Role of PARP activity in lung cancer‐induced cachexia: Effects on muscle oxidative stress, proteolysis, anabolic markers, and phenotype

• Published in: Journal of cellular physiology Vol. 232; no. 12; pp. 3744 - 3761
• Main Authors: Chacon‐Cabrera, Alba, Mateu‐Jimenez, Mercè, Langohr, Klaus, Fermoselle, Clara, García‐Arumí, Elena, Andreu, Antoni L., Yelamos, Jose, Barreiro, Esther
• Format: Journal Article Publication
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.12.2017
• Subjects: 62 Statistics; 62D05 Sampling theory, sample surveys; 62H Multivariate analysis; 92 Biology and other natural sciences; 92D Genetics and population dynamics; Adenocarcinoma; Adenosine diphosphate; AKT protein; Animals; Anàlisi multivariable; Anàlisi numèrica; Apoptosis; Atrophy; Biomarkers - metabolism; Body composition; Cachexia; Cachexia - enzymology; Cachexia - etiology; Cachexia - genetics; Cachexia - pathology; Cancer; cancer-induced cachexia; Catabolism; Cell Line, Tumor; Chromatin; Chronic conditions; Chronic illnesses; Classificació AMS; Degradation; Deoxyribonucleic acid; Diaphragm; Diaphragm (anatomy); Diaphragm - enzymology; Diaphragm - pathology; DNA; Female; Fibers; Genetics; Genotype; Genotype & phenotype; Genètica; Inflammation; Lung cancer; Lung Neoplasms - complications; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Markers; Matemàtica aplicada a les ciències; Matemàtiques i estadística; Metabolism; Mice; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - pathology; Mitochondrial DNA; Mostreig (Estadística); Multivariate analysis; muscle anabolism and catabolism and mitochondrial content; muscle atrophy and myosin loss; Muscle contraction; Muscle Fibers, Skeletal - enzymology; Muscle Fibers, Skeletal - pathology; Muscle Proteins - metabolism; Muscle, Skeletal - enzymology; Muscle, Skeletal - pathology; Muscles; Myosin; NF-kappa B - metabolism; NF-κB protein; Nuclei; Nuclei (cytology); Organ Size; Oxidation; Oxidative Stress; PARP activity; Parp-1-/- and Parp-2-/- mice; Parp‐1−/− and Parp‐2−/− mice; Phenotype; Poly (ADP-Ribose) Polymerase-1 - deficiency; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - deficiency; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Polymers; Probabilitat; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein composition; Proteins; Proteolysis; Ribose; Rodents; Sampling (Statistics); Signal Transduction; Time Factors; Tyrosine; Ubiquitin-protein ligase; Ubiquitination; Àrees temàtiques de la UPC; Parp-1−/− and Parp-2−/− mice; muscle atrophy and myosin loss; PARP activity; muscle anabolism and catabolism and mitochondrial content; cancer-induced cachexia
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.25851

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. The study findings imply that activation of either PARP‐1 or ‐2 is likely to play a relevant role in muscle protein catabolism via oxidative stress, NF‐κB signaling, and enhanced proteasomal degradation in cancer‐induced cachexia. Despite the potential limitations of PARP activity inhibition, since it plays a key role in DNA maintenance, exploration of its reliability, and likely applicability as a possible target for future therapeutic interventions deserves attention in models of cancer‐induced cachexia.