Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-κB/YY1/miR-133 axis and NF-κB/YY1/BMP-7 axis
Open accessAbstract
Muscles of sarcopenic people show hypotrophic myofibers and infiltration with adipose and, at later stages, fibrotic tissue. The origin of infiltrating adipocytes resides in fibro-adipogenic precursors and nonmyogenic mesenchymal progenitor cells, and in satellite cells, the adult stem cells of skeletal muscles. Myoblasts and brown adipocytes share a common Myf5+ progenitor cell: the cell fate depends on levels of bone morphogenetic protein 7 (BMP-7), a TGF-β family member. S100B, a Ca 2+-binding protein of the EF-hand type, is expressed at relatively high levels in myoblasts from sarcopenic humans and exerts anti-myogenic effects via NF-κB-dependent inhibition of MyoD, a myogenic transcription factor acting upstream of the essential myogenic factor, myogenin. Adipogenesis requires high levels of ROS, and myoblasts of sarcopenic subjects show elevated ROS levels. Here we show that: (1) ROS overproduction in myoblasts results in upregulation of S100B levels via NF-κB activation; and (2) ROS/NF-κB-induced accumulation of S100B causes myoblast transition into brown adipocytes. S100B activates an NF-κB/Ying Yang 1 axis that negatively regulates the promyogenic and anti-adipogenic miR-133 with resultant accumulation of the brown adipogenic transcription regulator, PRDM-16. S100B also upregulates BMP-7 via NF-κB/Ying Yang 1 with resultant BMP-7 autocrine activity. Interestingly, myoblasts from sarcopenic humans show features of brown adipocytes. We also show that S100B levels and NF-κB activity are elevated in brown adipocytes obtained by culturing myoblasts in adipocyte differentiation medium and that S100B knockdown or NF-κB inhibition in myoblast-derived brown adipocytes reconverts them into fusion-competent myoblasts. At last, interstitial cells and, unexpectedly, a subpopulation of myofibers in muscles of geriatric but not young mice co-express S100B and the brown adipocyte marker, uncoupling protein-1. These results suggest that S100B is an important intracellular molecular signal regulating Myf5+ progenitor cell differentiation into fusion-competent myoblasts or brown adipocytes depending on its levels.
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S100B stimulates NF-κB activity with resultant upregulation of YY1 and YY1-dependent inhibition of microRNA-133, ultimately leading to the transition of myoblasts into adipocytes.
“In turn, S100B stimulates NF‐κB activity with resultant upregulation of YY1 and YY1‐dependent inhibition of microRNA‐133, a promyogenic and anti‐adipogenic microRNA,[ 32 ] ultimately leading to the transition of myoblasts into adipocytes.[ 31 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [31]
ROS overproduction in myoblasts causes accumulation of S100B, which promote the myoblast-to-adipocyte transition, and myoblasts from sarcopenic subjects show properties of (pre)adipocytes.
“ROS overproduction in myoblasts causes accumulation of S100B, which promote the myoblast‐to‐adipocyte transition, and myoblasts from sarcopenic subjects show properties of (pre)adipocytes.[ 31 ]”
From Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review (2022) · cites this paper as [31]
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Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review
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- Authors
- Morozzi, G., Beccafico, S., Bianchi, R., Riuzzi, F., Bellezza, I., Giambanco, I., Arcuri, C., Minelli, A., & Donato, R.
- Affiliations
- University of Perugia (IT)
- Corresponding author
- Donato, Rosario
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2017-09-08
- Volume
- 24
- Issue
- 12
- Pages
- 2077-2088
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5686349
- OpenAlex
- W2750887238
- Cited by
- 58
- References
- 61
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 8 · 2019: 6 · 2018: 8
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondazione Cassa di Risparmio di Perugia (2016-0136.021)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- S100B, brown adipocytes, myoblasts, sarcopenia, oxidative stress, reactive oxygen species, NF-κB, YY1, miR-133, BMP-7, adipogenesis, skeletal muscle, UCP1, satellite cells, aging, Myf5
- MeSH terms
- Animals, Humans, Male, Transfection, NF-kappa B, Reactive Oxygen Species, Oxidative Stress, Myoblasts, MicroRNAs, YY1 Transcription Factor, Mice, Adipocytes, Brown, Bone Morphogenetic Protein 7, S100 Calcium Binding Protein beta Subunit
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