NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression

Boulinguiez, Alexis; Duhem, Christian; Mayeuf-Louchart, Alicia; Pourcet, Benoît; Sebti, Yasmine; Kondratska, Kateryna; Montel, Valérie; Delhaye, Stéphane; Thorel, Quentin; Beauchamp, Justine; Hebras, Aurore; M, Gimenez; Couvelaere, Marie; Zecchin, Mathilde; Ferri, Lise; Prevarskaya, Natalia; Forand, Anne; Gentil, Christel; Ohana, Jessica; Piétri‐Rouxel, France; Bastide, Bruno; Staels, Bart; Duez, Hélène; Lancel, Steve

doi:10.1172/jci.insight.153584

“…147 Extensive research since has further revealed the regulatory roles of REV-ERBs in skeletal muscle function. 86,149,150 For example, REV-ERBβ has been implicated in skeletal muscle lipid metabolism since ectopic expression of its dominant-negative form upregulated expression of genes associated with fatty acid uptake in skeletal muscle. 151 Consistently, SR8278, an antagonist of REV-ERBs, was found to activate expression of myogenesis genes including Myogenic determination 1 (Myod), Myogenin (Myog), and Major histocompatibility complex 3 (Mhc3), suggesting a role of REV-ERBs in myogenesis.…”

Section: Muscle Pathologiesmentioning

confidence: 99%

Circadian stabilization loop: the regulatory hub and therapeutic target promoting circadian resilience and physiological health

Kim

¹

,

Yoo

²

,

Chen

³

2022

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The circadian clock is a fundamental biological mechanism that orchestrates essential cellular and physiological processes to optimize fitness and health. The basic functional unit is the cell-autonomous oscillator, consisting of intersecting negative feedback loops. Whereas the core loop is primarily responsible for rhythm generation, auxiliary loops, most notably the secondary or stabilization loop, play pivotal roles to confer temporal precision and molecular robustness. The stabilization loop contains opposing nuclear receptor subfamilies REV-ERBs and retinoic acid receptor-related orphan receptors (RORs), competing to modulate rhythmic expression of the basic helix-loop-helix ARNT like 1 (Bmal1) genes in the core loop as well as other clock-controlled genes. Therefore, REV-ERBs and RORs are strategically located to interface the oscillator and the global transcriptomic network, promoting cellular homeostasis and physiological fitness throughout lifespan. Disruption of REV-ERB and ROR functions has been linked with diseases and aging, and pharmacological manipulation of these factors has shown promise in various mouse disease models. Nobiletin is a natural compound that directly binds to and activates RORα/γ, modulating circadian rhythms, and shows robust in vivo efficacies to combat clock-associated pathophysiologies and age-related decline. Results from several studies demonstrate an inverse relation between nobiletin efficacy and clock functional state, where nobiletin elicits little effect in young and healthy mice with growing efficacy as the clock is perturbed by environmental and genetic challenges. This mode of action is consistent with the function of the stabilization loop to promote circadian and physiological resilience. Future studies should further investigate the function and mechanism of REV-ERBs and RORs, and test strategies targeting these factors against disease and aging.

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“…These disturbances may perturb the expression of circadian clock genes [ 37 ]. Notably, clock genes capture our interest as they orchestrate immune function, energy metabolism, and mitophagy [ 25 , 38 , 39 ], thus exerting diverse impacts on mammalian physiology. However, the mechanisms by which the circadian clock affects UC remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis

Chen,

Li,

Li

et al. 2023

IJMS

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Background: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. Methods: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1’s role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1’s regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. Results: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. Conclusions: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation.

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“… 146 Extensive research since has further revealed the regulatory roles of REV-ERBs in skeletal muscle function. 84 , 148 , 149 For example, REV-ERBβ has been implicated in skeletal muscle lipid metabolism since ectopic expression of its dominant-negative form upregulated expression of genes associated with fatty acid uptake in skeletal muscle. 150 Consistently, SR8278, an antagonist of REV-ERBs, was found to activate expression of myogenesis genes including Myogenic determination 1 ( Myod ), Myogenin ( Myog ), and Major histocompatibility complex 3 ( Mhc3 ), suggesting a role of REV-ERBs in myogenesis.…”

Section: Therapeutic Relevance Of Rev-erbs and Rorsmentioning

confidence: 99%

Circadian stabilization loop: the regulatory hub and therapeutic target promoting circadian resilience and physiological health

Kim

¹

,

Yoo

²

,

Chen

³

2022

View full text Add to dashboard Cite

The circadian clock is a fundamental biological mechanism that orchestrates essential cellular and physiological processes to optimize fitness and health. The basic functional unit is the cell-autonomous oscillator, consisting of intersecting negative feedback loops. Whereas the core loop is primarily responsible for rhythm generation, auxiliary loops, most notably the secondary or stabilization loop, play pivotal roles to confer temporal precision and molecular robustness. The stabilization loop contains opposing nuclear receptor subfamilies REV-ERBs and retinoic acid receptor-related orphan receptors (RORs), competing to modulate rhythmic expression of the basic helix-loop-helix ARNT like 1 (Bmal1) genes in the core loop as well as other clock-controlled genes. Therefore, REV-ERBs and RORs are strategically located to interface the oscillator and the global transcriptomic network, promoting cellular homeostasis and physiological fitness throughout lifespan. Disruption of REV-ERB and ROR functions has been linked with diseases and aging, and pharmacological manipulation of these factors has shown promise in various mouse disease models. Nobiletin is a natural compound that directly binds to and activates RORα/γ, modulating circadian rhythms, and shows robust in vivo efficacies to combat clock-associated pathophysiologies and age-related decline. Results from several studies demonstrate an inverse relation between nobiletin efficacy and clock functional state, where nobiletin elicits little effect in young and healthy mice with growing efficacy as the clock is perturbed by environmental and genetic challenges. This mode of action is consistent with the function of the stabilization loop to promote circadian and physiological resilience. Future studies should further investigate the function and mechanism of REV-ERBs and RORs, and test strategies targeting these factors against disease and aging.

show abstract

NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression

Cited by 11 publications

References 38 publications

Circadian stabilization loop: the regulatory hub and therapeutic target promoting circadian resilience and physiological health

Circadian stabilization loop: the regulatory hub and therapeutic target promoting circadian resilience and physiological health

Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis

Circadian stabilization loop: the regulatory hub and therapeutic target promoting circadian resilience and physiological health

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