# Circadian Clock and Muscle Health

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $74,601

## Abstract

We have shown that disruption of the muscle circadian clock mechanism through loss of the core clock gene,
Bmal1, is sufficient to induce significant muscle weakness and surprisingly, increased mortality. Based on
these findings, the overall objective of this grant is to pursue the fundamental understanding of the role of the
muscle circadian clock in regulating a daily program of gene expression and how clock disruption leads to
significant muscle weakness and diminished systemic health.
We found that MyoD1 can modulate expression of the core clock gene, Bmal1 making it a bona fide tissue-
specific circadian clock modifier1. We have also determined that MyoD1 and CLOCK:BMAL1 share peak
binding at over 3000 sites across the muscle genome. These new findings provide support for our studies to
define the mechanism(s) through which MyoD1 modulates the network properties of the clock mechanism as
well as understanding the role of MyoD1 as a clock co-factor in the daily genomic and transcriptomic
landscape in adult muscle.
Downstream from MyoD1 and the clock factors, my lab has identified two muscle specific genes, Rbm20 and
Tcap, that we propose link clock disruption with muscle weakness. Loss of muscle Bmal1, results in significant
decreases in Rbm20 and Tcap expression and we find changes in sarcomere structure including variability of
sarcomere length, distortions in M and Z lines and altered myofilament orientation. Lastly, the global Bmal1
knock out mouse, Bmal1KO, has been used as a model of advanced aging as it exhibits significant aging-like
pathologies and has a median lifespan of 37wks. In preliminary experiments using this global Bmal1 KO
mouse we rescued Bmal1 in skeletal muscles using an AAV vector with a muscle specific promoter. We found
that this was sufficient to significantly improve muscle strength but also significantly extended lifespan. These
are complementary to our findings of increased mortality with loss of muscle Bmal1 and demonstrate that
rescuing Bmal1 only in skeletal muscle improves systemic health. In addition, with aging and many chronic
diseases exhibiting muscle clock disruption, these results suggest that targeting the muscle clock mechanism
holds potential as a translational strategy. We propose to test the following three specific aims:
Specific Aim 1: To define the roles of MyoD1 within the core clock mechanism and as a co-factor for the daily
transcriptomic landscape in skeletal muscle.
Specific Aim 2: To test the clock controlled genes, Rbm20 and/or Tcap, for their roles in sarcomere structure
and muscle function.
Specific Aim 3: To determine the skeletal muscle specific changes required for improved lifespan in the Bmal1
KO mouse.

## Key facts

- **NIH application ID:** 11014604
- **Project number:** 3R01AR079220-04S1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Karyn A Esser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,601
- **Award type:** 3
- **Project period:** 2021-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11014604

## Citation

> US National Institutes of Health, RePORTER application 11014604, Circadian Clock and Muscle Health (3R01AR079220-04S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11014604. Licensed CC0.

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