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Intrinsic muscle clock is necessary for musculoskeletal health
Open accessAbstract
KEY POINTS: The endogenous molecular clock in skeletal muscle is necessary for maintenance of phenotype and function. Loss of Bmal1 solely from adult skeletal muscle (iMSBmal1(-/-) ) results in reductions in specific tension, increased oxidative fibre type and increased muscle fibrosis with no change in feeding or activity. Disruption of the molecular clock in adult skeletal muscle is sufficient to induce changes in skeletal muscle similar to those seen in the Bmal1 knockout mouse (Bmal1(-/-) ), a model of advanced ageing. iMSBmal1(-/-) mice develop increased bone calcification and decreased joint collagen, which in combination with the functional changes in skeletal muscle results in altered gait. This study uncovers a fundamental role for the skeletal muscle clock in musculoskeletal homeostasis with potential implications for ageing. ABSTRACT: 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.
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“Disruption of the muscle clock has also been shown to have significant impact on glucose intolerance and insulin resistance with very small changes in fiber types (Dyar et al., 2014; Schroder et al., 2015; Harfmann et al., 2016).”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Schroder et al., 2015
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“In addition, prolonged loss of Bmal1 function was also associated with increased fibrosis within the muscle.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Schroder et al., 2015
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Muscle type and fiber type specificity in muscle wasting
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Correa-de-Araujo, R., Addison, O., Miljkovic, I., Goodpaster, B. H., Bergman, B. C., Clark, R. V., Elena, J. W., Esser, K. A., Ferrucci, L., Harris-Love, M. O., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00963 · Cited by 468
Muscle‐bone crosstalk and potential therapies for sarco‐osteoporosis
Li, G., Zhang, L., Wang, D., AIQudsy, L., Jiang, J. X., Xu, H., & Shang, P. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28946 · Cited by 166
Maurel, D. B., Jähn, K., & Lara-Castillo, N. (2017) · Biomedicines · doi:10.3390/biomedicines5040062 · Cited by 127
Effects of exercise on circadian rhythms in humans
Shen, B., Ma, C., Wu, G., Liu, H., Chen, L., & Yang, G. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1282357 · Cited by 135
Circadian Metabolism: From Mechanisms to Metabolomics and Medicine
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Metadata
- Authors
- Schroder, E. A., Harfmann, B. D., Zhang, X., Srikuea, R., England, J. H., Hodge, B. A., Wen, Y., Riley, L. A., Yu, Q., Christie, A., Smith, J. D., Seward, T., Wolf Horrell, E. M., Mula, J., Peterson, C. A., Butterfield, T. A., & Esser, K. A.
- Affiliations
- University of Kentucky (US)
- Center for Muscle Biology University of Kentucky Lexington KY USA
- Corresponding author
- Esser, Karyn A.
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2015-11-23
- Volume
- 593
- Issue
- 24
- Pages
- 5387-5404
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC4704520
- OpenAlex
- W2100177722
- Cited by
- 145
- References
- 80
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 21 · 2023: 11 · 2022: 13 · 2021: 16 · 2020: 16 · 2019: 9 · 2018: 8 · 2017: 10 · 2016: 12
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (T32CA165990)
- National Institute of Environmental Health Sciences (RC1ES018636)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR066082)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- circadian clock, Bmal1, skeletal muscle, muscle-specific knockout, muscle fiber type, muscle fibrosis, muscle strength, bone mineralization, aging, gait
- MeSH terms
- Animals, Biological Clocks, Bone and Bones, Calcinosis, Collagen, Fibrosis, Gait, Joints, Mice, Inbred C57BL, Phenotype, Muscle, Skeletal, Mice, ARNTL Transcription Factors
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