title: MicroRNA expression and protein acetylation pattern in respiratory and limb muscles of Parp-1(-/-) and Parp-2(-/-) mice with lung cancer cachexia.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Alba
authors.initials: A
authors.lastname: Chacon-Cabrera
authors.affiliation: 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.
authors.forename: Clara
authors.initials: C
authors.lastname: Fermoselle
authors.affiliation: Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Salmela
authors.affiliation: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III (ISCIII), C/ Monforte de Lemos 5, Madrid E-28029, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Yelamos
authors.affiliation: 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. Electronic address: ebarreiro@imim.es.
authors.forename: Esther
authors.initials: E
authors.lastname: Barreiro
mesh_terms: D000107:Acetylation; D000818:Animals; D002100:Cachexia / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse
keywords: Cancer-induced cachexia; Muscle structure and function; Muscle-enriched microRNAs; Myogenic transcription factors; Parp-1(−/−) and Parp-2(−/−) mice; Protein hyperacetylation