaced by fat. Magnification 300x.
This study review discusses the epigenetic modifications of skeletal muscle regeneration and the interplay of factors that define epigenetic homeostasis in Duchenne muscular dystrophy.

Epigenetic modifications in muscle regeneration have an important role in Duchenne muscular dystrophy (DMD) and may serve as treatment targets aimed at increasing the regenerative potential of diseased muscles in these patients, according to a review published in Clinical Epigenetics.

Patients with DMD are often described as having muscle weakness, as well as loss of function and independence. This phenotype is dependent on the mutation site in the DMD gene and the expression profile of dystrophin.

The current review discussed the epigenetic regulation of skeletal muscle regeneration and the interplay of various factors that define the specific state of epigenetic homeostasis in health and DMD.

The progressive loss of myofibers and their ineffective regeneration in patients with DMD results in an accumulation of fibrotic and adipose tissue, leading to skeletal muscle mass loss and function. The disease may lead to diaphragm dysfunction or cardiac failure, with premature death in the 3rd or 4th decade of life.

DMD is currently incurable; treatment is aimed at symptomatic relief and is limited to corticosteroids to reduce secondary inflammatory processes in these patients. However, recent studies have shown that epigenetic mechanisms such as DNA methylation or histone modification may have an important role in regulating muscle regeneration and regenerative medicine.

Myogenesis is coordinated by a complex set of epigenetic mechanisms that include DNA methylation, histone modifications, and regulatory noncoding RNA expression. As such, targeting epigenetic modifiers is a promising pharmacological strategy for muscle diseases.

As dystrophin is associated with the serine-threonine protein kinase 2, lack of dystrophin leads to diminished levels of serine-threonine protein kinase 2 and β-syntrophin in satellite cells, decreased asymmetric divisions, and increased abnormal mitotic divisions.  

In muscles of patients with DMD, the loss of dystrophin results in partial compensatory assembly of the utrophin-based complex and other proteins and protein complexes. In neither case is the correct signal transduction functions restored.

Lack of dystrophin also causes loss of nitric oxide synthase binding sites, resulting in reduced nitric oxide signaling and reduced nitric oxide-dependent S-nitrosylation of histone deacetylase 2. Additionally, restoring nitric oxide dependent inhibition of histone deacetylase 2 was reported to have beneficial effects in dystrophic mice.

In patients with DMD, increased levels of tumor necrosis factor-alpha and nuclear factor kappa-light-chain-enhancer of activated B cells impair regenerative potential of satellite cells. Data indicated that this is linked to the epigenetic silencing of Notch-1 through hypermethylation of its promoter region.

Fibro-adipogenic progenitors have a significant role in fat deposition and fibrosis in skeletal muscle. These progenitors may serve as an important treatment target to restore the balance between skeletal muscle regeneration and degeneration in patients with DMD.

“Although further research is needed in this field, the outcome of the most recent therapeutic advances gives patients hope for a treatment that would significantly alleviate their condition,” concluded the study researchers.


Rugowska A, Starosta A, Konieczny P. Epigenetic modifications in muscle regeneration and progression of Duchenne muscular dystrophy. Clin Epigenetics. 2021 Jan 19;13(1). doi:10.1186/s13148-021-01001-z

This article originally appeared on Neurology Advisor