Abstract
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, nonmyogenic mesenchymal progenitor cells, and satellite cells, the adult stem cells of skeletal muscles. Myoblasts and brown adipocytes share a common Myf5+ progenitor cell, and cell fate decision depends on levels of BMP7, a TGF-β family member; high BMP7 levels cause Myf5+ progenitor cells to differentiate in brown adipocytes. When expressed at relatively high levels as observed in myoblasts from sarcopenic humans, intracellular S100B, a Ca2+-binding protein of the EF-hand type (1), exerts anti-myogenic effects that are reversed by S100B knockdown (2,3). We show that ROS-activated NF-κB induces accumulation of S100B that causes myoblasts to convert into brown preadipocytes via 1) an NF-κB/YY1 axis that negatively regulates the promyogenic and anti-brown adipogenic miR-133 with consequent accumulation of the pro-brown adipogenic transcription factor, PRDM16, and 2) an NF-κB/YY1/BMP7 axis with resultant BMP7 autocrine activity. Also, culturing L6C8 (S100b-overexpressing) myoblasts (2) in adipocyte differentiation medium causes NF-κB-dependent upregulation of S100B expression, which precedes and is required for lipid droplet formation. Lastly, S100B knockdown in myoblast-derived brown adipocytes reconvert them into fusion competent myoblasts. Thus, S100B is a major molecular determinant of cell fate decision of proliferating myoblasts; while modulating myoblast differentiation (2,3), at high levels S100B promotes myoblast-brown adipocyte transition, which might have pathophysiological implications in sarcopenia.This work was supported by grants from MIUR FIRB RBFR12BUMH_003 and Fondazione CRP 2016.0136.021.
