Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-[kappa]B/YY1/miR-133 axis and NF-[kappa]B/YY1/BMP-7 axis

• Published in: Cell death and differentiation Vol. 24; no. 12; p. 2077
• Main Authors: Morozzi, Giulio, Beccafico, Sara, Bianchi, Roberta, Riuzzi, Francesca, Bellezza, Ilaria, Giambanco, Ileana, Arcuri, Cataldo, Minelli, Alba, Donato, Rosario
• Format: Journal Article
• Language: English
• Published: Rome Nature Publishing Group 01.12.2017
• Subjects: Adipocytes; Adipogenesis; Autocrine signalling; Bone morphogenetic protein 7; Calcium-binding protein; Cell fate; Cell fusion; EF-hand; Interstitial cells; Mesenchyme; Myoblasts; MyoD protein; Myogenin; NF-κB protein; Oxidative stress; Progenitor cells; Proteins; Rodents; S100b protein; Satellite cells; Skeletal muscle; Stem cell transplantation; Stem cells
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2017.132

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 Ca2+ -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.