Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters

Martino, Tami A.; Oudit, Gavin Y.; Herzenberg, Andrew M.; Tata, Nazneen; Koletar, Margaret M.; Kabir, Golam; Belsham, Denise D.; Backx, Peter H.; Ralph, Martin R.; Sole, Michael J.

doi:10.1152/ajpregu.00829.2007

Cited by 273 publications

(221 citation statements)

References 26 publications

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“…In contrast to the tau mutation, the Per2 Brdm1 mutation does not strongly affect the circadian period and had a negligible effect on activity patterns in outdoor conditions (14). We cannot exclude the possibility that the effects we report for the tau mutation may be due to an unknown noncircadian pleiotropic effect, even though the earlier laboratory studies on tau mutant hamsters have clearly revealed health consequences as a result of the deleterious impact of inappropriate entrainment to artificial lighting regimes (17).…”

Section: Discussioncontrasting

confidence: 57%

“…In another study, heterozygote tau mutant hamsters (expressing a free-running 22-h circadian period in absence of time cues) were kept on a 24-h LD cycle, to which these animals entrained with fractured activity patterns and earlier onset of activity. This aberrant rhythmicity in the 24-h LD cycle was associated with cardiac defects, which did not arise in heterozygotes kept on a 22-h LD cycle (16,17). The effects were also not observed after ablation of the central circadian pacemaker in the hypothalamus (suprachiasmatic nucleus) or in homozygous hamsters, which do not entrain to modulo-24, and free run across such lighting regimes.…”

Section: Discussionmentioning

confidence: 89%

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Natural selection against a circadian clock gene mutation in mice

Spoelstra

Wikelski

Daan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

134

119

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Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1e (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against shortperiod genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.circadian rhythms | survival | reproduction | resonance | tau mutation C ircadian clocks are a ubiquitous feature of life on earth, and serve to maintain synchrony of internal physiology with the external 24-h environment. Colin Pittendrigh, one of the founders of chronobiology, hypothesized that natural selection should favor circadian systems to operate in resonance with the external cycle (1, 2). A prediction from this hypothesis is that individuals exhibiting circadian rhythms with frequencies that are not in close resonance with the 24-h cycle should be selected against in nature. The hypothesis was initially supported by laboratory experiments in fly species that lived longer in a 24-h light-dark (LD) cycle than in non-24-h LD cycles (2-4). Stronger support emerged from dyadic competition experiments in batch cultures of cyanobacteria carrying single gene mutations affecting their circadian period (τ). Strains (either wild type or mutant) with a τ similar to the external LD cycle outcompeted strains with a τ different from the Zeitgeber (5, 6). Whether periods out of resonance with the external cycle entail a real fitness deficit in a natural setting has not been tested in any of these systems.The Ck1e tau (hereafter defined as the tau mutation) is a gain-offunction mutation (7) that accelerates the cellular dynamics of the circadian PERIOD protein (8, 9) and affects circadian behavior and physiology (10). It was f...

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 89%

Natural selection against a circadian clock gene mutation in mice

Spoelstra

Wikelski

Daan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

134

119

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“…Circadian rhythms and the core clock factors CLOCK and BMAL1 have been implicated in a growing number of systemic pathologies, including metabolic disease, aging, and cardiovascular disease (16)(17)(18). To date, however, no genetic studies have examined what role circadian rhythms play in adult skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function

Andrews

Zhang

McCarthy

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

319

341

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MyoD, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function. We report that MyoD is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the MyoD promoter. Skeletal muscle of Clock Δ19 and Bmal1 −/− mutant mice exhibited ∼30% reductions in normalized maximal force. A similar reduction in force was observed at the single-fiber level. Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of Clock Δ19 , Bmal1 −/− , and MyoD −/− mice. The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several MyoD target genes. EM analysis also demonstrated that muscle from both Clock Δ19 and Bmal1 −/− mice had a 40% reduction in mitochondrial volume. The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration. This mitochondrial pathology was not seen in muscle of MyoD −/− mice. We suggest that altered expression of both Pgc-1α and Pgc-1β in Clock Δ19 and Bmal1 −/− mice may underlie this pathology. Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle. The identification of MyoD as a clock-controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle.circadian clock | myofilaments | mitochondria A fundamental, evolutionarily conserved property of most organisms, from cyanobacteria to plants and animals, is the daily cycling of their internal physiology as well as certain behaviors in animals, such as sleep and feeding (1). The timing of these circadian rhythms is synchronized to the environment by external cues, with light and nutrient availability being two of the most salient entrainment cues (2). The synchronization of endogenous circadian rhythms with the daily cycles in the environment provides an adaptive mechanism for organisms to anticipate cyclic demands on cellular physiology and behavior (3, 4). At the molecular level, the circadian clock represents a well-defined gene regulatory network composed of transcriptional-translational feedback loops (5). The positive arm of the loop is composed of the transcription factors CLOCK and BMAL1, which heterodimerize and bind to E-box elements on target genes such as Per1 to drive the negative part of the feedback loop (5). More recently, the same molecular clock factors that have been identified in the central clock in the suprachiasmatic nucleus have been found to exist in most peripheral tissues (reviewed in ref. 6).We recently characterized the circadian transcriptome of adult skeletal muscle. These mRNAs exhibit significant oscillation in gene expression with a repeating period len...

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“…Adverse cardiac events show significant diurnal variations (82), and mortality is higher for people whose professions expose them to frequent disruption of the biorhythm (e.g., flight crews, shift workers) (83). A recent animal experiment showed that in the long run, disruption of the biorhythm by genetic manipulation caused target organ damage in kidney and heart (84). Against this background, the findings of the observational DOPPS are remarkable that self-reported disturbed sleep is a powerful predictor of mortality (85), most tightly related to pain, pruritus, and depression.…”

Section: Disrupted Biorhythmmentioning

confidence: 99%