RT Journal Article SR Electronic T1 Dystrophin involvement in peripheral circadian SRF signalling JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101014 DO 10.26508/lsa.202101014 VO 4 IS 10 A1 Corinne A Betts A1 Aarti Jagannath A1 Tirsa LE van Westering A1 Melissa Bowerman A1 Subhashis Banerjee A1 Jinhong Meng A1 Maria Sofia Falzarano A1 Lara Cravo A1 Graham McClorey A1 Katharina E Meijboom A1 Amarjit Bhomra A1 Wooi Fang Lim A1 Carlo Rinaldi A1 John R Counsell A1 Katarzyna Chwalenia A1 Elizabeth O’Donovan A1 Amer F Saleh A1 Michael J Gait A1 Jennifer E Morgan A1 Alessandra Ferlini A1 Russell G Foster A1 Matthew JA Wood YR 2021 UL https://www.life-science-alliance.org/content/4/10/e202101014.abstract AB 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.