Adiposity is associated with widespread transcriptional changes and downregulation of longevity pathways in aged skeletal muscle.
Adiposity is associated with widespread transcriptional changes and downregulation of longevity pathways in aged skeletal muscle.
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DOI：
10.1002/jcsm.13255
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发表时间：
2023-08
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影响因子：
--
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中科院分区：
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在健康的老年人中，已经确定了许多与骨骼肌质量和功能受损相关的因素。虽然肥胖症的患病率在这个年龄组中显著增加，但关于肥胖症对衰老骨骼肌的特定影响或构成这种影响的分子机制以及相关疾病风险的信息很少。在这里，我们使用来自赫特福德郡肌肉减少症研究的40名老年社区居民男性的肌肉活检中的RNA测序检查了基因组范围内的转录变化，包括肥胖（体重指数[BMI] >30 kg/m2，n = 7），超重（BMI 25-30，n = 19），正常体重（BMI < 25，n = 14）以及百分比和总脂肪量。此外，我们使用EPIC DNA甲基化阵列数据来研究老年骨骼肌组织中DNA甲基化和基因表达之间的相关性，并研究了改变的调控途径中的基因与肌肉组织学参数之间的关系。肥胖个体在肌肉组织中表现出显著的修饰转录特征，共有542个差异表达基因与肥胖相关（错误发现率≤0.05），其中425个基因与正常体重相比上调。上调的基因在免疫应答中富集（P = 3.18 × 10−41）和炎症（白细胞活化，P = 1.47 × 10−41;肿瘤坏死因子，P = 2.75 × 10−15）信号通路和下调基因丰富的长寿（P = 1.5 × 10−3）和AMP活化蛋白激酶（AMPK）（P = 4.5 × 10−3）信号通路。此外，长寿和AMPK信号通路中的差异表达基因与DNA甲基化的变化相关，分别鉴定了256和360个显著的胞嘧啶-磷酸-鸟嘌呤-基因相关性。在肌肉转录组中观察到脂肪质量百分比和总脂肪质量的类似变化。肥胖进一步与II型快纤维面积的显著增加相关（P = 0.026），其中长寿和AMPK途径中的关键调控基因显著相关。我们首次提供了一个全球性的骨骼肌转录谱老年人与肥胖和不肥胖，表明调制的关键基因和途径参与肌肉功能的调节，DNA甲基化的变化与这些途径和基因之间的关联涉及肌肉调节和肌纤维类型的变化的修饰途径。
Amongst healthy older people, a number of correlates of impaired skeletal muscle mass and function have been defined. Although the prevalence of obesity is increasing markedly in this age group, information is sparse about the particular impacts of obesity on ageing skeletal muscle or the molecular mechanisms that underlie this and associated disease risk. Here, we examined genome‐wide transcriptional changes using RNA sequencing in muscle biopsies from 40 older community‐dwelling men from the Hertfordshire Sarcopenia Study with regard to obesity (body mass index [BMI] >30 kg/m2, n = 7), overweight (BMI 25–30, n = 19), normal weight (BMI < 25, n = 14), and per cent and total fat mass. In addition, we used EPIC DNA methylation array data to investigate correlations between DNA methylation and gene expression in aged skeletal muscle tissue and investigated the relationship between genes within altered regulatory pathways and muscle histological parameters. Individuals with obesity demonstrated a prominent modified transcriptional signature in muscle tissue, with a total of 542 differentially expressed genes associated with obesity (false discovery rate ≤0.05), of which 425 genes were upregulated when compared with normal weight. Upregulated genes were enriched in immune response (P = 3.18 × 10−41) and inflammation (leucocyte activation, P = 1.47 × 10−41; tumour necrosis factor, P = 2.75 × 10−15) signalling pathways and downregulated genes enriched in longevity (P = 1.5 × 10−3) and AMP‐activated protein kinase (AMPK) (P = 4.5 × 10−3) signalling pathways. Furthermore, differentially expressed genes in both longevity and AMPK signalling pathways were associated with a change in DNA methylation, with a total of 256 and 360 significant cytosine–phosphate–guanine–gene correlations identified, respectively. Similar changes in the muscle transcriptome were observed with respect to per cent fat mass and total fat mass. Obesity was further associated with a significant increase in type II fast‐fibre area (P = 0.026), of which key regulatory genes within both longevity and AMPK pathways were significantly associated. We provide for the first time a global transcriptomic profile of skeletal muscle in older people with and without obesity, demonstrating modulation of key genes and pathways implicated in the regulation of muscle function, changes in DNA methylation associated with such pathways and associations between genes within the modified pathways implicated in muscle regulation and changes in muscle fibre type.
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影响因子：
7.8
作者：
Pawlikowska L;Hu D;Huntsman S;Sung A;Chu C;Chen J;Joyner AH;Schork NJ;Hsueh WC;Reiner AP;Psaty BM;Atzmon G;Barzilai N;Cummings SR;Browner WS;Kwok PY;Ziv E;Study of Osteoporotic Fractures
通讯作者：
Study of Osteoporotic Fractures
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
13.1
作者：
Shur NF;Creedon L;Skirrow S;Atherton PJ;MacDonald IA;Lund J;Greenhaff PL
通讯作者：
Greenhaff PL
影响因子：
16
作者：
Shimomura, I;Matsuda, M;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
4.8
作者：
Previs, SF;Withers, DJ;Shulman, GI
通讯作者：
Shulman, GI