Betts, CA, Jagannath, A, van Westering, TLE, Bowerman, M ORCID: https://orcid.org/0000-0002-3579-6403, Banerjee, S, Meng, J, Falzarano, MS, Cravo, L, McClorey, G, Meijboom, KE, Bhomra, A, Lim, WF, Rinaldi, C, Counsell, JR, Chwalenia, K, O’Donovan, E, Saleh, AF, Gait, MJ, Morgan, JE, Ferlini, A, Foster, RG and Wood, MJA (2021) Dystrophin involvement in peripheral circadian SRF signalling. Life Science Alliance, 4 (10). e202101014 - e202101014.

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Abstract

Absence of dystrophin, an essential sarcolemmal protein required for muscle contraction, leads to the devastating muscle-wasting disease Duchenne muscular dystrophy. Dystrophin has an actin-binding domain, which binds and stabilises filamentous-(F)-actin, an integral component of the RhoA-actin-serum-response-factor-(SRF) pathway. This pathway plays a crucial role in circadian signalling, whereby the suprachiasmatic nucleus (SCN) transmits cues to peripheral tissues, activating SRF and transcription of clock-target genes. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised dystrophin loss causes circadian deficits. We show for the first time alterations in the RhoA-actin-SRF-signalling pathway, in dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios, altered MRTF levels, dysregulated core-clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from Duchenne patients harbouring an array of mutations. Furthermore, we show dystrophin is absent in the SCN of dystrophic mice which display disrupted circadian locomotor behaviour, indicative of disrupted SCN signalling. Therefore, dystrophin is an important component of the RhoA-actin-SRF pathway and novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.

Item Type: Article
Additional Information: This is the final published version (version of record). It was first published online via Life Science Alliance, LLC at http://doi.org/10.26508/lsa.202101014 - please refer to any applicable terms of use of the publisher.
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Depositing User: Symplectic
Date Deposited: 20 Aug 2021 09:50
Last Modified: 20 Aug 2021 09:55
URI: https://eprints.keele.ac.uk/id/eprint/9919

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