Bmal1 function in skeletal muscle regulates sleep
- Morehouse School of Medicine, United States
- University of Florida, United States
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
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.
Article and author information
Author details
J Christopher Ehlen
Joseph S Takahashi
Funding
National Institute on Minority Health and Health Disparities (G12 MD007602)
- J Christopher Ehlen
- Jason P DeBruyne
National Institute of Neurological Disorders and Stroke (R01 NS078410)
- Ketema N Paul
National Heart, Lung, and Blood Institute (T32 HL116077)
- Allison J Brager
National Institute of Mental Health (P50 MH074924)
- Joseph S Takahashi
National Institute of General Medical Sciences (SC1 GM109861)
- Jason P DeBruyne
Howard Hughes Medical Institute
- Joseph S Takahashi
National Heart, Lung, and Blood Institute (T32 HL007609)
- Cloe L Gray
National Institute of Neurological Disorders and Stroke (U54 NS060659)
- Ketema N Paul
National Institute of Neurological Disorders and Stroke (U54 NS083932)
- J Christopher Ehlen
- Jason P DeBruyne
- Ketema N Paul
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense.
Ethics
Animal experimentation: All procedures involving animals were approved by the Morehouse School of Medicine institutional animal care and use committee, protocol reference number 15-17. Animal studies conformed to recommendations published in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 16,445
- views
-
- 2,049
- downloads
-
- 113
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Bmal1 function in skeletal muscle regulates sleep
eLife 6:e26557.
https://doi.org/10.7554/eLife.26557
Further reading
-
A specific gene in skeletal muscle helps to regulate sleep.
-
- Neuroscience
Life histories of oviparous species dictate high metabolic investment in the process of gonadal development leading to ovulation. In vertebrates, these two distinct processes are controlled by the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), respectively. While it was suggested that a common secretagogue, gonadotropin-releasing hormone (GnRH), oversees both functions, the generation of loss-of-function fish challenged this view. Here, we reveal that the satiety hormone cholecystokinin (CCK) is the primary regulator of this axis in zebrafish. We found that FSH cells express a CCK receptor, and our findings demonstrate that mutating this receptor results in a severe hindrance to ovarian development. Additionally, it causes a complete shutdown of both gonadotropins secretion. Using in-vivo and ex-vivo calcium imaging of gonadotrophs, we show that GnRH predominantly activates LH cells, whereas FSH cells respond to CCK stimulation, designating CCK as the bona fide FSH secretagogue. These findings indicate that the control of gametogenesis in fish was placed under different neural circuits, that are gated by CCK.
