Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting.
Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting.
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DOI：
10.1038/s41598-017-10238-9
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发表时间：
2017-08-31
影响因子：
4.6
通讯作者：
Narkar VA
中科院分区：
文献类型：
--
作者：
Sopariwala DH;Yadav V;Badin PM;Likhite N;Sheth M;Lorca S;Vila IK;Kim ER;Tong Q;Song MS;Rodney GG;Narkar VA
骨骼肌萎缩在许多慢性疾病中普遍存在，需要对肌肉质量的分子调控进行研究。核受体共激活物过氧化物酶体增殖物活化受体共激活物1α (PGC1α)及其剪接变体PGC1α4增加骨骼肌质量。然而，另一种PGC1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型快速抽搐肌纤维的损失相关。矛盾的是，PGC1β抑制泛素蛋白水解降解途径基因，导致泛素蛋白在肌肉中积累。然而，PGC1β过表达会触发凋亡和自噬基因的上调，导致这些细胞退行性过程的强烈激活，并伴随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，这可能促进肌病。因此，随着时间的推移，PGC1β的激活会对肌肉质量产生负面影响，特别是快速收缩肌肉，这应该与它在骨骼肌中的已知有氧作用一起考虑。
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.
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影响因子：
8.8
作者：
Carnio S;LoVerso F;Baraibar MA;Longa E;Khan MM;Maffei M;Reischl M;Canepari M;Loefler S;Kern H;Blaauw B;Friguet B;Bottinelli R;Rudolf R;Sandri M
通讯作者：
Sandri M
影响因子：
3.3
作者：
Barreiro, Esther;Ferrer, Dolores;Gea, Joaquim
通讯作者：
Gea, Joaquim
影响因子：
3.5
作者：
Carmignac, Virginie;Svensson, Martina;Durbeej, Madeleine
通讯作者：
Durbeej, Madeleine
影响因子：
11.2
作者：
Gallot, Yann S.;Durieux, Anne-Cecile;Freyssenet, Damien G.
通讯作者：
Freyssenet, Damien G.
影响因子：
4.8
作者：
Doyle, Alexander;Zhang, Guohua;Li, Yi-Ping
通讯作者：
Li, Yi-Ping