Tuntevski Kiril, Hajira Ameena, Nichols Austin, Alway Stephen E, Mohamed Junaith S
Department of Human Performance West Virginia University School of Medicine Morgantown WV USA.
Laboratory of Muscle Biology and Sarcopenia Department of Physical Therapy College of Health Professions University of Tennessee Health Science Center Memphis TN USA.
FASEB Bioadv. 2020 Jul 3;2(7):387-397. doi: 10.1096/fba.2020-00017. eCollection 2020 Jul.
Stroke causes severe long-term disability in patients due to the induction of skeletal muscle atrophy and weakness, but the molecular mechanisms remain elusive. Using a preclinical mouse model of cerebral ischemic stroke, we show that stroke robustly induced atrophy and significantly decreased SirT1 gene expression in the PTA (paralytic tibialis anterior) muscle. Muscle-specific SirT1 gain-of-function mice are resistant to stroke-induced muscle atrophy and this protective effect requires its deacetylase activity. Although SirT1 counteracts the stroke-induced up-regulation of atrogin1, MuRF1 and ZNF216 genes, we found a mechanism that regulates the ZNF216 gene transcription in post-stroke muscle. Stroke increased the expression of the ZNF216 gene in PTA muscle by activating PARP-1, which binds on the ZNF216 promoter. The SirT1 gain-of-function or SirT1 activator, resveratrol, reversed the PARP-1-mediated up-regulation of ZNF216 expression at the promoter level, suggesting a contradicted role for SirT1 and PARP-1 in the regulation of ZNF216 gene. Overall, our study for the first-time demonstrated that (a) stroke causes muscle atrophy, in part, through the SirT1/PARP-1/ZNF216 signaling mechanism; (b) SirT1 can block muscle atrophy in response to different types of atrophic signals via different signaling mechanisms; and (c) SirT1 is a critical regulator of post-stroke muscle mass.
中风会导致患者出现严重的长期残疾，这是由于骨骼肌萎缩和无力所致，但其分子机制仍不清楚。利用脑缺血性中风的临床前小鼠模型，我们发现中风会强烈诱导萎缩，并显著降低PTA（麻痹性胫前肌）肌肉中SirT1基因的表达。肌肉特异性SirT1功能增强型小鼠对中风诱导的肌肉萎缩具有抗性，且这种保护作用需要其脱乙酰酶活性。尽管SirT1可抵消中风诱导的atrogin1、MuRF1和ZNF216基因的上调，但我们发现了一种在中风后肌肉中调节ZNF216基因转录的机制。中风通过激活结合在ZNF216启动子上的PARP-1，增加了PTA肌肉中ZNF216基因的表达。SirT1功能增强型或SirT1激活剂白藜芦醇在启动子水平上逆转了PARP-1介导的ZNF216表达上调，这表明SirT1和PARP-1在ZNF216基因调控中起相反作用。总体而言，我们的研究首次证明：（a）中风部分通过SirT1/PARP-1/ZNF216信号机制导致肌肉萎缩；（b）SirT1可通过不同信号机制阻断对不同类型萎缩信号的肌肉萎缩反应；（c）SirT1是中风后肌肉质量的关键调节因子。
