Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS).
Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS).
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DOI：
10.1002/jcsm.12876
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
EpiGen Global Research Consortium
中科院分区：
文献类型：
--
作者：
Antoun E;Garratt ES;Taddei A;Burton MA;Barton SJ;Titcombe P;Westbury LD;Baczynska A;Migliavacca E;Feige JN;Sydall HE;Dennison E;Dodds R;Roberts HC;Richardson P;Sayer AA;Shaw S;Cooper C;Holbrook JD;Patel HP;Godfrey KM;Lillycrop KA;EpiGen Global Research Consortium
肌肉减少症是与年龄相关的肌肉质量、力量和功能的丧失。 DNA甲基化等表观遗传过程整合了遗传和环境暴露，被认为有助于肌肉减少症的发生。本研究旨在确定肌肉甲基化组的差异是否与肌肉减少症及其组成指标相关：握力、四肢瘦质量指数 (ALMi) 和步态速度。使用 Infinium Human MmethylationEPIC BeadChip，我们测量了来自赫特福德郡肌肉减少症研究 (HSS) 和赫特福德郡肌肉减少症研究扩展 (HSSe) 的 83 名平均（标准差）年龄为 75.7 (3.6) 岁的男性参与者（其中 12 名患有肌肉减少症）的股外侧肌活检中的 DNA 甲基化，并检查了与肌肉减少症及其组成部分的关联。确定了差异甲基化 CpG (dmCpG) 的通路、组蛋白标记和转录因子富集，并使用亚硫酸氢钠焦磷酸测序来验证肌肉减少症相关的 dmCpG。使用 EZH2 抑制剂 GSK343 处理从 HSSe 男性个体股外侧肌活检中分离出的人原代成肌细胞 (n = 6)，以评估表观遗传过程中的扰动如何影响成肌细胞分化和融合，通过 PAX7 和 MYHC 免疫细胞化学进行测量，并使用 Seahorse XF96 测定线粒体生物能学。肌肉减少症与 176 个 dmCpG（错误发现率≤0.05）和 141 个差异甲基化区域（Stouffer ≤0.05）的差异甲基化相关。肌少症相关的 dmCpG 富含与肌管融合（P = 1.40E-03）、氧化磷酸化（P = 2.78E-02）和电压门控钙通道（P = 1.59E-04）相关的基因。 ALMi 与 71 个 dmCpG 相关，握力与 49 个 dmCpG 相关，步态速度与 23 个 dmCpG 相关（错误发现率≤0.05）。与肌肉减少症和 ALMi (P = 3.4E-35)、肌肉减少症和步态速度 (P = 4.78E-03) 以及肌肉减少症和握力 (P = 7.55E-06) 相关的 dmCpG 之间存在显着重叠。与 H3K27 三甲基化位点（所有 P ≤ 0.05）和 EZH2 靶基因（所有 P ≤ 0.05）的肌少症、ALMi、握力和步态速度相关的 dmCpG 也存在过度表达。此外，用EZH2抑制剂GSK343抑制剂处理人原代成肌细胞会导致PAX7表达增加（P≤0.05）、肌管融合减少（P=0.043）和ATP产量增加（P=0.008），同时参与氧化磷酸化和肌生成的基因的DNA甲基化发生改变。这些发现表明，肌肉甲基化组的差异与肌肉减少症以及老年人肌肉质量、力量和功能的个体测量有关。这表明基因表观遗传调控的变化可能会导致晚年肌肉功能受损。
Sarcopenia is the age‐related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed. Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia‐associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96. Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia‐associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E‐03), oxidative phosphorylation (P = 2.78E‐02), and voltage‐gated calcium channels (P = 1.59E‐04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E‐35), sarcopenia and gait speed (P = 4.78E‐03), and sarcopenia and grip strength (P = 7.55E‐06). There was also an over‐representation of the sarcopenia, ALMi, grip strength, and gait speed‐associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis. These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
7.8
作者：
Matteini AM;Tanaka T;Karasik D;Atzmon G;Chou WC;Eicher JD;Johnson AD;Arnold AM;Callisaya ML;Davies G;Evans DS;Holtfreter B;Lohman K;Lunetta KL;Mangino M;Smith AV;Smith JA;Teumer A;Yu L;Arking DE;Buchman AS;Chibinik LB;De Jager PL;Evans DA;Faul JD;Garcia ME;Gillham-Nasenya I;Gudnason V;Hofman A;Hsu YH;Ittermann T;Lahousse L;Liewald DC;Liu Y;Lopez L;Rivadeneira F;Rotter JI;Siggeirsdottir K;Starr JM;Thomson R;Tranah GJ;Uitterlinden AG;Völker U;Völzke H;Weir DR;Yaffe K;Zhao W;Zhuang WV;Zmuda JM;Bennett DA;Cummings SR;Deary IJ;Ferrucci L;Harris TB;Kardia SL;Kocher T;Kritchevsky SB;Psaty BM;Seshadri S;Spector TD;Srikanth VK;Windham BG;Zillikens MC;Newman AB;Walston JD;Kiel DP;Murabito JM
通讯作者：
Murabito JM
影响因子：
14.9
作者：
Aljanabi, SM;Martinez, I
通讯作者：
Martinez, I
影响因子：
3
作者：
Bader, GD;Hogue, CW
通讯作者：
Hogue, CW
影响因子：
5.8
作者：
Aryee, Martin J.;Jaffe, Andrew E.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.