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Molecular mechanisms underlying COPD-muscle dysfunction unveiled through a systems medicine approach.

ABSTRACT: MOTIVATION:Skeletal muscle dysfunction is a systemic effect in one-third of patients with chronic obstructive pulmonary disease (COPD), characterized by high reactive-oxygen-species (ROS) production and abnormal endurance training-induced adaptive changes. However, the role of ROS in COPD remains unclear, not least because of the lack of appropriate tools to study multifactorial diseases. RESULTS:We describe a discrete model-driven method combining mechanistic and probabilistic approaches to decipher the role of ROS on the activity state of skeletal muscle regulatory network, assessed before and after an 8-week endurance training program in COPD patients and healthy subjects. In COPD, our computational analysis indicates abnormal training-induced regulatory responses leading to defective tissue remodeling and abnormal energy metabolism. Moreover, we identified tnf, insr, inha and myc as key regulators of abnormal training-induced adaptations in COPD. The tnf-insr pair was identified as a promising target for therapeutic interventions. Our work sheds new light on skeletal muscle dysfunction in COPD, opening new avenues for cost-effective therapies. It overcomes limitations of previous computational approaches showing high potential for the study of other multi-factorial diseases such as diabetes or cancer. CONTACT:jroca@clinic.ub.es or martacascante@ub.eduSupplementary information: Supplementary data are available at Bioinformatics online.

SUBMITTER: Marin de Mas I

PROVIDER: S-EPMC6544513 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Molecular mechanisms underlying COPD-muscle dysfunction unveiled through a systems medicine approach.

Marín de Mas Igor I Fanchon Eric E Papp Balázs B Kalko Susana S Roca Josep J Cascante Marta M

Bioinformatics (Oxford, England) 20161006 1

<h4>Motivation</h4>Skeletal muscle dysfunction is a systemic effect in one-third of patients with chronic obstructive pulmonary disease (COPD), characterized by high reactive-oxygen-species (ROS) production and abnormal endurance training-induced adaptive changes. However, the role of ROS in COPD remains unclear, not least because of the lack of appropriate tools to study multifactorial diseases.<h4>Results</h4>We describe a discrete model-driven method combining mechanistic and probabilistic ap ...[more]

PMID: 27794560

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Project description:BackgroundThe coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients.AimTo gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction.MethodsThe transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.ResultsAnalysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.ConclusionSevere COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.

Project description:BackgroundElucidating the candidate genes and key metabolites responsible for pulp and peel coloration is essential for breeding pitaya fruit with new and improved appeal and high nutritional value. Here, we used transcriptome (RNA-Seq) and metabolome analysis (UPLC-MS/MS) to identify structural and regulatory genes and key metabolites associated with peel and pulp colors in three pitaya fruit types belonging to two different Hylocereus species.ResultOur combined transcriptome and metabolome analyses suggest that the main strategy for obtaining red color is to increase tyrosine content for downstream steps in the betalain pathway. The upregulation of CYP76ADs is proposed as the color-breaking step leading to red or colorless pulp under the regulation by WRKY44 transcription factor. Supported by the differential accumulation of anthocyanin metabolites in red pulped pitaya fruit, our results showed the regulation of anthocyanin biosynthesis pathway in addition to betalain biosynthesis. However, no color-breaking step for the development of anthocyanins in red pulp was observed and no biosynthesis of anthocyanins in white pulp was found. Together, we propose that red pitaya pulp color is under the strict regulation of CYP76ADs by WRKYs and the anthocyanin coexistence with betalains is unneglectable. We ruled out the possibility of yellow peel color formation due to anthocyanins because of no differential regulation of chalcone synthase genes between yellow and green and no detection of naringenin chalcone in the metabolome. Similarly, the no differential regulation of key genes in the carotenoid pathway controlling yellow pigments proposed that the carotenoid pathway is not involved in yellow peel color formation.ConclusionsTogether, our results propose several candidate genes and metabolites controlling a single horticultural attribute i.e. color formation for further functional characterization. This study presents useful genomic resources and information for breeding pitaya fruit with commercially attractive peel and pulp colors. These findings will greatly complement the existing knowledge on the biosynthesis of natural pigments for their applications in food and health industry.

Project description:Although a number of nongenetic factors have been reported to be able to modulate skeletal muscle phenotypes in meat-type birds, neither the underlying mechanisms nor the muscle group-specific phenotypic and molecular responses have been fully understood. In the present study, a total of 240 broiler ducks were used to compare the effects of floor raising system (FRS) and net raising system (NRS) on the physicochemical properties and global gene expression profiles of both breast and thigh muscles at the posthatching week 4 (W4), W8, and W13. Our results showed that compared with FRS, NRS generally induced higher pH, lower lightness (L?) and yellowness (b?), lower drip loss and cooking loss, and lower shear force in either breast or thigh muscles during early posthatching stages but subsequently showed less pronounced or even reverse effects. Meanwhile, it was observed that the raising system differently changed the myofiber characteristics depending on the muscle group and the developmental stage. Genome-wide transcriptome analysis showed that compared with FRS, NRS induced the most extensive gene expression changes in breast muscle (BM) at W4 but in thigh muscle (TM) at W13, suggesting the asynchronous molecular responses of BM and TM to the raising system and period. Most of differentially expressed genes in either BM or TM between NRS and FRS were enriched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms associated with regulation of muscle cellular functions, metabolic and contractile activities, and tissue remodeling, indicating similar molecular mechanisms principally responsible for the raising system-caused phenotypic changes in both muscle groups. Nevertheless, several crucial pathways (e.g., adipocytokine signaling, AGE-RAGE signaling, and apoptosis) and genes (e.g., ANO6, ACER2, UCP3, DTL, and TMEM120A) were tightly related to the muscle group-specific adaptive remodeling on different raising systems. These data could not only contribute to a better understanding of the molecular mechanisms behind meat quality but also provide novel insights into the molecular causes of the muscle group-specific adaptive remodeling in response to environmental stimuli.

Project description:BACKGROUND AND HYPOTHESIS: Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice. OBJECTIVE AND METHOD: Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework. RESULTS: In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice. CONCLUSIONS: The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.

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Molecular mechanisms underlying COPD-muscle dysfunction unveiled through a systems medicine approach.

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Molecular mechanisms underlying COPD-muscle dysfunction unveiled through a systems medicine approach.

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