Altered H19/miR-675 expression in skeletal muscle is associated with low muscle mass in community-dwelling older adults
Altered H19/miR-675 expression in skeletal muscle is associated with low muscle mass in community-dwelling older adults
复制标题
骨骼肌中 H19/miR-675 表达的改变与社区老年人的低肌肉质量有关
DOI：
10.1002/rco2.44
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发表时间：
2021
影响因子：
--
通讯作者：
Antoun E
中科院分区：
文献类型：
--
作者：
Antoun E
背景虽然人们对肌肉衰老的发病机制有了越来越多的了解，但对其分子机制却知之甚少。基于对老年高加索男性肌肉活检组织的表达分析，我们对非编码的长RNA H19的表达进行了深入的分析，以确定可能导致肌肉质量随年龄减少的分子机制。方法我们对赫特福德郡萨科普尼亚研究(HSS)40名年龄在68-76岁的健康高加索男性的股外侧肌活检组织进行了转录组分析。使用qRT-PCR对130名年龄在73-83岁的独立男性和女性参与者进行了验证和复制，这些参与者被招募到HSS(HSSE)的延伸部分。结果ALMI越低，肌肉H19的表达越高(R2=0.177，P<0.001)。由H19外显子1编码的miR-675-5p/3与H19的表达呈正相关(P=0.192和0.182，P=0.03)，miR-675-5p的表达与ALMI呈负相关(R2=0.629，P=0.005)。H19印迹控制区CpG甲基化与H19表达呈负相关(Pearsonr=−0.211~−0.245，P≤=0.05)。此外，miR-675-3p的靶标Smad1和Smad5的RNA和蛋白水平与miR-675-3p和miR-675-5p的表达呈负相关(r2分别为0.792和0.760)和miR-675-5p的表达呈负相关(r2分别为0.584和0.723)，Smad1和5RNA的表达水平与较大的II型纤维尺寸呈正相关(r2分别为0.184和0.246，P均<0.05)。
BackgroundDespite increasing knowledge of the pathogenesis of muscle ageing, the molecular mechanisms are poorly understood. Based on an expression analysis of muscle biopsies from older Caucasian men, we undertook an in‐depth analysis of the expression of the long non‐coding RNA,H19, to identify molecular mechanisms that may contribute to the loss of muscle mass with age.MethodsWe carried out transcriptome analysis ofvastus lateralismuscle biopsies from 40 healthy Caucasian men aged 68–76 years from the Hertfordshire Sarcopenia Study (HSS) with respect to appendicular lean mass adjusted for height (ALMi). Validation and replication was carried out using qRT‐PCR in 130 independent male and female participants aged 73–83 years recruited into an extension of the HSS (HSSe). DNA methylation was assessed using pyrosequencing.ResultsLower ALMi was associated with higher muscleH19expression (r2= 0.177,P< 0.001). The microRNAs,miR‐675‐5p/3pencoded by exon 1 ofH19, were positively correlated withH19expression (Pearsonr= 0.192 and 0.182, respectively,P< 0.03), andmiR‐675‐5pexpression negatively associated with ALMi (r2= 0.629,P= 0.005). The methylation of CpGs within the H19 imprinting control region (ICR) were negatively correlated withH19expression (Pearsonr= −0.211 to −0.245,P≤ 0.05). Moreover, RNA and protein levels ofSMAD1and5, targets ofmiR‐675‐3p, were negatively associated withmiR‐675‐3p(r2= 0.792 and 0.760, respectively) andmiR‐675‐5p(r2= 0.584 and 0.723, respectively) expression, andSMAD1and5RNA levels positively associated with greater type II fibre size (r2= 0.184 and 0.246, respectively,P< 0.05).ConclusionsIncreased expression profiles ofH19/miR‐675‐5p/3pand lower expression of the anabolicSMAD1/5effectors of bone morphogenetic protein (BMP) signalling are associated with low muscle mass in older individuals.