Abstract
Histone deacetylase (HDAC) inhibitors, which regulate gene expression by inhibiting the deacetylation of histones and nonhistone proteins, have been shown to exert a wide array of biological effects; these include anti-cancer, anti-obesity, and anti-diabetes effects, as well as cardiovascular-protective activity. However, the effects of class I HDAC inhibition on lipotoxicity in C2C12 myotubes and skeletal muscle tissue remain poorly understood. In this study, we investigated the molecular mechanism underlying the protective effect of class I HDAC inhibition under lipotoxic conditions, i.e., in palmitate (PA)-treated C2C12 myotubes and skeletal muscle tissue in high fat (HF)/high fructose (HFr) diet mice. PA treatment of C2C12 myotubes increased HDAC3 protein expression and impaired mitochondrial oxidation, resulting in increased mitochondrial ROS generation and an accumulation of intracellular triglycerides (TG). Prolonged exposure led to increased inflammatory cytokine expression and insulin resistance. In contrast, MS-275, a class I HDAC inhibitor, dramatically attenuated lipotoxicity, preventing PA-induced insulin resistance and inflammatory cytokine expression. Similar beneficial effects were also seen following HDAC3 knockdown. In addition, MS-275 increased the mRNA expression of peroxisome proliferator activator receptor γ-coactivator 1α (PGC1α) and mitochondrial transcription factor A (TFAM), which serve as transcriptional coactivators in the context of mitochondrial metabolism and biogenesis, and restored expression of peroxisome proliferator-activated receptor alpha (PPARα), medium-chain acyl-coenzyme A dehydrogenase (MCAD), enoyl-CoA hydratase, and 3-hydroxyacyl CoA dehydrogenase (EHHADH). In vivo, treatment of HF/HFr-fed mice with MS-275 ameliorated hyperglycemia, insulin resistance, stress signals, and TNF-α expression in skeletal muscle. Taken together, these results suggest that HDAC3 inhibition rather than HDAC1/2 inhibition by MS-275 protects against lipotoxicity in C2C12 myotubes and skeletal muscle, and may be effective for the treatment of obesity and insulin resistance.
Highlights
Obesity is a rapidly growing global epidemic, and an important comorbidity of numerous metabolic diseases including diabetes, dyslipidemia, hypertension, and cardiovascular disease (Eckel et al, 2005; Poirier et al, 2006)
These results suggested that PA induced mitochondrial dysfunction and lipotoxicity in C2C12 myotubes, leading to significant increases in insulin resistance and inflammation
Impaired fatty acid oxidation and increased fatty acid content in skeletal muscle results in an accumulation of intracellular fat in skeletal muscle and chronic low-grade inflammation. This accumulation of excess fat in skeletal muscle leads to mitochondrial dysfunction and inflammation, which is associated with insulin resistance (Hoeks and Schrauwen, 2012; Meex et al, 2019)
Summary
Obesity is a rapidly growing global epidemic, and an important comorbidity of numerous metabolic diseases including diabetes, dyslipidemia, hypertension, and cardiovascular disease (Eckel et al, 2005; Poirier et al, 2006). Any abnormality in glucose metabolism in muscle tissue may induce lipotoxicity, resulting in systemic lipid accumulation and insulin resistance (Petersen et al, 2007; Petersen and Shulman, 2002; DeFronzo and Tripathy, 2009). Fatty acids and various cytokines secreted from intermuscular adipose tissue and peri-muscular adipose tissue have been shown to activate inflammatory signals (Sachs et al, 2019). This combination of lipid intermediaries and inflammatory signals stimulates serine kinases such as phospho-C-JUN-N-terminal kinase (p-JNK), IkB kinase (IKK), and protein kinase C θ (PKC θ), leading to insulin resistance (Glass and Olefsky, 2012; Wu and Ballantyne, 2017)
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