Cryptochromes Suppress HIF1α in Muscles

Vaughan, Megan; Wallace, Martina; Handzlik, Michal K.; Chan, Alanna B.; Metallo, Christian M.; Lamia, Katja

doi:10.1016/j.isci.2020.101338

Cited by 28 publications

(30 citation statements)

References 56 publications

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“…In contrast to our finding that maximum sprint speed is indistinguishable between ZT13 and ZT21 in sedentary animals, male mice robustly increased their maximum sprint capacity in a striking time of day dependent manner after six weeks of running wheel training. As we 32 and others 54 have seen in prior studies, female mice tend to be more active than males; in addition, both maximum speed and tissue glycogen content are significantly greater in trained c57BL/6J female mice than they are in males. The explanation for this robust sexual dimorphism is unclear 54 .…”

Section: Discussionsupporting

confidence: 66%

Daily running enhances molecular and physiological circadian rhythms in skeletal muscle

Duglan

Vallve²,

Vaughan³

et al. 2020

Preprint

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Identifying molecular adaptations underlying improved fitness in response to training is of critical interest in exercise physiology. Circadian rhythms broadly modulate metabolism, including muscle substrate utilization and exercise capacity. Here we show that time of day influences the increase in exercise capacity afforded by training: when maximum running speed is measured at the beginning of the nighttime active period in mice, there is no measurable benefit from training, while maximum increase in performance occurs at the end of the night. Incidentally, we describe an improved method to motivate running in rodent exercise studies that obviates the use of electrical stimulation. Furthermore, we describe daily rhythms in carbohydrate and lipid metabolism and transport associated with the time-dependent response to training. Thus, we show that circadian rhythms modulate muscle-intrinsic responses to training and provide resources for the optimal design of exercise studies in rodents.

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Section: Discussionsupporting

confidence: 66%

Daily running enhances molecular and physiological circadian rhythms in skeletal muscle

Duglan

Vallve²,

Vaughan³

et al. 2020

Preprint

Self Cite

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“…Only recently, CRY1, but not CRY2, was identified as a negative regulator of HIF-1α in the mouse fibroblast NIH3-T3 and MEF cell lines, at the level of transactivation capacity, as well as at the level of protein quantity (Dimova et al 2019). Furthermore, CRY1 and CRY2 are reported to suppress HIF1α-BMAL1 heterodimers in mouse muscles (Vaughan et al 2020). Against this background, the contemporaneously increased quantities of CRY1 and HIF-1α protein over the period of 2 h after the 6 h tNMR treatment seem astonishing (Figure 5B and D).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Nuclear Magnetic Resonance affects the core clock mechanism and associated Hypoxia-inducible factor-1

Thöni

Oliva

Mauracher

et al. 2021

Chronobiology International

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The influence of low intensity electromagnetic fields on circadian clocks of cells and tissues has gained increasing scientific interest, either as a therapeutic tool or as a potential environmental hazard. Nuclear Magnetic Resonance (NMR) refers to the property of certain atomic nuclei to absorb the energy of radio waves under a corresponding magnetic field. NMR forms the basis for Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy and, in a low-intensity form, for NMR therapy (tNMR). Since the circadian clock is bi-directionally intertwined with hypoxic signaling in vertebrates and mammals, we hypothesized that low intensity electromagnetic fields, such as tNMR, might not only affect circadian clocks but also Hypoxia-Inducible Factor-1α (HIF-1α). As master regulator of the hypoxic signaling pathway, HIF-1α is known to dampen the circadian amplitude under reduced oxygen availability, while the hypoxic response of cells and organisms, itself, is tightly clock controlled. In a first experiment, we investigated if tNMR is able to act as Zeitgeber for the core clock mechanism of unsynchronized zebrafish and mouse fibroblast cells, using direct light irradiation and treatment with the glucocorticoid Dexamethasone as references. tNMR significantly affected the cell autonomous clocks of unsynchronized mouse fibroblast cells NIH3-T3, but did not act as a Zeitgeber. Similar to light irradiation and in contrast to treatment with Dexamethasone, tNMR did not synchronize expression profiles of murine clock genes. However, irradiation with tNMR as well as light significantly altered mRNA and protein expression levels of Cryptochrome1, Cryptochrome2 and Clock1 for more than 24 h. Changes in mRNA and protein after different treatment durations, namely 6 and 12 h, appeared to be nonlinear. A nonlinear doseresponse relationship is known as hallmark of electromagnetic field induced effects on biological systems. The most prominent alterations were detected in murine HIF-1α protein, again in a nonlinear dose-response. In contrast to murine cells, zebrafish fibroblasts did not respond to tNMR at all. Light, a potent Zeitgeber for the peripheral clocks of fish, led to the expected synchronized clock gene oscillations of high amplitude, as did Dexamethasone. Hence, we conclude, mammalian peripheral clocks are more susceptible to tNMR than the direct light entrainable fish fibroblasts. Although light and tNMR did not act as Zeitgebers for the circadian clocks of unsynchronized murine cells, the significant observed effects might indicate downstream cellphysiological ramifications, which are worth future investigation. However, beside the effects tNMR exerts on the core clock mechanism of mammalian cells, the technology might be the first non-pharmacological approach to modify HIF-1α protein in cells and tissues. HIF-1α and the associated circadian clock play key roles in diseases with underlying ischemic background, such as infarct, stroke, and cancer and, also infectious diseases, such as Covid-19. Hence, low intensity magnet...

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“…Elevated expression of hypoxia-regulated transcripts can enhance cell survival under stressful conditions and contribute to tumorigenesis (Choudhry and Harris, 2018; Semenza, 2013, 2017). We and others recently demonstrated that CRY1 and CRY2 suppress both the protein accumulation and transcriptional activation of HIF1α and HIF2α(Dimova et al, 2019; Vaughan, 2020). HIFs are closely related to CLOCK and BMAL1 (Fribourgh and Partch, 2017) and we and others have shown that BMAL1 dimerizes with HIF1α (Hogenesch et al, 1998; Vaughan, 2020; Wu et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…We and others recently demonstrated that CRY1 and CRY2 suppress both the protein accumulation and transcriptional activation of HIF1α and HIF2α(Dimova et al, 2019; Vaughan, 2020). HIFs are closely related to CLOCK and BMAL1 (Fribourgh and Partch, 2017) and we and others have shown that BMAL1 dimerizes with HIF1α (Hogenesch et al, 1998; Vaughan, 2020; Wu et al, 2017). Given that the CRY2 D325H mutation reduces its association with and repression of CLOCK:BMAL1, it may also influence repression of HIF1α/BMAL1 by altering protein-protein interactions, although it is unclear whether the interaction of CRYs with HIFs involves the secondary pocket.…”

Section: Discussionmentioning

confidence: 99%

CRY2missense mutations suppress P53 and enhance cell growth

Chan

Parico

Fribourgh

et al. 2021

Preprint

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Disruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA repair enzymes. While CRYs lack DNA repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SCFFBXL3-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC. Neither mutant affects steady state levels of overexpressed c-MYC, and they have divergent impacts on circadian rhythms and on the ability of CRY2 to interact with SCFFBXL3. Unexpectedly, stable expression of either CRY2 D325H or of CRY2 S510L robustly suppresses P53 target gene expression, suggesting that this is the primary mechanism by which they influence cell growth.

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Cryptochromes Suppress HIF1α in Muscles

Cited by 28 publications

References 56 publications

Daily running enhances molecular and physiological circadian rhythms in skeletal muscle

Daily running enhances molecular and physiological circadian rhythms in skeletal muscle

Therapeutic Nuclear Magnetic Resonance affects the core clock mechanism and associated Hypoxia-inducible factor-1

CRY2missense mutations suppress P53 and enhance cell growth

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