PGC-1α isoform heterodimerization restricts transcription factor docking and limits metabolic adaptations in skeletal muscle. PGC-1α isoform heterodimerization restricts transcription factor docking and limits metabolic adaptations in skeletal muscle

The PGC-1a gene is expressed as several transcriptional coactivator variants that regulate numerous adaptive processes. These include thermogenesis, hepatic metabolism, neuroprotection, and skeletal muscle adaptation to exercise training. To support such diverse functions, PGC-1 isoform expression and activation are under tight tissue- and context-specific control. Notably, PGC-1 isoforms generated by alternative gene promoter usage, and splicing are highly induced in skeletal muscle upon exercise. Here we show that PGC-12 and 3 are PGC-11 dimerization partners that limit its activity. Skeletal muscle PGC-12 and PGC-13 transgenics have reduced exercise performance and strength, which partially overlaps with PGC-1 loss-of-function. Mechanistically, PGC-11/3 dimerization precludes ERR recruitment and coactivation, so their co-expression in skeletal muscle impairs the innate bioenergetic adaptations characteristic of PGC-11 transgenics and reduces oxidative metabolism gene expression and exercise capacity. Removing this break to PGC-1a1 activity may have therapeutic applications in metabolic diseases and increase responsiveness to training. Overall design: Gastrocnemius muscle from either wild-type or HSA-PGC-1a3 transgenic mouse was used for RNASeq analysis to determine the overall changes of transcriptome of PGC-1a3 mice.

PGC-1α基因可转录为多种转录辅激活变体（transcriptional coactivator variants），参与调控诸多适应性生物学过程，包括产热、肝脏代谢、神经保护以及骨骼肌对运动训练的适应性重塑。为支撑多样的生物学功能，PGC-1α的异构体表达与激活受到严格的组织特异性和情境特异性调控。值得注意的是，通过可变基因启动子使用与可变剪接产生的PGC-1α异构体，在运动后的骨骼肌中会被高度诱导表达。
本研究证实，PGC-1α2与α3是PGC-1α1的二聚化伙伴，可抑制其活性。骨骼肌特异性过表达PGC-1α2或PGC-1α3的转基因小鼠，其运动能力与肌肉力量均出现下降，该表型与PGC-1α功能缺失小鼠的表型部分重合。从机制层面分析，PGC-1α1与α3形成二聚体后，会阻碍雌激素相关受体α（ERRα）的招募与共激活过程；因此二者在骨骼肌中共表达时，会削弱PGC-1α1转基因小鼠所特有的先天生物能量适应特征，同时降低氧化代谢相关基因的表达水平与运动耐力。
解除对PGC-1α1活性的这一抑制作用，有望为代谢疾病提供全新的治疗策略，并提升机体对运动训练的响应性。
整体实验设计：本研究以野生型小鼠及HSA-PGC-1α3转基因小鼠的腓肠肌为实验材料，开展RNA测序（RNASeq）分析，以明确PGC-1α3过表达对小鼠转录组的整体调控变化。