The clock regulator Bmal1 protects against muscular dystrophy

Gao, Hongbo; Xiong, Xuekai; Lin, Yayu; Chatterjee, Somik; Ma, Ke

doi:10.1016/j.yexcr.2020.112348

Cited by 17 publications

(31 citation statements)

References 35 publications

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“…Circadian clock modulates key stem cell behaviors in tissue remodeling processes involving epidermal, intestinal stem cells or myogenic progenitors (Chatterjee et al, 2013; Chatterjee et al, 2019; Chatterjee et al, 2014; Karpowicz et al, 2013; Plikus et al, 2013). Clock function is required for coordinating stem cell activation with environmental stimuli (Janich et al, 2011), and clock components, Bmal1 and Rev-erbα, exert antagonistic roles in muscle stem cell proliferation and differentiation during muscle regeneration (Chatterjee et al, 2013; Chatterjee et al, 2019; Chatterjee et al, 2014; Gao et al, 2020). Stem cell quiescence and self-renewal properties are intimately linked with its physical niche environment (McBeath et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Actin cytoskeleton signaling via MRTF/SRF entrains circadian clock

Xiong

Nam

et al. 2022

Preprint

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The circadian clock is entrained to daily environmental cues. Integrin-linked intracellular signaling via actin cytoskeleton dynamics transduces extracellular matrix interactions to Myocardin-related Transcription Factor (MRTF)/Serum Response Factor (SRF)-mediated transcription. Actin cytoskeleton organization in liver displays diurnal oscillations and SRF-MRTF activity exert transcriptional control to entrain clock. By interrogating disparate upstream events involved in actin cytoskeleton-MRTF-A/SRF signaling cascade, here we show that this signaling cascade transduce cellular niche cues to modulate circadian clock function. Pharmacological inhibitions of MRTF-A/SRF, by disrupting actin polymerization or blocking ROCK kinase, induced period lengthening with augmented clock amplitude, and genetic loss-of-functions of Srf or Mrtf-a mimic that of actin-depolymerizing agents. In contrast, actin-polymerization induced by Jasplakinolide shortened period with attenuated amplitude. In addition, interfering with cell-matrix interaction through blockade of integrin, inhibition of focal adhesion kinase or attenuating matrix rigidity led to reduced period length while enhancing amplitude. Mechanistically, we identify that core clock repressors, Per2, Nr1d1, and Nfil3, are direct transcriptional targets of MRTF-A/SRF in mediating actin dynamic-induced clock response. Collectively, our findings defined an integrin-actin cytoskeleton-MRTF/SRF pathway in linking clock entrainment with extracellular microenvironment that may facilitate cellular adaptation to its physical niche.Summary statementOur study revealed the role of actin cytoskeleton-MRTF/SRF signaling in entraining circadian clock to its extracellular physical niche environment.

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Section: Discussionmentioning

confidence: 99%

Actin cytoskeleton signaling via MRTF/SRF entrains circadian clock

Xiong

Nam

et al. 2022

Preprint

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“…The master clock transcription activator, ARNT-like 1 (BMAL1), which shows a clear upregulation trend in the muscle of both exercised mdx mice and patients, has a very important role in muscle, not only by participating in the maintenance of muscle mass but also in fiber regeneration. Indeed, genetic ablation of BMAL1 in engineered injured muscle significantly impairs fiber regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction (Chatterjee et al, 2015) and, specifically in mdx mice, it was demonstrated that the loss of Bmal1 aggravates the disease phenotype by increasing creatin kinase levels and injury areas and decreasing muscular force (Hongbo et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Circadian Genes as Exploratory Biomarkers in DMD: Results From Both the mdx Mouse Model and Patients

et al. 2021

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Duchenne muscular dystrophy (DMD) is a rare genetic disease due to dystrophin gene mutations which cause progressive weakness and muscle wasting. Circadian rhythm coordinates biological processes with the 24-h cycle and it plays a key role in maintaining muscle functions, both in animal models and in humans. We explored expression profiles of circadian circuit master genes both in Duchenne muscular dystrophy skeletal muscle and in its animal model, the mdx mouse. We designed a customized, mouse-specific Fluidic-Card-TaqMan-based assay (Fluid-CIRC) containing thirty-two genes related to circadian rhythm and muscle regeneration and analyzed gastrocnemius and tibialis anterior muscles from both unexercised and exercised mdx mice. Based on this first analysis, we prioritized the 7 most deregulated genes in mdx mice and tested their expression in skeletal muscle biopsies from 10 Duchenne patients. We found that CSNK1E, SIRT1, and MYOG are upregulated in DMD patient biopsies, consistent with the mdx data. We also demonstrated that their proteins are detectable and measurable in the DMD patients’ plasma. We suggest that CSNK1E, SIRT1, and MYOG might represent exploratory circadian biomarkers in DMD.

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“…Hair follicle stem cell activation was gated by circadian clock to protect against genotoxic stress during regeneration (34), while intestinal stem cell regeneration was found to be regulated by clock genes in Drosophila or murine models (35,40). Our previous studies demonstrated that clock regulators, Bmal1 and Rev-erbα, plays antagonistic roles in muscle regeneration by modulating muscle stem cell proliferation and differentiation in response to injury (36)(37)(38)41). Stem cell quiescence and self-renewal properties are intimately linked with its physical niche environment (42).…”

Section: Discussionmentioning

confidence: 99%

Integrin signalingviaactin cytoskeleton activates MRTF/SRF to entrain circadian clock

Xiong

et al. 2021

Preprint

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The circadian clock is entrained to daily environmental cues. Integrin-linked intracellular signaling via actin cytoskeleton dynamics transduces cellular niche signals to induce Myocardin-related Transcription Factor (MRTF)/Serum Response Factor (SRF)-mediated transcription. So far, how the integrin-associated signaling cascade may transmit cellular physical cues to entrain circadian clock remains to be defined. Using combined pharmacological and genetic approaches, here we show that the transcription factors mediating integrin to actin cytoskeleton signaling, MRTF-A and SRF, exert direct transcriptional control of core clock components, and that this signaling cascade modulates key properties of clock circadian activity. Pharmacological inhibition of MRTF/SRF activity by disrupting actin polymerization significantly augmented clock amplitude with period shortening , whereas an actin polymerizing compound attenuated oscillation amplitude with period lengthening. Genetic loss-of-function of Srf or Mrtf mimics that of actin-depolymerizing agents, validating the role of actin dynamics in driving clock function. Furthermore, integrin-mediated focal adhesion with extracellular matrix and its downstream signaling modulates the circadian clock, as blockade of integrin, focal adhesion kinase or Rho-associated kinase (ROCK) increased clock amplitude and shortened period length. Mechanistically, we identify specific core clock transcription regulators, Per1 , Per2 and Nr1d1 , as direct target genes of MRTF-A/SRF. Collectively, our findings uncovered an integrin-actin cytoskeleton-MRTF/SRF signaling cascade in linking clock entrainment to its extracellular microenvironment, which may mediate cellular adaptation to its physical niche.

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The clock regulator Bmal1 protects against muscular dystrophy

Cited by 17 publications

References 35 publications

Actin cytoskeleton signaling via MRTF/SRF entrains circadian clock

Actin cytoskeleton signaling via MRTF/SRF entrains circadian clock

Circadian Genes as Exploratory Biomarkers in DMD: Results From Both the mdx Mouse Model and Patients

Integrin signalingviaactin cytoskeleton activates MRTF/SRF to entrain circadian clock

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