Betts, C, Jagannath, A, van Westering, TLE, Bowerman, M, Banerjee, S, Meng, J, Falzarano, MS, Cravo, L, McClorey, G, Meijboom, K, Bhomra, A, Lim, WF, Rinaldi, C, Counsell, J, Chwalenia, K, O’Donovan, E, Saleh, A, Gait, M, Morgan, J, Ferlini, A, Foster, R and Wood, MJA (2021) Dystrophin regulates peripheral circadian SRF signalling. BioRxiv.

[thumbnail of 1341_2_merged_1627550395.pdf]
Preview
Text
1341_2_merged_1627550395.pdf - Accepted Version

Download (2MB) | Preview

Abstract

Dystrophin is a sarcolemmal protein essential for muscle contraction and maintenance, absence of which leads to the devastating muscle wasting disease Duchenne muscular dystrophy (DMD)[1, 2]. Dystrophin has an actin-binding domain [3–5], which specifically binds and stabilises filamentous (F)-actin[6], an integral component of the RhoA-actin-serum response factor (SRF)-pathway[7]. The RhoA-actin-SRF-pathway plays an essential role in circadian signalling whereby the hypothalamic suprachiasmatic nucleus, transmits systemic cues to peripheral tissues, activating SRF and transcription of clock target genes[8, 9]. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised that dystrophin loss causes circadian deficits. Here we show for the first time alterations in the RhoA-actin-SRF-signalling-pathway, in both dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios and nuclear MRTF, dysregulation of core clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from DMD patients harbouring an array of mutations. Further, disrupted circadian locomotor behaviour was observed in dystrophic mice indicative of disrupted SCN signalling, and indeed dystrophin protein was absent in the SCN of dystrophic animals. Dystrophin is thus a critically important component of the RhoA-actin-SRF-pathway and a novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.

Item Type: Article
Additional Information: All information regarding this AAM can be found on the publisher website.
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > School of Medicine
Depositing User: Symplectic
Date Deposited: 12 Jan 2023 11:42
Last Modified: 12 Jan 2023 11:42
URI: https://eprints.keele.ac.uk/id/eprint/11833

Actions (login required)

View Item
View Item