Olie Cyriel S, Riaz Muhammad, Konietzny Rebecca, Charles Philip D, Pinto-Fernandez Adan, Kiełbasa Szymon M, Aartsma-Rus A, Goeman Jelle J, Kessler Benedikt M, Raz Vered
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
iScience. 2019 Feb 22;12:318-332. doi: 10.1016/j.isci.2019.01.024. Epub 2019 Jan 22.
Reduced poly(A)-binding protein nuclear 1 (PABPN1) levels cause aging-associated muscle wasting. PABPN1 is a multifunctional regulator of mRNA processing. To elucidate the molecular mechanisms causing PABPN1-mediated muscle wasting, we compared the transcriptome with the proteome in mouse muscles expressing short hairpin RNA to PABPN1 (shPab). We found greater variations in the proteome than in mRNA expression profiles. Protein accumulation in the shPab proteome was concomitant with reduced proteasomal activity. Notably, protein acetylation appeared to be decreased in shPab versus control proteomes (63%). Acetylome profiling in shPab muscles revealed prominent peptide deacetylation associated with elevated sirtuin-1 (SIRT1) deacetylase. We show that SIRT1 mRNA levels are controlled by PABPN1 via alternative polyadenylation site utilization. Most importantly, SIRT1 deacetylase inhibition by sirtinol increased PABPN1 levels and reversed muscle wasting. We suggest that perturbation of a multifactorial regulatory loop involving PABPN1 and SIRT1 plays an imperative role in aging-associated muscle wasting. VIDEO ABSTRACT.
聚腺苷酸结合蛋白核1（PABPN1）水平降低会导致与衰老相关的肌肉萎缩。PABPN1是mRNA加工的多功能调节因子。为了阐明导致PABPN1介导的肌肉萎缩的分子机制，我们将表达针对PABPN1的短发夹RNA（shPab）的小鼠肌肉中的转录组与蛋白质组进行了比较。我们发现蛋白质组中的变化比mRNA表达谱中的变化更大。shPab蛋白质组中的蛋白质积累与蛋白酶体活性降低同时出现。值得注意的是，与对照蛋白质组相比，shPab中的蛋白质乙酰化似乎降低了（63%）。shPab肌肉中的乙酰化组分析揭示了与沉默调节蛋白1（SIRT1）脱乙酰酶升高相关的显著肽去乙酰化。我们表明，SIRT1 mRNA水平由PABPN1通过可变聚腺苷酸化位点利用来控制。最重要的是，sirtinol对SIRT1脱乙酰酶的抑制增加了PABPN1水平并逆转了肌肉萎缩。我们认为，涉及PABPN1和SIRT1的多因素调节环的扰动在与衰老相关的肌肉萎缩中起着至关重要的作用。视频摘要。
