Skeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin... Show moreSkeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin resistance, butyrate, a short -chain fatty acid (SCFA) produced from dietary fibre fermentation, prevents it. This preventive role of butyrate has been attributed to histone deacetylase (HDAC)-mediated transcription regulation and activation of mito-chondrial fatty-acid oxidation. Here we address the interplay between butyrate and the long-chain fatty acid palmitate and investigate how transcription, signalling and metabolism are integrated to result in the butyrate -induced skeletal muscle metabolism remodelling. Butyrate enhanced insulin sensitivity in palmitate-treated, insulin-resistant C2C12 cells, as shown by elevated insulin receptor 1 (IRS1) and pAKT protein levels and Slc2a4 (GLUT4) mRNA, which led to a higher glycolytic capacity. Long-chain fatty-acid oxidation capacity and other functional respiration parameters were not affected. Butyrate did upregulate mitochondrial proteins involved in its own oxidation, as well as concentrations of butyrylcarnitine and hydroyxybutyrylcarnitine. By knocking down the gene encoding medium-chain 3-ketoacyl-CoA thiolase (MCKAT, Acaa2), butyrate oxidation was inhibited, which amplified the effects of the SCFA on insulin sensitivity and glycolysis. This response was associated with enhanced HDAC inhibition, based on histone 3 acetylation levels. Butyrate enhances insulin sensitivity and induces glycolysis, without the requirement of upregulated long-chain fatty acid oxidation. Butyrate catabolism functions as an escape valve that attenuates HDAC inhibition. Thus, inhibition of butyrate oxidation indirectly prevents insulin resistance and stimulates glycolytic flux in myotubes treated with butyrate, most likely via an HDAC-dependent mechanism. Show less
Chondrosarcoma is the second most common primary bone malignancy, representing one fourth of all primary bone sarcomas. It is typically resistant to radiation and chemotherapy treatments. However,... Show moreChondrosarcoma is the second most common primary bone malignancy, representing one fourth of all primary bone sarcomas. It is typically resistant to radiation and chemotherapy treatments. However, the molecular mechanisms that contribute to cancer aggressiveness in chondrosarcomas remain poorly characterized. Here, we studied the role of mitochondrial transporters in chondrosarcoma aggressiveness including chemotherapy resistance. Histological grade along with stage are the most important prognostic biomarkers in chondrosarcoma. We found that high-grade human chondrosarcoma tumors have higher expression of the mitochondrial protein, translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), compared to low-grade tumors. TOMM20 overexpression in human chondrosarcoma cells induces chondrosarcoma tumor growth in vivo. TOMM20 drives proliferation, resistance to apoptosis and chemotherapy resistance. Also, TOMM20 induces markers of epithelial to mesenchymal transition (EMT) and metabolic reprogramming in these mesenchymal tumors. In conclusion, TOMM20 drives chondrosarcoma aggressiveness and resistance to chemotherapy. Show less
Nahon, J.E.; Hoekstra, M.; Harmelen, V. van; Rensen, P.C.N.; Dijk, K.W. van; Kooijman, S.; Eck, M. van 2019
