Jordan Bonifacio

Background: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive dystrophinopathy. More specifically, DMD is caused by a mutation in Dp427m, which is the form of dystrophin specific to muscle.¹ Regarding the clinical presentation, the disease has an early onset beginning around age three, exhibiting severe progressive muscle weakness and muscular degradation.¹ On a molecular level, those with DMD exhibit a significant reduction in the processes of mitophagy and autophagy, two cellular repair mechanisms tasked with clearing cellular debris.^2,3 Current treatments available are physical therapy and glucocorticoids, which aim to alleviate symptoms but not the root cause of the disease, as DMD currently has no cure.² However, in attempts to target the mechanisms of autophagy and mitophagy, new prospective treatments were explored including: autophagy rescue through supplementation of urolithin A and the transsulfuration pathway.^2,3 Both experiments showed promising results in the rescue of autophagy and mitophagy, suggesting that novel, more effective treatments for DMD could be possible in the near future.^2,3

Objective: In this review, our goal is to investigate the mechanisms of autophagy and mitophagy and how they play a role in the pathogenesis of DMD.

Search Methods: All information presented was retrieved through the PubMed database filtered based on studies conducted in the last 5 years related to the search term “duchenne muscular dystrophy.”

Results: In mice models with DMD (mdx mice) that exhibited a reduction in autophagy, a reduction in hydrogen sulfide was also noted. This led to a possible connection to the transsulfuration pathway (TSP), as hydrogen sulfide is a key product.² In order to assess if there was a true correlation between the metabolic pathway and DMD pathogenesis, specifically autophagy, mice models were given sodium hydrosulfide treatment.² The sodium hydrosulfide was utilized as a hydrogen sulfide donor to ameliorate the previously exhibited reduction.² Gene expression of TSP and autophagy genes was quantified through PCR and showed a significant reduction in the mdx mice.² Moreover, PCR was performed following sodium hydrosulfide treatment, which successfully showed rescue of autophagy gene expression.² Additionally, these treated mice exhibited reduced inflammation and muscle function restoration.² In a separate study, a similar goal of rescuing mitophagy and autophagy was enacted through the supplementation of a natural metabolite known as urolithin A, an activator to these metabolic processes.³ This treatment did not see much significance with the process of autophagy, but successfully restored mitophagy, leading to muscle stem cell activation.³

Conclusions: Studies have shown that the processes of autophagy and mitophagy play a key role in mitigating pathogenesis of DMD.^2,3 Specifically, studies surrounding autophagy and mitophagy rescue through urolithin A supplementation and targeted treatment of the transsulfuration pathway showed promising results.^2,3 Although these studies exhibited success, these potential treatments would still only be prospective adjunct therapies to the current regimen of glucocorticoids.^2,3

Work Cited:

1. Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. Published 2021 Feb 18. doi:10.1038/s41572-021-00248-3
2. Panza E, Vellecco V, Iannotti FA, et al. Duchenne’s muscular dystrophy involves a defective transsulfuration pathway activity. Redox Biol. 2021;45:102040. doi:10.1016/j.redox.2021.102040
3. Luan P, D’Amico D, Andreux PA, et al. Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy. Sci Transl Med. 2021;13(588):eabb0319. doi:10.1126/scitranslmed.abb0319
4. Cardone N, Taglietti V, Baratto S, et al. Myopathologic trajectory in Duchenne muscular dystrophy (DMD) reveals lack of regeneration due to senescence in satellite cells. Acta Neuropathol Commun. 2023;11(1):167. Published 2023 Oct 19. doi:10.1186/s40478-023-01657-z
5. Bhattarai S, Li Q, Ding J, et al. TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy. Nat Commun. 2022;13(1):879. Published 2022 Feb 15. doi:10.1038/s41467-022-28531-1