Bmal1 function in skeletal muscle regulates sleep

Abstract

Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep-amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle.

DOI: http://dx.doi.org/10.7554/eLife.26557.001

eLife digest

We spend nearly one third of our lives asleep. Sleep plays a critical role in human health and is regulated by multiple brain regions. Genes are some of the factors that control sleep. Recent studies have shown that mice in which a gene called Bmal1 had been completely removed, sleep more than mice that still have the gene. These Bmal1-deficient mice also respond differently to sleep loss. However, until now, it was not known which tissues and cells that carry active (or ‘expressed’) Bmal1 are involved in regulating sleep.

To find out if Bmal1 activity in the brain is sufficient to recover from sleep loss, Ehlen, Brager et al. compared genetically modified mice that either expressed Bmal1 only in the brain, or only in the muscle tissue that covers the skeleton. After the mice were kept awake for six hours, their sleep was monitored by measuring electrical signals on the surface of the skull. Contrary to what they expected, Ehlen et al. found that mice with Bmal1 expressed in the skeletal muscle were able to have a normal sleep pattern, while mice with Bmal1 expressed in the brain had an abnormal sleep pattern.

Further experiments show that removing Bmal1 from the skeletal muscle of mice, but allowing the gene to be expressed in other tissues, produced sleeping patterns that were similar to those seen in mice that were completely missing the Bmal1 gene. These results indicate that Bmal1 in skeletal muscle is important to help regulate sleep, and that the signal for sleepiness does not only originate from the brain.

This is the first study to show that skeletal muscle can regulate sleep. The next step will be to identify the specific signal the muscle uses to trigger the brain to sleep. Understanding the mechanisms that regulate sleep may help to develop new treatments for sleep disorders.

DOI: http://dx.doi.org/10.7554/eLife.26557.002