A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet Mice
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-protec...
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Frontiers Media S.A.
2020-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.601448/full |
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| author | Soo Jin Lee Sung-E Choi Han Byeol Lee Han Byeol Lee Min-Woo Song Min-Woo Song Young Ha Kim Jae Yeop Jeong Yup Kang Hae Jin Kim Tae Ho Kim Ja Young Jeon Kwan Woo Lee |
| author_facet | Soo Jin Lee Sung-E Choi Han Byeol Lee Han Byeol Lee Min-Woo Song Min-Woo Song Young Ha Kim Jae Yeop Jeong Yup Kang Hae Jin Kim Tae Ho Kim Ja Young Jeon Kwan Woo Lee |
| author_sort | Soo Jin Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T15:04:07Z |
| format | Article |
| id | doaj.art-8b5e571ff421483ebf7529b397729770 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-14T15:04:07Z |
| publishDate | 2020-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-8b5e571ff421483ebf7529b3977297702022-12-21T22:56:45ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-12-011110.3389/fphar.2020.601448601448A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet MiceSoo Jin Lee0Sung-E Choi1Han Byeol Lee2Han Byeol Lee3Min-Woo Song4Min-Woo Song5Young Ha Kim6Jae Yeop Jeong7Yup Kang8Hae Jin Kim9Tae Ho Kim10Ja Young Jeon11Kwan Woo Lee12Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South KoreaDepartment of Physiology, Ajou University School of Medicine, Suwon, South KoreaDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South KoreaDepartment of Biomedical Science, The Graduate School, Ajou University, Suwon, South KoreaDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South KoreaDepartment of Biomedical Science, The Graduate School, Ajou University, Suwon, South KoreaDivision of Cosmetics and Biotechnology, Hoseo University, Asan-si, South KoreaDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South KoreaDepartment of Physiology, Ajou University School of Medicine, Suwon, South KoreaDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine, Seoul Medical Center, Seoul, South KoreaDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South KoreaDepartment of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South KoreaHistone 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.https://www.frontiersin.org/articles/10.3389/fphar.2020.601448/fullHistone deacetylase inhibitorMS-275Insulin resistanceInflammationC2C12Lipotoxicity |
| spellingShingle | Soo Jin Lee Sung-E Choi Han Byeol Lee Han Byeol Lee Min-Woo Song Min-Woo Song Young Ha Kim Jae Yeop Jeong Yup Kang Hae Jin Kim Tae Ho Kim Ja Young Jeon Kwan Woo Lee A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet Mice Frontiers in Pharmacology Histone deacetylase inhibitor MS-275 Insulin resistance Inflammation C2C12 Lipotoxicity |
| title | A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet Mice |
| title_full | A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet Mice |
| title_fullStr | A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet Mice |
| title_full_unstemmed | A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet Mice |
| title_short | A Class I Histone Deacetylase Inhibitor Attenuates Insulin Resistance and Inflammation in Palmitate-Treated C2C12 Myotubes and Muscle of HF/HFr Diet Mice |
| title_sort | class i histone deacetylase inhibitor attenuates insulin resistance and inflammation in palmitate treated c2c12 myotubes and muscle of hf hfr diet mice |
| topic | Histone deacetylase inhibitor MS-275 Insulin resistance Inflammation C2C12 Lipotoxicity |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.601448/full |
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