Dystrophin could play the role of a mediator in circadian signaling in peripheral tissues, according to a new study published in Life Science Alliance.
This link between dystrophin and the circadian clock opens up new avenues for the development of therapies for diseases characterized by the lack of functional dystrophin protein, such as Duchenne muscular dystrophy (DMD) and other muscular dystrophies.
For example, light augmentation could be an appropriate therapy for patients with DMD to unmask the central clock, according to the authors of the study.
In DMD, mutations in the DMD gene lead to cells not producing functional dystrophin protein. Dystrophin normally binds to filamentous-(F)-actin, an integral part of the RhoA-actin-serum-response-factor-(SRF) pathway. SRF is a transcription factor that regulates the expression of more than 200 genes. Most of these genes play a role in cell growth and migration, cytoskeletal organization, and myogenesis. DMD was one of the first genes regulated by SRF to be identified.
The SRF pathway also plays a crucial role in circadian rhythm, the 24-hour endogenous molecular clock that regulates the timing of many physiological and behavioral processes, such as sleep-wake cycles, body temperature, feeding, and hormone production. Therefore, a disruption in SRF signaling also disrupts the circadian clock.
Because the SRF pathway operates in a feedback loop, a lack of dystrophin can have serious implications in terms of SRF regulation.
In order to investigate whether the loss of dystrophin leads to circadian deficits, a team of researchers led by Matthew JA Wood in the United Kingdom used dystrophin-deficient myotubes and dystrophic mouse models. They showed that the RhoA-actin-SRF-signaling pathway was indeed disrupted in these models.
More specifically, the researchers showed that the F/globular (G)-actin ratios were reduced, levels of myocardin-related transcription factor (MRTF) were altered, core-clock and downstream target-genes were dysregulated, and key circadian genes were downregulated in muscle biopsies from patients with DMD.
Finally, the researchers showed that dystrophin was absent in the suprachiasmatic nucleus, the site of the core clock, in dystrophic mice. These animals displayed disrupted circadian rhythms, which is indicative of disrupted circadian signaling.
The authors concluded, “dystrophin is an important component of the RhoA-actin-SRF pathway and novel mediator of circadian signaling in peripheral tissues, loss of which leads to circadian dysregulation.”
Betts CA, Jagannath A, van Westering TLE, et al. Dystrophin involvement in peripheral circadian SRF signalling. Life Sci Alliance. Published online August 13, 2021. doi:10.26508/lsa.202101014