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Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine
Open accessAbstract
UCP1-Tg mice with ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2α/ATF4) in SM. Targeting mitochondrial function in vitro by treating C 2 C 12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, β-klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.
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Metadata
- Authors
- Keipert, S., Ost, M., Johann, K., Imber, F., Jastroch, M., van Schothorst, E. M., Keijer, J., & Klaus, S.
- Affiliations
- Helmholtz Munich (DE)
- German Institute of Human Nutrition (DE)
- Department of Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands; and
- Wageningen University & Research (NL)
- Corresponding author
- Keipert, Susanne
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2014-03-01
- Volume
- 306
- Issue
- 5
- Pages
- E469-E482
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2169091672
- Cited by
- 221
- References
- 64
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 13 · 2023: 19 · 2022: 21 · 2021: 24 · 2020: 14 · 2019: 16 · 2018: 16 · 2017: 19 · 2016: 20 · 2015: 22 · 2014: 11
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- green
- research.wur.nl
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Site cant be reached (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- skeletal muscle, mitochondrial uncoupling, UCP1, FGF21, myokines, integrated stress response, β-Klotho, white adipose tissue browning, brown adipocytes, lipolysis, bone mass, longevity, FCCP, antimycin A, myxothiazol
- MeSH terms
- Uncoupling Protein 1, Animals, Body Composition, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Cell Line, Energy Metabolism, Fibroblast Growth Factors, Ion Channels, Mice, Transgenic, Mitochondria, Phosphorylation, Uncoupling Agents, Bone Density, Muscle, Skeletal, Mitochondrial Proteins, Myoblasts, Mice, Adipose Tissue, White
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