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 new 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 BEST 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 BETTER BEST part: impact of various muscle clock disruptions.


-Global Bmal1 knockout: these mice have zero Bmal1 anywhere in their body, from the moment of conception. Reduced muscle fiber size, reduced mitochondrial volume, and sarcopenia.

This is kinda like having parents who used smart devices at night prior to conception and you doing it, too.

-Muscle-specific Bmal1 knockout (slightly more relevant in this #context).
This is great: increased muscle size but decreased muscle strength! Not even “no change in muscle strength.” They were actually weaker than mice with smaller muscles.

-Muscle-specific Bmal1 knockout after development (at ~3 months of age, so they have Bmal1 everywhere during conception, gestation, and until adulthood, then lose it specifically in muscle). This is the weakest circadian disruption mentioned yet, although it still managed to show decreased muscle strength despite no change in muscle size LOL

This is like my generation. We didn’t have many LED-emitting smart phones, iPads, or computers to play on long into the night… but now as grown-ups we do…

-Clock mutant: reduced muscle strength and fewer mitochondria.

-Per2: no change in muscle mass yet reduced exercise tolerance.

-Rev-erb  alpha: reduced mitochondrial volume & lower exercise capacity.

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

My advice: in the morning, lots of sunlight & a protein-rich breakfast to co-entrain the central and peripheral clocks, and an exercise-session to doubly entrain the muscle clock -- I know this is a lot to ask and may be inconvenient, but I think it's a big step toward #optimal (but I understand adherence is numero uno, so do as much as you can).

Loss of muscle function & mobility reduces age-related quality of life more than anything else. Wear blue blockers at night because, yeah, the central clock matters for muscle, too.

Semi-speculation: they say there are some permanent effects of obesity, such that even after weight loss, your metabolism and neuroendocrine function isn’t the same as someone of similar body composition who didn't have obesity. I think this is just like that. Don’t do it in the first place, because it could take a while to correct, and even then, may not be as good as it could've been. Start now.

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