How Muscles May Hold Cues to Better Sleep

How Muscles May Hold Cues to Better Sleep

Researchers study how genes in muscle regulate sleep and recovery—work that may lead to better treatments and brain health.

Ketema Paul, PhD, holds dual professorships in the Department of Integrative Biology and Physiology and the Department of Psychiatry and Biobehavioral Sciences in the College of Letters and Science at the University of California, Los Angeles (UCLA). As a leading researcher in sleep and circadian rhythms, his work has revealed surprising regulatory mechanisms of sleep found outside the brain. The work could lead to new opportunities to treat sleep disorders and enhance resilience to sleep loss.

What sparked your interest in sleep and circadian rhythms, and what do you hope to find out?

My research has always centered on understanding how the circadian clock regulates sleep. From my early work in vision research to studying circadian rhythms and eventually exploring sleep homeostasis—which regulates the ability to recover from sleep loss—I’ve been driven by the fundamental question of how these systems interact. Using mouse models, my lab investigates the genetic and molecular mechanisms that link circadian regulation to sleep behavior.

One of our main focuses is identifying genes and molecules that contribute to sleep and response to sleep loss. We are also looking at how to manage and recover from sleep loss, as well as why men and women show differences in sleep and responses to sleep loss.

What insights are changing the game on sleep research?

Our most important finding so far was that the BMAL1 gene in skeletal muscle helps regulate sleep and the ability to recover from sleep loss. In a 2017 eLife paper, we reported that mice lacking BMAL1 in their skeletal muscle showed increased non-rapid eye movement (NREM) sleep and poorer recovery responses following sleep deprivation. However, restoring BMAL1 expression specifically in the skeletal muscle of BMAL1-deficient mice normalized NREM sleep amounts and improved recovery after sleep loss.

Although sleep is regulated by the brain, this work showed that body tissues also play a key role in sleep homeostasis. This mirrors earlier discoveries in circadian rhythms, which were once thought to be strictly neural but were later found to be active in tissues throughout the body. Our research was among the first to show that sleep regulation follows a similar pattern, integrating signals beyond the brain.

This surprising finding is still driving much of the research in my lab. We’re working to understand what specific circadian molecules in skeletal muscle are talking to the brain and what signals they use to help regulate sleep.

Why do you use mouse models?

Because sleep has been studied in mice for a long time, there is a lot of existing information about how mice sleep and how their sleep is similar and different from human sleep. To understand the genetic regulation of sleep, we use mice with characterized sleep patterns and knock out specific genes to see how these influence sleep.

I’m also working with Christopher Ehlen, PhD, at Morehouse School of Medicine, who is performing optogenetic and chemogenetic activation and silencing of neurons in certain brain areas of mouse models to measure how these regulate sleep. For this work, we conduct basic EEG recordings of sleep and then manipulate specific genes and genetic expression and combine that with sleep disruption and behavioral interventions. This research will help reveal both the neural and molecular mechanisms responsible for sleep homeostasis. We are also studying how those mechanisms interact with stress mechanisms.

How could your research eventually help people?

Our research could lead to more effective treatments for sleep disorders like insomnia, perhaps by targeting peripheral tissues such as skeletal muscle. Sleep issues tend to accompany a variety of mental illnesses and somatic body diseases, and we are hoping our research can improve sleep for people with these issues.

Our work could also improve performance, memory and cognitive function for people who aren’t able to sleep, such as people serving in the military or first responders working after a natural disaster. We’re hoping that by identifying mechanisms responsible for poorer cognitive performance when people don’t sleep, we can help people make fewer mistakes and have higher cognitive function when they do experience sleep loss.

What do you hope to find out next?

In addition to studying how BMAL1 in skeletal muscle protects against sleep loss, we are now investigating how sleep loss and recovery influence social behavior and responses to social stress. Additionally, my team is working with colleagues who study neurological and neurodegenerative disorders to understand how neurodegenerative disorders influence sleep. So far, we’ve studied Huntington’s disease and autism spectrum disorders and are currently working on muscular dystrophy.

How do you think we can continue to strengthen the scientific workforce?

I received mentorship from many highly esteemed scientists, and I have spent a lot of time paying that forward by making sure that I identify people—specifically people from underrepresented backgrounds like mine—who may not have had much exposure to scientific research during their formative years.

I’ve dedicated a significant amount of effort to making sure that we are more inclusive in our ability to reach bright people and bring them into our field. For example, I am the director of diversity mentorship programs at the UCLA Brain Research Institute and direct a summer program that’s a partnership with historically Black colleges and universities across the nation. I think it’s extremely important that we continue to broaden the avenues through which very bright people can come into research enterprises.

Interview conducted by science writer Nancy D. Lamontagne.

This article was originally published in the September 2025 issue of The Physiologist Magazine. Copyright © 2025 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.