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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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Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis
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Self-citationFGF21 as a Hepatokine, Adipokine, and Myokine in Metabolism and Diseases
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“In mice, excess carbohydrate intake increases expression levels of UCP1, FGFR1c and KLB mRNA in BAT, suggesting increases in FGF21 sensitivity and energy expenditure.”
BackgroundInfluentialSystemic effects of mitochondrial stress
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“Directly perturbing mitochondria by expressing the uncoupling protein 1 (UCP1) in skeletal muscle also induced the ISR and FGF21, and WAT browning was dependent on FGF21, despite no whole-body metabolic adaptations [117,118].”
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“Increased systemic FGF21 serum levels, either endogenously induced or exogenously administered, lead to the appearance of brown fat likestructures in WAT depots by the recruitment of beige fat cells e generally termed the “browning” of WAT [8,11,15,17].”
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Self-citationMild cold induced thermogenesis: are BAT and skeletal muscle synergistic partners?
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Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action
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“On the other hand, several studies indicate that MSTN inhibition can induce browning in white adipose tissue (WAT), i.e., the process of formation of brown adipocyte in WAT depots [23].”
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“Skeletal muscle has been recently identified as an endocrine organ that can regulate several physiological and metabolic pathways in response to muscle contraction [45].”
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Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux
Ost, M., Keipert, S., van Schothorst, E. M., Donner, V., van der Stelt, I., Kipp, A. P., Petzke, K., Jové, M., Pamplona, R., Portero‐Otín, M., et al. (2014) · The FASEB Journal · doi:10.1096/fj.14-261503 · Cited by 69
“2E), a strong marker of muscle protein breakdown related to autophagy in muscle wasting (34) as well asMap1lc3a and Atg7 [Table 4, previously validated on protein levels (10)], and Gadd45a (Supplemental Fig.”
BackgroundMethodInfluentialSelf-citationHomeostatic sensing of dietary protein restriction: a case for FGF21
Hill, C. M., Berthoud, H.-R., Münzberg, H., & Morrison, C. D. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.06.002 · Cited by 68
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“Increased FGF21 expression is also a hallmark of mitochondrial deficiency or stress in mice and humans (15,33,34).”
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Biology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy
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Association between serum FGF21 level and sarcopenia in older adults
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Myokines: Metabolic regulation in obesity and type 2 diabetes
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“These results indicate that skeletal muscle can secrete FGF21, which acts on adipocytes to promote browning and regulate thermogenesis [168].”
Skeletal Muscle and Bone – Emerging Targets of Fibroblast Growth Factor-21
Sun, H., Sherrier, M. C., & Li, H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.625287 · Cited by 54
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“genes, such as asparagine synthetase (Asns), phosphoserine aminotransferase 1 (Psat1) and phosphoglycerate dehydrogenase (Phgdh) are reportedly up-regulated by mitochondrial uncoupling in the muscle((35)) and were up-regulated in our microarray data as well, whereas other stress-response genes((12))”
BackgroundFGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway
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“However, there are some reports that FGF21 enhances mitochondrial functions in human dopaminergic neurons (via the Sirt1dependent regulation of PGC-1a) (42) and in skeletal muscle cells (43).”
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“Stress-ors such as OXPHOS uncoupling increase FGF21 expression to transmit ISR [85].”
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“Finally, other models of mitochondrial dysfunction such as ectopic overexpression of the uncoupling protein 1 in skeletal muscle (78) and impaired autophagy, which leads to mitochondrial dysfunction in muscle (81), are also associated with induction of ER stress.”
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“Recent studies have shown that the ISR can induce fgf21 expression (13, 21).”
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Self-citationTargeted mitochondrial uncoupling beyond UCP1 – The fine line between death and metabolic health
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Self-citationStress Signaling Between Organs in Metazoa
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“However, overexpression of UCP-1 in the skeletal muscles of mice (henceforth referred to as UCP-1–SM mice) reducesmusclemass, increases circulatingFGF-21 levels approximatelyfivefold, and triggers the activation of a compensatory stress response involving eIF2α/ATF4 in muscles (Keipert et al. 2014).”
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Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics
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“, 2017) or ectopic UCP1 expression (Keipert et al., 2014; Ost et al., 2015).”
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“Quantitative real-time PCR was performed essentially as described before (Keipert et al. 2014; Petrov et al. 2015) and followed the MIQE guidelines (Bustin et al. 2009).”
InfluentialSelf-citationNovel Mediators of Adipose Tissue and Muscle Crosstalk
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Montgomery, M. K., Mokhtar, R. A. M., Bayliss, J. A., Parkington, H. C., Suturin, V. M., Bruce, C. R., & Watt, M. J. (2018) · Diabetes · doi:10.2337/db17-0923 · Cited by 37
“Our data also support the premise that upregulation of FGF21 by peripheral tissues might be a more general response to cellular stresses (53,54).”
Result
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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