Role of PARP activity in lung cancer-induced cachexia: Effects on muscle oxidative stress, proteolysis, anabolic markers, and phenotype.
Strategies to treat cachexia are still at its infancy. Enhanced muscle protein breakdown and ubiquitin-proteasome system are common features of cachexia associated with chronic conditions including lung cancer (LC). Poly(ADP-ribose) polymerases (PARP), which play a major role in chromatin structure regulation, also underlie maintenance of muscle metabolism and body composition. We hypothesized that protein catabolism, proteolytic markers, muscle fiber phenotype, and muscle anabolism may improve in respiratory and limb muscles of LC-cachectic Parp-1-deficient (Parp-1-/-) and Parp-2-/-mice. In diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing mice (wild type, Parp-1-/-, and Parp-2-/-), PARP activity (ADP-ribose polymers, pADPr), redox balance, muscle fiber phenotype, apoptotic nuclei, tyrosine release, protein ubiquitination, muscle-specific E3 ligases, NF-κB signaling pathway, markers of muscle anabolism (Akt, mTOR, p70S6K, and mitochondrial DNA) were evaluated along with body and muscle weights, and limb muscle force. Compared to wild type cachectic animals, in both respiratory and limb muscles of Parp-1-/-and Parp-2-/-cachectic mice: cancer induced-muscle wasting characterized by increased PARP activity, protein oxidation, tyrosine release, and ubiquitin-proteasome system (total protein ubiquitination, atrogin-1, and 20S proteasome C8 subunit) were blunted, the reduction in contractile myosin and atrophy of the fibers was attenuated, while no effects were seen in other structural features (inflammatory cells, internal or apoptotic nuclei), and markers of muscle anabolism partly improved. Activation of either PARP-1 or -2 is likely to play a role in muscle protein catabolism via oxidative stress, NF-κB signaling, and enhanced proteasomal degradation in cancer-induced cachexia. Therapeutic potential of PARP activity inhibition deserves attention.
Pulmonology Department-Lung Cancer and Muscle Research Group, IMIM-Hospital del Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
Alba
A
Chacon-Cabrera
Pulmonology Department-Lung Cancer and Muscle Research Group, IMIM-Hospital del Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
Mercè
M
Mateu-Jimenez
Integrative Pharmacology and Systems Neuroscience Research Group, Neurosciences Research Program, Hospital del Mal Medical Research Institute (IMIM), Barcelona, Spain.|Department of Statistics and Operations Research, Universitat Politècnica de Barcelona/Barcelonatech, Barcelona, Spain.
Klaus
K
Langohr
Pulmonology Department-Lung Cancer and Muscle Research Group, IMIM-Hospital del Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Clara
C
Fermoselle
Unitat de Patologia Neuromuscular i Mitocondrial, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
Elena
E
García-Arumí
Unitat de Patologia Neuromuscular i Mitocondrial, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
Antoni L
AL
Andreu
Cancer Research Program-Immunology, Hospital del Mar Medical Research Institute (IMIM)-Hospital del Mar, Barcelona, Spain.|Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
Jose
J
Yelamos
Pulmonology Department-Lung Cancer and Muscle Research Group, IMIM-Hospital del Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
Esther
E
Barreiro
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002100:Cachexia / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003964:Diaphragm / Q000201:enzymology / Q000473:pathology; D005260:Female; D005838:Genotype; D008175:Lung Neoplasms / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000201:enzymology* / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D013997:Time Factors; D054875:Ubiquitination
D015415:Biomarkers; D009124:Muscle Proteins; D016328:NF-kappa B; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; D046988:Proteasome Endopeptidase Complex
PARP activity; Parp-1−/− and Parp-2−/− mice; cancer-induced cachexia; muscle anabolism and catabolism and mitochondrial content; muscle atrophy and myosin loss