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Type 2 diabetes is characterized by elevated blood glucose and reduced insulin sensitivity in target tissues. Moreover, reduced mitochondrial metabolism and expressional profile of genes governing mitochondrial metabolism (such as peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha [PGC‐1α]) are also reduced during insulin resistance. Epigenetic regulation via DNA methylation of genes including PGC‐1α may contribute to diminished mitochondrial capacity, while hypomethylation of PGC‐1α (such as that invoked by exercise) has been associated with increased PGC‐1α expression and favorable metabolic outcomes. The purpose of the present report is to characterize the effects of DNA hypomethylation on myotube metabolism and expression of several related metabolic targets. C2C12 myotubes were treated with 5‐Aza‐2′‐deoxycytidine (5‐Aza) for either 24 or 72 h both with and without hyperinsulinemic‐induced insulin resistance. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Metabolic gene and protein expression were assessed via quantitative real time polymerase chain reaction and western blot analysis, respectively. Though expression of PGC‐1α and other related targets remained unaltered, insulin resistance and 5‐Aza treatment significantly reduced mitochondrial metabolism. Similarly, peak glycolytic metabolism was diminished by 5‐Aza‐treated cells, while basal glycolytic metabolism was unaltered. 5‐Aza also reduced the expression of branched‐chain amino acid (BCAA) catabolic components, however BCAA utilization was enhanced during insulin resistance with 5‐Aza treatment. Together the present work provides proof‐of‐concept evidence of the potential role of DNA methylation in the regulation of mitochondrial metabolism and the potential interactions with insulin resistance in a model of skeletal muscle.
Type 2 diabetes is characterized by elevated blood glucose and reduced insulin sensitivity in target tissues. Moreover, reduced mitochondrial metabolism and expressional profile of genes governing mitochondrial metabolism (such as peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha [PGC‐1α]) are also reduced during insulin resistance. Epigenetic regulation via DNA methylation of genes including PGC‐1α may contribute to diminished mitochondrial capacity, while hypomethylation of PGC‐1α (such as that invoked by exercise) has been associated with increased PGC‐1α expression and favorable metabolic outcomes. The purpose of the present report is to characterize the effects of DNA hypomethylation on myotube metabolism and expression of several related metabolic targets. C2C12 myotubes were treated with 5‐Aza‐2′‐deoxycytidine (5‐Aza) for either 24 or 72 h both with and without hyperinsulinemic‐induced insulin resistance. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Metabolic gene and protein expression were assessed via quantitative real time polymerase chain reaction and western blot analysis, respectively. Though expression of PGC‐1α and other related targets remained unaltered, insulin resistance and 5‐Aza treatment significantly reduced mitochondrial metabolism. Similarly, peak glycolytic metabolism was diminished by 5‐Aza‐treated cells, while basal glycolytic metabolism was unaltered. 5‐Aza also reduced the expression of branched‐chain amino acid (BCAA) catabolic components, however BCAA utilization was enhanced during insulin resistance with 5‐Aza treatment. Together the present work provides proof‐of‐concept evidence of the potential role of DNA methylation in the regulation of mitochondrial metabolism and the potential interactions with insulin resistance in a model of skeletal muscle.
Elevated circulating branched‐chain amino acids (BCAAs) have been correlated with the severity of insulin resistance, leading to recent investigations that stimulate BCAA metabolism for the potential benefit of metabolic diseases. BT2 (3,6‐dichlorobenzo[b]thiophene‐2‐carboxylic acid), an inhibitor of branched‐chain ketoacid dehydrogenase kinase, promotes BCAA metabolism by enhancing BCKDH complex activity. The purpose of this report was to investigate the effects of BT2 on mitochondrial and glycolytic metabolism, insulin sensitivity, and de novo lipogenesis both with and without insulin resistance. C2C12 myotubes were treated with or without low or moderate levels of BT2 with or without insulin resistance. Western blot and quantitative real‐time polymerase chain reaction were used to assess protein and gene expression, respectively. Mitochondrial, nuclei, and lipid content were measured using fluorescent staining and microscopy. Cell metabolism was assessed via oxygen consumption and extracellular acidification rate. Liquid chromatography‐mass spectrometry was used to quantify BCAA media content. BT2 treatment consistently promoted mitochondrial uncoupling following 24‐h treatment, which occurred largely independent of changes in expressional profiles associated with mitochondrial biogenesis, mitochondrial dynamics, BCAA catabolism, insulin sensitivity, or lipogenesis. Acute metabolic studies revealed a significant and dose‐dependent effect of BT2 on mitochondrial proton leak, suggesting BT2 functions as a small‐molecule uncoupler. Additionally, BT2 treatment consistently and dose‐dependently reduced extracellular BCAA levels without altering expression of BCAA catabolic enzymes or pBCKDHa activation. BT2 appears to act as a small‐molecule mitochondrial uncoupler that promotes BCAA utilization, though the interplay between these two observations requires further investigation.
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