Intrinsic muscle clock is necessary for musculoskeletal health

Elizabeth A. Schroder, Brianna D. Harfmann, Xiping Zhang, Ratchakrit Srikuea, Jonathan H. England, Brian A. Hodge, Yuan Wen, Lance A. Riley, Qi Yu, Alexander Christie, Jeffrey D. Smith, Tanya Seward, Erin M. Wolf Horrell, Jyothi Mula, Charlotte A. Peterson, Timothy A. Butterfield, Karyn A. Esser

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Disruption of circadian rhythms in humans and rodents has implicated a fundamental role for circadian rhythms in ageing and the development of many chronic diseases including diabetes, cardiovascular disease, depression and cancer. The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop with Bmal1 encoding a core molecular clock transcription factor. Germline Bmal1 knockout (Bmal1 KO) mice have a shortened lifespan, show features of advanced ageing and exhibit significant weakness with decreased maximum specific tension at the whole muscle and single fibre levels. We tested the role of the molecular clock in adult skeletal muscle by generating mice that allow for the inducible skeletal muscle-specific deletion of Bmal1 (iMSBmal1). Here we show that disruption of the molecular clock, specifically in adult skeletal muscle, is associated with a muscle phenotype including reductions in specific tension, increased oxidative fibre type, and increased muscle fibrosis similar to that seen in the Bmal1 KO mouse. Remarkably, the phenotype observed in the iMSBmal1-/- mice was not limited to changes in muscle. Similar to the germline Bmal1 KO mice, we observed significant bone and cartilage changes throughout the body suggesting a role for the skeletal muscle molecular clock in both the skeletal muscle niche and the systemic milieu. This emerging area of circadian rhythms and the molecular clock in skeletal muscle holds the potential to provide significant insight into intrinsic mechanisms of the maintenance of muscle quality and function as well as identifying a novel crosstalk between skeletal muscle, cartilage and bone.

Original languageEnglish
Pages (from-to)5387-5404
Number of pages18
JournalJournal of Physiology
Issue number24
StatePublished - Dec 15 2015

Bibliographical note

Funding Information:
This work was supported by NIH grants RC1ES018636 (National Institute of Arthritis and Musculoskeletal and Skin Diseases) and R01AR066082 (National Institute of Environmental Health Sciences) to K.A.E.

Publisher Copyright:
© 2015 The Physiological Society.

ASJC Scopus subject areas

  • Physiology


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