Tag Archives: dopamine

The importance of entraining skeletal muscle’s circadian clock (and how)

“Literally, every single model of skeletal muscle circadian arrhythmia mimics aging sedentary people who skip breakfast, stay up late, and get sick.”

But first, the human studies that confirm these newer findings aren’t restricted to preclinical models: 1) a randomized CROSSOVER study; two weeks of modest caloric restriction. Same diet; either 5.5 or 8.5 hours of sleep.

In other words, circadian rhythms broke or woke (Nedeltcheva et al., 2010):

 

 

Same diet & energy expenditure + circadian arrhythmia = lose less fat and more muscle. This is basically the opposite of optimal. Large error bars because it was a CROSSOVER study, although it still managed to reach statistical significance.

And this happened despite lower 24-hour insulin AUC (Nedeltcheva et al., 2012). GRAVITAS.

 

 

And in an ad lib setting, “Laboratory studies in healthy young volunteers have shown that experimental sleep restriction is associated with a dysregulation of the neuroendocrine control of appetite consistent with increased hunger and with alterations in parameters of glucose tolerance suggestive of an increased risk of diabetes” (Van Cauter et al., 2007).

 

 

Part 2. THE BETTER PART: The muscle clock, how it works, and how to fix it.

 

 

 

Similar to other peripheral circadian clocks (eg, liver, adipose, lung, etc.), the muscle clock is entrained by LIGHT via the central pacemaker located in the SCN and feeding (via an as of yet unclear mechanism), but also scheduled exercise.

Interestingly, mice who had been subjected to a 6-hour phase advance adapted faster if they exercised early in the active phase (would be morning for humans).

 

 

Much of these data are summarized in a review in Frontiers in Neuroscience (Aoyama and Shibata, 2017).

The muscle clock is entrained by timed exercise but also feeding. This was demonstrated by showing the circadian rhythms in a subset of muscle-specific genes in fed mice were absent in fasted mice.

It is thought that the muscle clock’s function is to prepare us for the transition from the resting/fasting phase (night) to the active/fed phase (day)… and although I like that phrasing, this seems somewhat subjective (and really hard  to test/prove even on a hypothetical level).

 

 

Part 3. The BEST part: impact of various muscle clock disruptions.

Hint: THEY’RE ALL BAD.

 

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Circadian rhythms and cancer: potential mechanisms

Humans are incredible omnivorous beasts that can thrive on a great variety of diets, but crumble if you mess with their sleep.

Circadian arrhythmia is thought to be a driving force behind a few types of cancer.  But how, exactly, does seemingly harmless things like artificial light, skipping breakfast, or jet lag actually promote tumorigenesis?  There are many potential mechanisms, and I’d bet different circadian disruptions promote different cancers in different #contexts.

In some cell types, circadian disruptions which dampen amplitude increase proliferation.  This has led to some researchers to believe a robust circadian rhythm per se is tumor-suppressive.  In agreement with this, many tumor suppressors are direct targets of circadian transcription factors.  As was observed in some skin cancers, you may want suppressed proliferation at some times of the day but not others, so the tissue can renew properly.  But you don’t want, for example, skin cells to be proliferating while they’re being exposed to UV light, so this process happens at night (in circadian fashion).

Circadian transcription factors also directly interact with endogenous antioxidant systems.

 

circadian-image

 

Cancer clocks out for lunch: disruption of circadian rhythm and metabolic oscillation in cancer (Altman, 2016)

 

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Fiat lux

Humans have a peculiar relationship with light: differences in brightness, wavelength, and even circadian timing all have biologically meaningful effects.

The right combination of timed light exposure and hot Blue Blockers is probably not only the solution to jet lag, but also to a whole host of other health problems.  Maybe you can’t completely escape the bane of the modern condition, but there are some tools, widely available, accessible, and even free in some cases (eg, sun), that may be of benefit.  

The frequency of light impacts circadian rhythms. 

Wright showed this in 2004.  The subjects wore special glasses with LEDs that emitted light of varying frequency for 2 hours, from 6 to 8 in the morning (65 uW/cm2).  Salivary melatonin measurements commenced at 7 pm.  As seen in the figure below, blue but not red light induced a significant phase advance in melatonin onset:

AM blue light phase advance

And for the whole group:all colors

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It’s paleo: Hypothyroidism impairs reproductive success in bitches.

Kisspeptin was discovered in Hershey, Pennsylvania, and was named after Hershey’s Kisses.  It has 776 pubmed citations going back to 2001, and may (or may not) play a key part integrating circannual reproduction patterns and seasonal thyroid function.

Kisspeptin was originally identified as a protein that inhibited breast cancer and melanoma.  This might also provide insight into the WHO’s recent declaration of shift work as a “probable” carcinogen.

Exhibit A. TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin (Klosen 2013)

In this study, TSH infusion in short-day adapted hamsters (who are in winter non-breeding mode) induced summer phenotype & kisspeptin.  It also fattened them up a bit.  These TSH secreting neurons express melatonin receptors, but not those for TRH or T3 (Klosen 2002), so it is said to go something like this:Kisspeptin feedback diagram

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Paleo breeding: mating in the wild.

I’ve adapted much of this chart from Howell-Skalla (2002)  and Tsubota (1998).

Canadian polar bears: bona fide seasonal breeders.circannual hormones

The light cycle increases until June, then decreases until December.  Melatonin goes in the exact opposite direction. Testosterone peaks around the onset of breeding season (springtime, April/May), coinciding with LH (as expected). There is also a lot of bear-on-bear violence at this time due to: 1) testosterone-induced aggression; and 2) the high female:male ratio –-> females rear their cubs and are thus out of the game for about 3 years, but males like to breed every year.

Females followed a similar pattern, with estrogen peaking around breeding season and prolactin following the light cycle.

The authors mentioned that prolactin levels mirrored day length, and according to Wiley this would be the prolactin peak that normally occurs when you’re sleeping, but has spilled over into the daytime due to short sleep / long light cycle… not total prolactin levels (24h AUC?), which should be highest in winter (see below).

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The incredible camping experiment, circadian proper

Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle (Wright et al., 2013)

Abstract (edited): The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle, and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise

In other words, they compared circadian events during 2 weeks of normal life to 2 weeks of 100% camping.  And camping won.

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Lights Out! Get your melatonin.

From T.S. Wiley’s website:
“People spent summers, before electric lights, sleeping less & eating heavily in preparation for winter because the light triggered the hunger for carbohydrates. Now, light is available 24 hours a day. Heating and air-conditioning climate control our hormonal responses to consume carbohydrates now available year round. This is the scenario for obesity, Type II diabetes, and depression… In Wiley’s opinion, sleep is the best medicine.”

And Wikipedia:
“Wiley’s main thesis in Lights Out is that light is a physiological trigger that controls dopamine and hormones like cortisol. Wiley posits that with the extension of the natural day through artificial lighting, rest at the hormonal level is rarely adequate for optimum biological needs of the body. In her view, this results in both fatigue and unnatural appetite, which leads to weight gain, exhaustion, and disease. Wiley theorizes that the body’s responses are cyclical, reflecting the seasons of the year, and that the body’s needs vary seasonally. According to Wiley, during the winter months the body needs more sleep, and carbohydrates should be restricted as they would have been naturally during hunter-gatherer times.”

melatonin

Most of the first third of Wiley’s book “Lights Out: Sleep, Sugar, and Survival” centers around light exposure, melatonin, and the many, many effects of a screwed up circadian cycle.  Jane Plain and Jack Kruse have written volumes on the subject, please see their websites for more in-depth analyses and practical applications…

Much of this blog post is my take on that first third (I couldn’t wait to finish it before writing about it), plus a little input from Google, Pubmed, et al; some commentary & pseudo-fact-checking as well.  I’m going to finish the book, and hopefully it will inspire a few more blog posts as opposed to a tin foil hat.  Most of the stuff in Lights Out makes incredibly good sense, but: 1) that doesn’t mean it’s true; and 2) the strings of logic are far too long to do a proper fact-check.  But really it’s how well it makes sense (mostly) that has me intrigued.

divide and conquer

Melatonin is a sleep-inducing hormone controlled by the light-dark cycle.  It is known.  On the day-to-day, melatonin increases at night and decreases during the daytime.  From Wiley: on a seasonal level, longer days during the summer meant less melatonin overall during these months.  Since melatonin suppresses sex hormones (inconsistent? Eg, Smith et al., 2013), summer is supposed to be breeding time, so the baby is born in spring when food is plenty (I’m OK with this now, but will certainly disagree come December).  Melatonin also suppresses metabolic rate, so the decreased daylight and thus increased melatonin during the winter months helped to survive on less food (supported by Marrin et al., 2013).

Disruptions in circadian rhythms royally screws us up.  According to Wikipedia, fireplaces/candles and incandescent bulbs produce less of the melatonin-suppressive blue lights… use these at night in winter?


Antidepressant and circadian phase-shifting effects of light. (Lewy et al., 1987)
Abstract: Bright light can suppress nighttime melatonin production in humans, but ordinary indoor light does not have this effect. This finding suggested that bright light may have other chronobiologic effects in humans as well. Eight patients who regularly became depressed in the winter (as day length shortens) significantly improved after 1 week of exposure to bright light in the morning (but not after 1 week of bright light in the evening). The antidepressant response to morning light was accompanied by an advance (shift to an earlier time) in the onset of nighttime melatonin production. These results suggest that timing may be critical for the antidepressant effects of bright light.

Next:  Prolactin inhibits sex hormones, and melatonin stimulates prolactin (supported by Gill-Sharma 2009Campino et al., 2008).  Thus, less melatonin in summer means less prolactin = more sex & fertility.  She also says day sex is more likely to result in conception compared to night sex for this reason (couldn’t find a reference for or against this).

Dopamine inhibits prolactin, whereas TRH & melatonin stimulate it.  Melatonin also blunts ACTH-induced cortisol secretion (supported by Torres-Farfan 2003Campino 2008).  Winter = high melatonin, prolactin, and low cortisol & dopamine.  Summer = high dopamine & cortisol, and low melatonin & prolactin.  Prolactin is supposed to be high in winter, during pregnancy; low dopamine would support this.

Circadian rhythm

Dopamine is a summer hormone?  Lu et al. (2006) showed high dopaminergic activity was associated with light and wakefulness (ie, summertime).  However, Venero (2002) showed melatonin stimulated dopamine synthesis in specific brain regions, and Eisenberg (2010) showed increased dopamine synthesis in fall & winter relative to spring and summer.  Two  possible confounding factors come to mind: 1) Location, location, location!  Some of these discrepancies may be due to brain region-specific dopamine metabolism… actually, Lu is the only odd-man out, so perhaps dopamine is a winter hormone?  And 2) Wiley’s main premise is that we pwned the light… epigenetics and the like mean that we, including the people in those studies, have deeply screwed up light/dark summer/winter metabolic programs on an epigenetic level, so it’s possible those studies are riddles with artefacts.  However, Wiley also says that people get sick because they live in perpetual summer (lights on all the time = high dopamine), and Markianos (2013) showed elevated dopamine metabolites in overweight patients; in my experience these studies usually continuously enroll patients, year-round.


I’m really just blazing through abstracts here – this is why I call it “pseudo-fact-checking;” not to be confused with any degree of academic rigor.

To be continued… (no tin foil hats, I promise) (not yet at least)

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