Bmal1 function in skeletal muscle regulates sleep

  1. J Christopher Ehlen
  2. Allison J Brager
  3. Julie Baggs
  4. Lennisha Pinckney
  5. Cloe L Gray
  6. Jason P DeBruyne
  7. Karyn A Esser
  8. Joseph S Takahashi
  9. Ketema N Paul  Is a corresponding author
  1. Morehouse School of Medicine, United States
  2. University of Florida, United States
  3. 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

  1. J Christopher Ehlen

    Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3223-9262
  2. Allison J Brager

    Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States
    Competing interests
    No competing interests declared.
  3. Julie Baggs

    Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States
    Competing interests
    No competing interests declared.
  4. Lennisha Pinckney

    Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States
    Competing interests
    No competing interests declared.
  5. Cloe L Gray

    Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States
    Competing interests
    No competing interests declared.
  6. Jason P DeBruyne

    Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States
    Competing interests
    No competing interests declared.
  7. Karyn A Esser

    Myology Institute, College of Medicine, University of Florida, Gainsville, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5791-1441
  8. Joseph S Takahashi

    Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Joseph S Takahashi, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0384-8878
  9. Ketema N Paul

    Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States
    For correspondence
    ketema.paul@ucla.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0226-9559

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.

Reviewing Editor

  1. Louis J Ptáček, University of California, San Francisco, United States

Publication history

  1. Received: March 6, 2017
  2. Accepted: July 12, 2017
  3. Accepted Manuscript published: July 20, 2017 (version 1)
  4. Version of Record published: August 29, 2017 (version 2)

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.

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  1. J Christopher Ehlen
  2. Allison J Brager
  3. Julie Baggs
  4. Lennisha Pinckney
  5. Cloe L Gray
  6. Jason P DeBruyne
  7. Karyn A Esser
  8. Joseph S Takahashi
  9. Ketema N Paul
(2017)
Bmal1 function in skeletal muscle regulates sleep
eLife 6:e26557.
https://doi.org/10.7554/eLife.26557
  1. Further reading

Further reading

  1. A specific gene in skeletal muscle helps to regulate sleep.

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Jinli Geng, Yingjun Tang ... Xiaodong Liu
    Research Article

    Dynamic Ca2+ signals reflect acute changes in membrane excitability (e.g. responses to stimuli), and also mediate intracellular signaling cascades that normally take longer time to manifest (e.g., regulations of transcription). In both cases, chronic Ca2+ imaging has been often desired, but largely hindered by unexpected cytotoxicity intrinsic to GCaMP, a popular series of genetically-encoded Ca2+ indicators. Here, we demonstrate the performance of GCaMP-X in chronic Ca2+ imaging with long-term probe expression in cortical neurons, which has been designed to eliminate the unwanted interactions between conventional GCaMP indicators and endogenous (apo)calmodulin-binding proteins. By expressing in live adult mice at high levels over an extended time frame, GCaMP-X indicators showed less damage and improved performance in two-photon imaging of acute Ca2+ responses to whisker deflection or spontaneous Ca2+ fluctuations. Chronic Ca2+ imaging data (³1 month) were acquired from cultured cortical neurons expressing GCaMP-X, unveiling that spontaneous/local Ca2+ transients would progressively develop into autonomous/global Ca2+ oscillations. Besides the morphological indices of neurite length and soma size, the major metrics of oscillatory Ca2+, including rate, amplitude and synchrony were also examined along with the multiple stages (from neonatal to mature) during neural development. Dysregulations of both neuritogenesis and Ca2+ oscillations were observed typically in 2-3 weeks, which were exacerbated by stronger or prolonged expression of GCaMP. In comparison, neurons expressing GCaMP-X exhibited significantly less damage. By varying the timepoints of virus infection or drug induction, GCaMP-X outperformed GCaMP similarly in cultured mature neurons. These data altogether highlight the unique importance of oscillatory Ca2+ to morphology and health of neurons, presumably underlying the differential performance between GCaMP-X and GCaMP. In summary, GCaMP-X provides a viable option for Ca2+ imaging applications involving long-time and/or high-level expression of Ca2+ probes.