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

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 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-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.

Cellular and molecular mechanisms of sarcopenia: the S100B perspective

“…69,135,136 It is presently unknown whether the elevated levels of S100B found in senescent myoblasts 135 are a consequence or a cause of senescence. While S100B stimulates NF-κB activity, 93 NF-κB stimulates S100B expression in myoblasts 137 (Figure 4). While S100B stimulates NF-κB activity, 93 NF-κB stimulates S100B expression in myoblasts 137 (Figure 4).…”

“…Yet the finding that downregulation of S100B partly restored their proliferation and differentiation capability 135 suggests that at elevated levels, S100B contributes to myoblast senescence. While S100B stimulates NF-κB activity, 93 NF-κB stimulates S100B expression in myoblasts 137 (Figure 4). Given the reported NF-κB/ Nrf2 interplay whereby excess NF-κB activity leads to reduced Nrf2 activity, 43 it is possible that up-regulated S100B in myoblasts from sarcopenic subjects reduces Nrf2 levels and/or activity through its stimulatory effect on NF-κB, thereby fostering oxidative stress.…”

“…139 Besides inhibiting myoblast differentiation and participating in the process of myoblast aging, elevated S100B levels also promote myoblast-brown adipocyte transition, and myoblasts from sarcopenic subjects show properties of brown (pre)adipocytes. 137 As mentioned earlier, SCs and their progeny (i.e. myoblasts) accumulate ROS owing to redox imbalance, 41,57,74,75 a condition predisposing per se to adipogenic differentiation given that ROS promote adipogenesis and antioxidants or ROS scavengers suppress ROS effects on adipogenesis.…”

“…In turn, S100B stimulates NF-κB activity with resultant up-regulation of YY1 and YY1-dependent inhibition of miR-133, a promyogenic and anti-adipogenic microRNA, [142][143][144] ultimately leading to transition of myoblasts to brown adipocytes 137 ( Figure 4). 145 ROS/S100B-stimulated NF-κB also upregulates, in a YY1-dependent manner, bone morphogenetic protein 7 (BMP7), 137 which, once secreted, causes myoblast progenitors 146,147 and cultured myoblasts 137 to differentiate into brown adipocytes by repressing the expression of the adipogenic inhibitors, necdin and preadipocyte factor 1, and inducing the key molecular determinant, PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM16), and UCP-1 ( Figure 4). 145 ROS/S100B-stimulated NF-κB also upregulates, in a YY1-dependent manner, bone morphogenetic protein 7 (BMP7), 137 which, once secreted, causes myoblast progenitors 146,147 and cultured myoblasts 137 to differentiate into brown adipocytes by repressing the expression of the adipogenic inhibitors, necdin and preadipocyte factor 1, and inducing the key molecular determinant, PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM16), and UCP-1 ( Figure 4).…”

“…BMP7, bone morphogenetic protein 7; BMPR, bone morphogenetic factor receptor; ROS, reactive oxygen species; UCP-1, uncoupling protein 1; YY1, Yin Yang 1. and thus accumulates within cells (Figure 4). Whatever the cause of elevated S100B levels in aged SCs/myoblasts, that is high ROS/NF-κB-induced S100B expression and/or reduced S100B release (also Morozzi et al 137 ), intracellular S100B might be regarded as intrinsic, cell-autonomous factor concurring to determine changes in SCs ultimately leading to reduced SCs' ability to maintain muscle mass.…”