S100B impairs glycolysis via enhanced poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase in rodent muscle cells

Abstract

S100 calcium-binding protein B (S100B), a multifunctional macromolecule mainly expressed in nerve tissues and adipocytes, has been suggested to contribute to the pathogenesis of obesity. To clarify the role of S100B in insulin action and glucose metabolism in peripheral tissues, we investigated the effect of S100B on glycolysis in myoblast and myotube cells. Rat myoblast L6 cells were treated with recombinant mouse S100B to examine glucose consumption, lactate production, glycogen accumulation, glycolytic metabolites and enzyme activity, insulin signaling, and poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Glycolytic metabolites were investigated by enzyme assays or metabolome analysis, and insulin signaling was assessed by Western blot analysis. Enzyme activity and poly(ADP-ribosyl)ation of GAPDH was evaluated by an enzyme assay and immunoprecipitation followed by dot blot with an anti-poly(ADP-ribose) antibody, respectively. S100B significantly decreased glucose consumption, glucose analog uptake, and lactate production in L6 cells, in either the presence or absence of insulin. In contrast, S100B had no effect on glycogen accumulation and insulin signaling. Metabolome analysis revealed that S100B increased the concentration of glycolytic intermediates upstream of GAPDH. S100B impaired GAPDH activity and increased poly(ADP-ribosyl)ated GAPDH proteins. The effects of S100B on glucose metabolism were mostly canceled by a poly(ADP-ribose) polymerase inhibitor. Similar results were obtained in CC myotube cells. We conclude that S100B as a humoral factor may impair glycolysis in muscle cells independent of insulin action, and the effect may be attributed to the inhibition of GAPDH activity from enhanced poly(ADP-ribosyl)ation of the enzyme.

Evaluation of dietary and lifestyle changes as modifiers of S100β levels in Alzheimer’s disease

“…Administration of insulin resulted in increased secretion of S100β via PI3K signalling, thus further impairing glucose utilisation. Further in vitro investigations in rat muscle cells by Hosokawa et al (144) in 2017, reported that S100β treatment impaired glycolysis and suppressed glucose utilisation, even in the absence of insulin. This may be a feature of disrupted glycolysis, and impaired brain glucose transport observed in AD brain hypometabolism (145).…”

Cellular and molecular mechanisms of sarcopenia: the S100B perspective

“…88,89 In the infarcted heart, S100B, released by surviving cardiomyocytes, might cause cardiomyocyte apoptosis 103 and might promote vascular endothelial growth factor (VEGF) secretion and VEGF-dependent myofibroblast proliferation potentially contributing to scar formation. 116 Notably, muscles of S100B KO mice show reduced levels of poly(ADP-ribosyl)ated GAPDH, 118 but there is no information about the consequences of S100B deletion on muscular performance in terms of muscle strength and resistance to intense physical activity and/or of metabolic rearrangements. 22 Notably, elevated levels of S100B are detected in human serum following intense physical exercise (e.g.…”

“…marathon, swimming races, and soccer games). 118 Also, down-regulation of S100B in myoblasts during the first few hours of culture in differentiation medium is permissive for differentiation as persistence of relatively high S100B levels results in the inhibition of myogenic differentiation. [106][107][108] Extracellular effects of S100B are largely brought about by its interaction with RAGE (receptor for advanced glycation end products, encoded by AGER/ Ager) 109,110 ; however, at least in the case of muscle injury, S100B can activate either RAGE or the basic fibroblast growth factor (bFGF)/FGF receptor 1 (FGFR1) complex depending on its own local concentration, myoblast density, and bFGF availability.…”

“…117 However, extracellular S100B has been reported to impair glycolysis in cultured muscle cells independently of insulin action via inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity by enhanced poly(ADP-ribosyl)ation of GAPDH with no apparent role for RAGE or FGFR. 116 Notably, muscles of S100B KO mice show reduced levels of poly(ADP-ribosyl)ated GAPDH, 118 but there is no information about the consequences of S100B deletion on muscular performance in terms of muscle strength and resistance to intense physical activity and/or of metabolic rearrangements. While the receptor transducing that S100B's effect remains to be determined, the possibility cannot be excluded that S100B exerts it by acting from inside muscle cells following uptake from the cell milieu.…”

“…119 Interestingly, myoblasts down-regulate S100B expression once transferred from proliferation medium to differentiation medium via a p38 MAPK-driven transcriptional mechanism as well as a post-translational, proteasome-dependent mechanism, and myoblasts that have not been committed to differentiation resume expressing S100B once transferred back to proliferation medium. 118 Also, down-regulation of S100B in myoblasts during the first few hours of culture in differentiation medium is permissive for differentiation as persistence of relatively high S100B levels results in the inhibition of myogenic differentiation. 120 Down-regulation of S100B expression at the beginning of cell differentiation in not unique to myoblasts being observed also in neuronal precursor cells, oligodendrocytes, astrocytes, and chondrocytes.…”