Inflammatory Events and Oxidant Production in the Diaphragm, Gastrocnemius, and Blood of Rats Exposed to Chronic Intermittent Hypoxia: Therapeutic Strategies

Domínguez-Álvarez, Marisol; Gea, Joaquim; Barreiro, Esther

doi:10.1002/jcp.25600

Cited by 13 publications

(15 citation statements)

References 55 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In majority of the previous studies, the duration of inflammation was mostly 1–4 days . In some studies, the duration of inflammation was relatively long for 7–14 days . These studies evaluated the effects of acute or subacute inflammation on the diaphragmatic atrophy.…”

Section: Discussionmentioning

confidence: 55%

See 1 more Smart Citation

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems

Komatsu

Okazaki

Ebihara

et al. 2018

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

BackgroundRepetition of the onset of aspiration pneumonia in aged patients is common and causes chronic inflammation. The inflammation induces proinflammatory cytokine production and atrophy in the muscles. The proinflammatory cytokines induce muscle proteolysis by activating calpains and caspase‐3, followed by further degradation by the ubiquitin‐proteasome system. Autophagy is another pathway of muscle atrophy. However, little is known about the relationship between aspiration pneumonia and muscle. For swallowing muscles, it is not clear whether they produce cytokines. The main objective of this study was to determine whether aspiration pneumonia induces muscle atrophy in the respiratory (the diaphragm), skeletal (the tibialis anterior, TA), and swallowing (the tongue) systems, and their possible mechanisms.MethodsWe employed a mouse aspiration pneumonia model and computed tomography (CT) scans of aged pneumonia patients. To induce aspiration pneumonia, mice were inoculated with low dose pepsin and lipopolysaccharide solution intra‐nasally 5 days a week. The diaphragm, TA, and tongue were isolated, and total RNA, proteins, and frozen sections were stored. Quantitative real‐time polymerase chain reaction determined the expression levels of proinflammatory cytokines, muscle E3 ubiquitin ligases, and autophagy related genes. Western blot analysis determined the activation of the muscle proteolysis pathway. Frozen sections determined the presence of muscle atrophy. CT scans were used to evaluate the muscle atrophy in aged aspiration pneumonia patients.ResultsThe aspiration challenge enhanced the expression levels of proinflammatory cytokines in the diaphragm, TA, and tongue. Among muscle proteolysis pathways, the aspiration challenge activated caspase‐3 in all the three muscles examined, whereas calpains were activated in the diaphragm and the TA but not in the tongue. Activation of the ubiquitin‐proteasome system was detected in all the three muscles examined. The aspiration challenge activated autophagy in the TA and the tongue, whereas weak or little activation was detected in the diaphragm. The aspiration challenge resulted in a greater proportion of smaller myofibers than in controls in the diaphragm, TA, and tongue, suggesting muscle atrophy. CT scans clearly showed that aspiration pneumonia was followed by muscle atrophy in aged patients.ConclusionsAspiration pneumonia induced muscle atrophy in the respiratory, skeletal, and swallowing systems in a preclinical animal model and in human patients. Diaphragmatic atrophy may weaken the force of cough to expectorate sputum or mis‐swallowed contents. Skeletal muscle atrophy may cause secondary sarcopenia. The atrophy of swallowing muscles may weaken the swallowing function. Thus, muscle atrophy could become a new therapeutic target of aspiration pneumonia.

show abstract

Section: Discussionmentioning

confidence: 55%

“…12,14,20,25 In some studies, the duration of inflammation was relatively long for 7-14 days. 26,27 These studies evaluated the effects of acute or subacute inflammation on the diaphragmatic atrophy. In this study, the duration of inflammation in the mouse model was 28 days.…”

Section: Discussionmentioning

confidence: 99%

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems

Komatsu

Okazaki

Ebihara

et al. 2018

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

show abstract

“…In general, a combination of reduced metabolism and systemic immune dysfunction that is predicted based on transcriptomic levels in AEM cages could contribute to abnormal responses to stressors, including infection, and play a role in systemic decline in organ functions in a manner that resembles the aging process. These deficits in metabolism and immunity can be caused by multiple factors specific to the cage environment, such as the changes in gas composition leading to a mild CO 2 -dependent hypoxia/hypercapnia 50 . Furthermore, the relatively few transcriptional changes associated with Bion-M1-matched AEM could be caused by a lower increase in CO 2 compared to shuttle-matched AEM.…”

Section: Discussionmentioning

confidence: 99%

Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: A systems biology GeneLab case study

Beheshti

Cekanaviciute

Smith

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Spaceflight introduces a combination of environmental stressors, including microgravity, ionizing radiation, changes in diet and altered atmospheric gas composition. In order to understand the impact of each environmental component on astronauts it is important to investigate potential influences in isolation. Rodent spaceflight experiments involve both standard vivarium cages and animal enclosure modules (AEMs), which are cages used to house rodents in spaceflight. Ground control AEMs are engineered to match the spaceflight environment. There are limited studies examining the biological response invariably due to the configuration of AEM and vivarium housing. To investigate the innate global transcriptomic patterns of rodents housed in spaceflight-matched AEM compared to standard vivarium cages we utilized publicly available data from the NASA GeneLab repository. Using a systems biology approach, we observed that AEM housing was associated with significant transcriptomic differences, including reduced metabolism, altered immune responses, and activation of possible tumorigenic pathways. Although we did not perform any functional studies, our findings revealed a mild hypoxic phenotype in AEM, possibly due to atmospheric carbon dioxide that was increased to match conditions in spaceflight. Our investigation illustrates the process of generating new hypotheses and informing future experimental research by repurposing multiple space-flown datasets.

show abstract

“…A relevant factor that may have contributed to muscle wasting is hypoxia, especially in the patients. In fact, body-and muscle-mass loss was identified in experimental models of chronic continuous or intermittent hypoxia (14,15,22,51,52). Biological mechanisms, such as protein synthesis inhibition (38), mitochondrial enzyme alterations (6,27), aerobic to anaerobic shift due to mitochondrial loss (24), a rise in leptin concentrations, and a decrease in metabolic parameters (sugar and cholesterol) (30), mediate hypoxia-induced body-and muscle-mass loss, as demonstrated in those animal models.…”

Section: Discussionmentioning

confidence: 99%

The phosphodiesterase-4 inhibitor roflumilast reverts proteolysis in skeletal muscle cells of patients with COPD cachexia

Barreiro

Puig-Vilanova

Salazar‐Degracia

et al. 2018

Journal of Applied Physiology

Self Cite

View full text Add to dashboard Cite

Peripheral muscle weakness and mass loss are characteristic features in severe chronic obstructive pulmonary disease (COPD). We hypothesized that the phosphodiesterase (PDE)-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 μM roflumilast N-oxide (RNO) for three time cohorts (1, 6, and 24 h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting. In COPD patients at 6 h RNO treatment, myotube tyrosine release, total protein ubiquitination, and tripartite motif-containing protein 32 levels were significantly lower than healthy controls, whereas at 24 h RNO treatment, myotube myosin heavy chain ( MyHC) -I and MyHC-IIx expression levels were upregulated in both patients and controls. In the 6-h RNO cohort, in patients and controls, myotube expression of nuclear factor (erythroid-derived 2)-like 2 ( NRF2) and its downstream antioxidants sirtuin-1, FGF-inducible 14, and insulin-like growth factor-1 was upregulated, whereas that of myocyte-specific enhancer factor 2C, myogenic differentiation, myogenin, myostatin, atrogin-1, and muscle RING-finger protein-1 was downregulated. In myotubes of severe COPD patients with cachexia, roflumilast-induced cAMP signaling exerts beneficial effects by targeting muscle protein breakdown (tyrosine release), along with reduced expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In both patients and controls, roflumilast also favored antioxidant defense through upregulation of the NRF2 pathway and that of the histone deacetylase sirtuin-1, whereas it improved the expression of slow- and fast-twitch myosin isoforms. These findings show that muscle dysfunction and wasting may be targeted by roflumilast-induced cAMP signaling in COPD. These results have potential therapeutic implications, as this PDE-4 inhibitor is currently available for the treatment of systemic inflammation and exacerbations in patients with severe COPD. NEW & NOTEWORTHY In myotubes of cachectic chronic obstructive pulmonary disease (COPD) patients, cAMP signaling exerted beneficial effects by targeting muscle proteolysis and reducing gene expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In myotubes of patients and controls, roflumilast also favored antioxidant defense through upregulation of the nuclear factor (erythroid-derived 2)-like 2 pathway, of sirtuin-1, and of gene expression of slow- and fast-twitch isoforms. These findings have potential clinical implications for the treatment of muscle wasting in patients with COPD and cachexia.

show abstract

Inflammatory Events and Oxidant Production in the Diaphragm, Gastrocnemius, and Blood of Rats Exposed to Chronic Intermittent Hypoxia: Therapeutic Strategies

Cited by 13 publications

References 55 publications

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems

Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: A systems biology GeneLab case study

The phosphodiesterase-4 inhibitor roflumilast reverts proteolysis in skeletal muscle cells of patients with COPD cachexia

Contact Info

Product

Resources

About