Alcohol Disrupts Circadian Clocks in Skeletal Muscle

It is becoming increasingly clear that our circadian rhythms play a fundamental role in health (and disease) and therefore, maintaining “aligned” and robust rhythms is a must. Without going into an in-depth discussion on our body’s circadian system, in nearly every tissue there are genetic “clocks” that control protein translation and the eventual expression of genes related to mood, metabolism, hormones, cognitive function, and physical performance. These genes oscillate throughout the day, peaking and troughing at different times that correspond to when our physiology needs them. It’s a fine-tuned, coordinated act of biology that matches our internal environment with external conditions.

Unfortunately, several things in our modern environment can throw our circadian rhythms out of line including mistimed light exposure, food intake, and poor sleeping habits. Modernity is a blessing for productivity and 24/7 living, but a curse to our circadian clocks.

Circadian clocks and skeletal muscle function & metabolism. Lefta et al. 2011

One “modern” vice that may also impact circadian rhythms is alcohol consumption. Though many can moderate their alcohol intake, there is no denying that in America and throughout the world, a lot of people just drink too much, and often too much at one time — referred to as binge drinking (exceeding 5 drinks for men and 4 drinks for women in a 2-hour sitting.) The subjective effects of a nighttime bender on sleep and the next day’s productivity are obvious, but could alcohol be causing these effects through its impact on our circadian rhythms?

A study published in the American Journal of Physiology: Endocrinology and Metabolism, investigated the effects of a single binge drinking episode on the expression and pattern of circadian rhythm genes. Specifically, they looked at gene expression in skeletal muscle, a tissue with a major role in metabolism and performance, which may provide insight into the effects of alcohol on several metabolic and/or muscle-related diseases.

Brief study methods

This study was conducted on female mice who were randomly assigned to either a control condition who received a saline injection or a “binge drinking” condition who received an injection of alcohol at a dose of 5g/kilogram of body weight. This dose was justified by the authors as being translatable to human consumption in terms of its effect on blood alcohol concentration (BAC.)

Muscle samples were taken from groups of mice at baseline, 4, 8, 12, 16, and 24 hours post injection. A follow-up experiment extended this sampling to 28, 32, 36, 40, 44, and 48 hours post injection.

The muscle samples then underwent RNA sequencing, cDNA synthesis, real-time PCR, and Western-blot analyses to quantify genes and proteins of interest, which can be seen in the tables below and most of which play an integral role in the core molecular clock in skeletal muscle.

Results

Below is a brief outline of some of the main findings.

• Binge alcohol consumption disrupted the expression of circadian genes up to 48 hours post injection, including clock, Bmal1, Per1, Per2, Cry1, Cry2.
• Alcohol disrupted the expression of clock-controlled genes including Rorɑ, Rev-erbɑ, Myod1, Dbp, Tef, and Bhlhe40

• The changes in clock genes and clock-controlled genes persisted well beyond the point at which blood alcohol content returned to baseline (~12 hours), indicating that binge drinking had lasting effects
• Alcohol disrupted (abolished) the oscillation in several circadian and clock-controlled genes from 0–24 and up to 48 hours post injection
• Skeletal muscle and liver clock-related genes were affected differently by alcohol consumption — indicating unique effects of alcohol on different tissues in the body
• The alcohol binge increased levels of corticosterone (cortisol) in the mice for up to 8 hours

• Blocking the increase in corticosterone had little effect on the alcohol-induced reduction in core clock gene expression, suggesting the effects were independent of this hormone

In large quantities, alcohol is not good for the brain or the body. Even in more moderate quantities, alcohol is likely detrimental, but can probably be consumed with minor adverse effects. However, this study provides some very compelling data that acute alcohol intoxication can impact circadian rhythm gene expression and that these effects may last up to 2 days. Though this study was conducted in mice, it nonetheless supports what is known and what many of us may have experienced.

This study is important in telling us not about alcohol’s negative health effects, but the route through which they are mediated. As I mentioned in the introduction, circadian clock genes control the expression of genes responsible for metabolism and skeletal muscle function, among others. The negative effects of alcohol on insulin resistance, glucose tolerance, fat storage, muscle building, and exercise performance are thus likely driven through its effects on the circadian system — a sort of “alcohol-induced jet lag” for lack of a better analogy.

In a majority of real-life scenarios, alcohol consumption is also paired with known circadian disruptors including late-night light exposure, sleep deprivation, and food intake at odd times of the day (nobody needs that 2 a.m. pizza.)

The official word for an environmental cue that provides time-of-day information to our circadian system is Zeitgeber. Given these results, alcohol can definitely be classified as such and therefore, the amount and timing of alcohol consumption, like that of food, seems to play an integral role in our physiology.

Study cited

Binge alcohol disrupts skeletal muscle core molecular clock independent of glucocorticoids. Abigail L. Tice, Joseph A. Laudato, Michael L. Rossetti, Christopher A. Wolff, Karyn A. Esser, Choogon Lee, Charles H. Lang, Cynthia Vied, Bradley S. Gordon, and Jennifer L. Steine. American Journal of Physiology-Endocrinology and Metabolism 2021 321:5, E606-E620