DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults.
DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults.
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DOI：
10.1186/s13395-023-00326-y
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发表时间：
2023-10-28
期刊：
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然衰老与胰岛素抵抗（IR）增加有关，但肌肉（葡萄糖清除的主要器官）中IR增加的分子机制尚未在老年人中阐明。由于表观遗传过程被认为有助于衰老相关疾病的发展，我们研究了差异DNA甲基化是否与来自社区居住的老年人的人原代肌肉干细胞（成肌细胞）中的IR相关。我们测量了DNA甲基化（Infinium HumanMethylationEPIC BeadChip）在股外侧肌活检的成肌细胞培养物中（119名男性/女性，平均年龄78.24岁），并检查了差异甲基化胞嘧啶磷酸鸟嘌呤（CpG）位点（dmCpG）、区域（DMR）和与HOMA 2-IR相关的基因途径，HOMA 2-IR是评估胰岛素抵抗的指标，以及糖化血红蛋白HbA 1c水平38个dmCpGs（错误发现率（FDR）< 0.05）与HOMA 2-IR相关，其中dmCpGs富含与JNK、AMPK和胰岛素信号传导相关的基因。在模型中加入BMI（6 dmCpG）、非典型瘦体重指数（ALMi）（7 dmCpG）、握力（15 dmCpG）或步态速度（23 dmCpG）作为协变量后，与HOMA 2-IR相关的甲基化信号减弱。有8个DMR（Stouffer < 0.05）与HOMA 2-IR相关，包括T-box转录因子（TBX 1）和核受体亚家族-2组F成员-2（NR 2F 2）内的DMR;在调整BMI、ALMi、握力或步态速度后，TBX 1和NR 2F 2内的DMR仍与HOMA 2-IR相关。49个dmCpG和21个DMR与HbA 1c相关，其中cg 13451048位于与HOMA 2-IR和HbA 1c相关的核糖核酸外切酶家族成员3（ERI 3）内。HOMA 2-IR和HbA 1c与加速表观遗传衰老无关。这些研究结果表明，胰岛素抵抗与人类原代成肌细胞的差异DNA甲基化有关，肌肉质量和身体成分对IR相关的甲基化变化有显著贡献。在线版本包含补充材料，可在10.1186/s13395-023-00326-y获得。
While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in the muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to the development of ageing-associated diseases, we investigated whether differential DNA methylation was associated with IR in human primary muscle stem cells (myoblasts) from community-dwelling older individuals. We measured DNA methylation (Infinium HumanMethylationEPIC BeadChip) in myoblast cultures from vastus lateralis biopsies (119 males/females, mean age 78.24 years) from the Hertfordshire Sarcopenia Study extension (HSSe) and examined differentially methylated cytosine phosphate guanine (CpG) sites (dmCpG), regions (DMRs) and gene pathways associated with HOMA2-IR, an index for the assessment of insulin resistance, and levels of glycated hemoglobin HbA1c. Thirty-eight dmCpGs (false discovery rate (FDR) < 0.05) were associated with HOMA2-IR, with dmCpGs enriched in genes linked with JNK, AMPK and insulin signaling. The methylation signal associated with HOMA2-IR was attenuated after the addition of either BMI (6 dmCpGs), appendicular lean mass index (ALMi) (7 dmCpGs), grip strength (15 dmCpGs) or gait speed (23 dmCpGs) as covariates in the model. There were 8 DMRs (Stouffer < 0.05) associated with HOMA2-IR, including DMRs within T-box transcription factor (TBX1) and nuclear receptor subfamily-2 group F member-2 (NR2F2); the DMRs within TBX1 and NR2F2 remained associated with HOMA2-IR after adjustment for BMI, ALMi, grip strength or gait speed. Forty-nine dmCpGs and 21 DMRs were associated with HbA1c, with cg13451048, located within exoribonuclease family member 3 (ERI3) associated with both HOMA2-IR and HbA1c. HOMA2-IR and HbA1c were not associated with accelerated epigenetic ageing. These findings suggest that insulin resistance is associated with differential DNA methylation in human primary myoblasts with both muscle mass and body composition making a significant contribution to the methylation changes associated with IR. The online version contains supplementary material available at 10.1186/s13395-023-00326-y.
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影响因子：
4.8
作者：
Boncompagni, Simona;Moussa, Charbel E. -H.;Shtifman, Alexander
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