Henagan Tara M, Stewart Laura K, Forney Laura A, Sparks Lauren M, Johannsen Neil, Church Timothy S
Department of Nutrition Science, Purdue University, 700 W. State Street, West Lafayette, IN 47907, USA.
Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO 80639, USA.
PPAR Res. 2014;2014:895734. doi: 10.1155/2014/895734. Epub 2014 Dec 28.
PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1α -1 nucleosome (-1N) position is associated with splice variant NTPGC1α but not FLPGC1α expression. Division of participants based on the -1N position revealed that those individuals with a -1N phased further upstream from the transcriptional start site (UP) expressed lower levels of NTPGC1α than those with the -1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the -1N may be a potential epigenetic regulator of NTPGC1α splice variant expression, and -1N position and NTPGC1α variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133.
PGC1α是一种转录共激活因子，它与过氧化物酶体增殖物激活受体（PPARs）及其他因子相互作用，以调节骨骼肌代谢。PGC1α会发生剪接，产生多种mRNA变体，其中NTPGC1α变体具有与全长PGC1α（FLPGC1α）相似的生物学功能。心血管疾病（CVD）与肥胖症和2型糖尿病相关，且骨骼肌中1型氧化纤维比例较低以及线粒体功能受损，这些特征由PGC1α的表达决定。PGC1α在骨骼肌中的表达受到表观遗传调控，以决定线粒体的适应性，并且表观遗传修饰可能调节mRNA剪接。我们在本文中报告，骨骼肌PGC1α -1核小体（-1N）的位置与剪接变体NTPGC1α的表达相关，但与FLPGC1α的表达无关。根据-1N位置对参与者进行划分后发现，那些-1N在转录起始位点（TSS）上游相位更远（UP）的个体，其NTPGC1α的表达水平低于-1N更靠近TSS（DN）的个体。UP组的体脂百分比以及血清总胆固醇和低密度脂蛋白胆固醇有所增加。这些发现表明，-1N可能是NTPGC1α剪接变体表达的潜在表观遗传调节因子，并且骨骼肌中-1N的位置和NTPGC1α变体的表达与心血管疾病风险相关。该试验已在clinicaltrials.gov上注册，标识符为NCT00458133。
