Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, TX, 77030, USA.
Department of Biochemistry and Cell Biology, Rice University, Houston, TX, 77005, USA.
Sci Rep. 2017 Aug 31;7(1):10237. doi: 10.1038/s41598-017-10238-9.
Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1α) and its splice variant PGC1α4 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1β, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1β in the skeletal muscle, we have found that PGC1β progressively decreases skeletal muscle mass predominantly associated with loss of type 2b fast-twitch myofibers. Paradoxically, PGC1β represses the ubiquitin-proteolysis degradation pathway genes resulting in ubiquitinated protein accumulation in muscle. However, PGC1β overexpression triggers up-regulation of apoptosis and autophagy genes, resulting in robust activation of these cell degenerative processes, and a concomitant increase in muscle protein oxidation. Concurrently, PGC1β up-regulates apoptosis and/or autophagy transcriptional factors such as E2f1, Atf3, Stat1, and Stat3, which may be facilitating myopathy. Therefore, PGC1β activation negatively affects muscle mass over time, particularly fast-twitch muscles, which should be taken into consideration along with its known aerobic effects in the skeletal muscle.
骨骼肌减少在许多慢性疾病中很常见，因此需要研究肌肉质量的分子调控机制。核受体共激活因子过氧化物酶体增殖物激活受体共激活因子 1α（PGC1α）及其剪接变异体 PGC1α4 可增加骨骼肌质量。然而，PGC1 的其他亚型 PGC1β 对肌肉大小的影响尚不清楚。在骨骼肌中选择性过表达 PGC1β 的转基因小鼠中，我们发现 PGC1β 逐渐减少骨骼肌质量，主要与 2b 型快肌纤维的丢失有关。矛盾的是，PGC1β 抑制了泛素-蛋白酶体降解途径基因，导致肌肉中泛素化蛋白的积累。然而，PGC1β 的过表达会引发细胞凋亡和自噬基因的上调，导致这些细胞退化过程的强烈激活，以及肌肉蛋白氧化的增加。同时，PGC1β 上调凋亡和/或自噬转录因子，如 E2f1、Atf3、Stat1 和 Stat3，这可能有助于肌病的发生。因此，PGC1β 的激活会随着时间的推移对肌肉质量产生负面影响，特别是快肌，这应该与它在骨骼肌中的已知有氧效应一起考虑。
