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Dystrophin regulates peripheral circadian SRF signalling

Betts, Corinne A; Jagannath, Aarti; van Westering, Tirsa LE; Bowerman, Melissa; Banerjee, Subhashis; Meng, Jinhong; Falzarano, Maria Sofia; Cravo, Lara; McClorey, Graham; Meijboom, Katharina E; Bhomra, Amarjit; Fang Lim, Wooi; Rinaldi, Carlo; Counsell, John R; Chwalenia, Katarzyna; O’Donovan, Elizabeth; Saleh, Amer F; Gait, Michael J; Morgan, Jennifer E; Ferlini, Alessandra; Foster, Russell G; Wood, Matthew JA

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Authors

Corinne A Betts

Aarti Jagannath

Tirsa LE van Westering

Subhashis Banerjee

Jinhong Meng

Maria Sofia Falzarano

Lara Cravo

Graham McClorey

Katharina E Meijboom

Amarjit Bhomra

Wooi Fang Lim

Carlo Rinaldi

John R Counsell

Katarzyna Chwalenia

Elizabeth O’Donovan

Amer F Saleh

Michael J Gait

Jennifer E Morgan

Alessandra Ferlini

Russell G Foster

Matthew JA Wood



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.

Other Type Other
Acceptance Date Jun 23, 2021
Publication Date Jun 23, 2021
Publisher Cold Spring Harbor Laboratory Press
DOI https://doi.org/10.1101/2021.06.23.449492

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