Chacon-Cabrera Alba, Fermoselle Clara, Salmela Ida, Yelamos Jose, Barreiro Esther
Pulmonology Department-Lung Cancer Research Group, IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), C/ Dr. Aiguader, 88, Barcelona E-08003, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
Pulmonology Department-Lung Cancer Research Group, IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), C/ Dr. Aiguader, 88, Barcelona E-08003, Spain.
Biochim Biophys Acta. 2015 Dec;1850(12):2530-43. doi: 10.1016/j.bbagen.2015.09.020. Epub 2015 Oct 12.
Current treatment options for cachexia, which impairs disease prognosis, are limited. Muscle-enriched microRNAs and protein acetylation are involved in muscle wasting including lung cancer (LC) cachexia. Poly(ADP-ribose) polymerases (PARP) are involved in muscle metabolism. We hypothesized that muscle-enriched microRNA, protein hyperacetylation, and expression levels of myogenic transcription factors (MTFs) and downstream targets, muscle loss and function improve in LC cachectic Parp-1(−/−) and Parp-2(−/−) mice.
Body and muscle weights, grip strength, muscle phenotype, muscle-enriched microRNAs (miR-1, -133, -206, and -486), protein acetylation, acetylated levels of FoxO1, FoxO3, and PGC-1α, histone deacetylases (HDACs) including SIRT1, MTFs, and downstream targets (α-actin, PGC-1α, and creatine kinase) were evaluated in diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) wild type (WT), Parp-1(−/−) and Parp-2−/− mice.
Compared to WT cachectic animals, in both respiratory and limb muscles of Parp-1(−/−) and Parp-2(−/−) cachectic mice: downregulation of muscle-specific microRNAs was counterbalanced especially in gastrocnemius of Parp-1(−/−) mice; increased protein acetylation was attenuated (improvement in HDAC3, SIRT-1, and acetylated FoxO3 levels in both muscles, acetylated FoxO1 levels in the diaphragm); reduced MTFs and creatine kinase levels were mitigated; body and muscle weights, strength, and muscle fiber sizes improved, while tumor weight and growth decreased.
These molecular findings may explain the improvements seen in body and muscle weights, limb muscle force and fiber sizes in both Parp-1(−/−) and Parp-2(−/−) cachectic mice.
PARP-1 and -2 play a role in cancer-induced cachexia, thus selective pharmacological inhibition of PARP-1 and -2 may be of interest in clinical settings.
恶病质会影响疾病预后，目前针对恶病质的治疗选择有限。富含肌肉的微小RNA和蛋白质乙酰化参与包括肺癌（LC）恶病质在内的肌肉萎缩过程。聚（ADP - 核糖）聚合酶（PARP）参与肌肉代谢。我们假设在LC恶病质的Parp - 1（−/−）和Parp - 2（−/−）小鼠中，富含肌肉的微小RNA、蛋白质高乙酰化以及生肌转录因子（MTF）及其下游靶点的表达水平、肌肉损失和功能会得到改善。
对LC（LP07腺癌）野生型（WT）、Parp - 1（−/−）和Parp - 2−/−小鼠的膈肌和腓肠肌进行体重和肌肉重量、握力、肌肉表型、富含肌肉的微小RNA（miR - 1、- 133、- 206和- 486）、蛋白质乙酰化、FoxO1、FoxO3和PGC - 1α的乙酰化水平、包括SIRT1在内的组蛋白去乙酰化酶（HDAC）、MTF及其下游靶点（α - 肌动蛋白、PGC - 1α和肌酸激酶）的评估。
与WT恶病质动物相比，在Parp - 1（−/−）和Parp - 2（−/−）恶病质小鼠的呼吸肌和肢体肌肉中：肌肉特异性微小RNA的下调尤其在Parp - 1（−/−）小鼠的腓肠肌中得到平衡；蛋白质乙酰化增加得到缓解（两块肌肉中HDACs3、SIRT - 1和乙酰化FoxO3水平改善，膈肌中乙酰化FoxO1水平改善）；MTF和肌酸激酶水平降低得到缓解；体重、肌肉重量、力量和肌纤维大小得到改善，而肿瘤重量和生长减少。
这些分子学发现可能解释了在Parp - 1（−/−）和Parp - 2（−/−）恶病质小鼠中体重、肌肉重量、肢体肌肉力量和肌纤维大小所出现的改善情况。
PARP - 1和- 2在癌症诱导的恶病质中起作用，因此PARP - 1和- 2的选择性药理抑制在临床环境中可能具有意义。
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