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 <i>Bmal1</i> in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring <i>Bmal1</i> expression in the brains of <i>Bmal1</i>-knockout mice did not rescue <i>Bmal1</i>-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 <i>Bmal1</i> reduced the recovery response to sleep loss. Together, these findings demonstrate that <i>Bmal1</i> 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.