Publications
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Pavitt M, Lewis AP, Buttery SC, et al., 2018, Late Breaking Abstract - Dietary nitrate supplementation increases exercise endurance time in COPD patients using ambulatory oxygen, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 2
Watson G, Baker C, Polkey M, et al., 2018, The impact of obesity on pulmonary haemodynamic interpretation, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Benson V, Mohan D, Allinder M, et al., 2018, Prevalence of physical limitation in COPD: the short physical performance battery (SPPB), 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Jones S, Nolan C, Patel S, et al., 2018, Five-repetition sit-to-stand and mortality in COPD: a prospective cohort study, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 3
Luo Y-M, He B-T, Wu Y-X, et al., 2018, Histamine challenge test assessed by the ratio of diaphragm EMG recorded from surface electrodes to tidal volume, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Walsted ES, Faisal A, Pavitt MJ, et al., 2018, Laryngeal laser surgery reduces neural respiratory drive and work of breathing in exercise-induced laryngeal obstruction, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Polkey MI, Zhong N-S, Luo Y-M, 2018, Tai Chi Is Not Equivalent to Pulmonary Rehabilitation Response, CHEST, Vol: 154, Pages: 733-734, ISSN: 0012-3692
Polkey MI, Zhong N-S, Luo Y-M, 2018, Tai Chi Recreational Exercise Is Not Rehabilitation Response, CHEST, Vol: 154, Pages: 731-732, ISSN: 0012-3692
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Bansal T, Haji GS, Rossiter HB, et al., 2018, Exercise ventilatory irregularity can be quantified by approximate entropy to detect breathing pattern disorder, RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY, Vol: 255, Pages: 1-6, ISSN: 1569-9048
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- Citations: 16
Willis-Owen SAG, Thompson AR, Kemp P, et al., 2018, COPD is accompanied by co-ordinated transcriptional perturbation in the quadriceps affecting the mitochondria and extracellular matrix, Scientific Reports, Vol: 8, ISSN: 2045-2322
Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.
RATNESWARAN C, PENGO MF, XIAO S, et al., 2018, The acute effect of continuous positive airway pressure titration on blood pressure in awake overweight/obese patients with obstructive sleep apnoea, Blood Pressure, Vol: 27, Pages: 206-214, ISSN: 0803-7051
Objectives: Continuous positive airway pressure (CPAP) improves upper airway obstruction in patients with obstructive sleep apnoea (OSA), who often are overweight-obese. Although it is thought that CPAP improves long-term blood pressure control (BP), the impact of acute and short-term CPAP use on the cardiovascular system in obese patients has not been described in detail.Methods: Obese patients (body mass index, BMI > 25 kg/m2) with OSA were studied awake, supine during incremental CPAP titration (4–20 cmH2O, +2 cmH2O/3 mins). BP was measured continuously with a beat-to-beat BP monitor (Ohmeda 2300, Finapres Medical Systems, Amsterdam/NL), BP variability (BPV) was calculated as the standard deviation of BP at each CPAP level, the 95% confidence interval (95%CI) was calculated and changes in BP and BPV were reported.Results: 15 patients (12 male, 48 ± 10) years, BMI 38.9 ± 5.8 kg/m2) were studied; the baseline BP was 131.0 ± 10.2/85.1 ± 9.1 mmHg. BP and BPV increased linearly with CPAP titration (systolic BP r = 0.960, p < .001; diastolic BP r = 0.961, p < .001; systolic BPV r = 0.662, p = .026; diastolic BPV r = 0.886, p < .001). The systolic BP increased by +17% (+23.15 (7.9, 38.4) mmHg; p = .011) and the diastolic BP by +23% (+18.27 (2.33, 34.21) mmHg; p = .009), when titrating CPAP to 20 cmH2O. Systolic BPV increased by +96% (+5.10 (0.67, 9.53) mmHg; p < .001) and was maximal at 14 cmH2O, and diastolic BPV by +97% (+3.02 (0.26, 5.78) mmHg; p < .001) at 16 cmH2O.Conclusion: Short-term incremental CPAP leads to significant increases in BP and BPV in obese patients with OSA while awake. Careful titration
Ritchie AI, Polkey MI, Donaldson GC, et al., 2018, Is peer review still anonymous?, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 278-280, ISSN: 1073-449X
Fisk M, Cheriyan J, Mohan D, et al., 2018, Vascular inflammation and aortic stiffness: potential mechanisms of increased vascular risk in chronic obstructive pulmonary disease, Respiratory Research, Vol: 19, ISSN: 1465-9921
Background: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition in which an important extra-pulmonary manifestation is cardiovascular disease. We hypothesized that COPD patients would have increased aortic inflammation and stiffness, as candidate mechanisms mediating increased cardiovascular risk, compared to two negative control groups: healthy never-smokers and smokers without COPD. We also studied patients with COPD due to alpha -1 antitrypsin deficiency (α 1 ATD) as a comparator lung disease group. Methods: Participants underwent 18 F-Fluorodeoxyglucose (FDG) positron emission tomography imaging to quantify aortic inflammation as the tissue-to-blood-ratio (TBR) of FDG uptake. Aortic stiffness was measured by carotid-femoral aortic pulse wave velocity (aPWV). Results: Eighty-five usual COPD (COPD due to smoking), 12 α 1 ATD-COPD patients and 12 each smokers and never-smokers were studied. There was no difference in pack years smoked between COPD patients and smokers (45 ± 25 vs 37 ± 19, p = 0.36), but α 1 ATD patients smoked significantly less (19 ± 11, p < 0.001 for both). By design, spirometry measures were lower in COPD and α 1 ATD-COPD patients compared to smokers and never-smokers. Aortic inflammation and stiffness were increased in COPD (TBR: 1.90 ± 0.38, aPWV: 9.9 ± 2.6 m/s) and α 1 ATD patients (TBR: 1.94 ± 0.43, aPWV: 9.5 ± 1.8 m/s) compared with smokers (TBR: 1.74 ± 0.30, aPWV: 7.8 ± 1.8 m/s, p < 0.05 all) and never-smokers (TBR: 1.71 ± 0.34, aPWV: 7.9 ± 1.7 m/s, p ≤ 0.05 all). Conclusions: In this cross-sectional prospective study, novel findings were that both usual COPD and α1ATD-COPD patients have increased aortic inflammation and stiffness compared to smoking and never-smoking controls, regardless of smoking history. These findings suggest that the presence of COPD lung disease per se may be asso
Sadaka AS, Montgomery AJ, Mourad SM, et al., 2018, Exercise response to oxygen supplementation is not associated with survival in hypoxemic patients with obstructive lung disease, International Journal of COPD, Vol: 13, Pages: 1607-1612, ISSN: 1176-9106
Purpose: Hypoxemia is associated with more severe lung disease and worse outcomes. In some patients with chronic obstructive lung diseases who desaturate on exertion, supplemental oxygen improves exercise capacity. The clinical significance of this exercise response to oxygen supplementation is not known.Patient and methods: We identified chronic obstructive lung disease patients at our center who underwent a six-minute walking test (6MWT) for ambulatory oxygen assessment and who desaturated breathing air and therefore had an additional walk test on supplemental oxygen, between August 2006 and June 2016. Responders were defined as walking >26m further with oxygen. Survival was determined up to 1st February 2017. We compared survival in oxygen responders and non-responders in patients with obstructive lung diseases.Results: 174 patients were included in the study, median age 70 years. 77(44.3%) of the patients were oxygen responders. Borg dyspnea score improved by 1.4(±1.4) units (P<0.0005) on oxygen. Median survival was 66 months with death occurring in 84(48.2%) patients. Kaplan-Meier analysis revealed no survival difference between both responders and non-responders (P=0.571). Cox regression analysis showed that more 6MWT desaturation, lower 6MWD on room air, male gender, lower hemoglobin and BMI were associated with higher mortality risk.Conclusion: Acute exercise response to supplemental oxygen is not associated with long-term survival in patients with obstructive lung disease. This supports the use of ambulatory oxygen treatment for symptomatic purposes only.
Polkey MI, Qiu Z-H, Zhou L, et al., 2018, Tai-Chi and pulmonary rehabilitation compared for treatment-naïve patients with COPD; A Randomized Controlled Trial, Chest, Vol: 153, Pages: 1116-1124, ISSN: 0012-3692
BackgroundIn COPD, functional status is improved by pulmonary rehabilitation (PR) but requires specific facilities. Tai Chi, which combines psychological treatment and physical exercise and requires no special equipment, is widely practiced in China and is becoming increasingly popular in the rest of the world. We hypothesized that Tai Chi is equivalent (ie, difference less than ±4 St. George’s Respiratory Questionnaire [SGRQ] points) to PR.MethodsA total of 120 patients (mean FEV1, 1.11 ± 0.42 L; 43.6% predicted) bronchodilator-naive patients were studied. Two weeks after starting indacaterol 150 μg once daily, they randomly received either standard PR thrice weekly or group Tai Chi five times weekly, for 12 weeks. The primary end point was change in SGRQ prior to and following the exercise intervention; measurements were also made 12 weeks after the end of the intervention.ResultsThe between-group difference for SGRQ at the end of the exercise interventions was –0.48 (95% CI PR vs Tai Chi, –3.6 to 2.6; P = .76), excluding a difference exceeding the minimal clinically important difference. Twelve weeks later, the between-group difference for SGRQ was 4.5 (95% CI, 1.9 to 7.0; P < .001), favoring Tai Chi. Similar trends were observed for 6-min walk distance; no change in FEV1 was observed.ConclusionsTai Chi is equivalent to PR for improving SGRQ in COPD. Twelve weeks after exercise cessation, a clinically significant difference in SGRQ emerged favoring Tai Chi. Tai Chi is an appropriate substitute for PR.
Nolan CM, Maddocks M, Canavan JL, et al., 2018, Increasing Physical Activity in Daily Life in Chronic Obstructive Pulmonary Disease: To Solve the Puzzle, Every Piece Counts Reply, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 197, Pages: 1089-1090, ISSN: 1073-449X
Fisk M, Cheriyan J, Mohan D, et al., 2018, The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial, PLoS ONE, Vol: 13, ISSN: 1932-6203
BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis. OBJECTIVES: This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l). METHODS: This was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). RESULTS: We screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups. CONCLUSIONS: In this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifesta
Walsted ES, Faisal A, Jolley CJ, et al., 2018, Increased respiratory neural drive and work of breathing in exercise-induced laryngeal obstruction., Journal of Applied Physiology, Vol: 124, Pages: 356-363, ISSN: 8750-7587
Exercise induced laryngeal obstruction (EILO), a phenomenon in which the larynx closes inappropriately during physical activity, is a prevalent cause of exertional dyspnea in young individuals. The physiological ventilatory impact of EILO and its relationship to dyspnea are poorly understood. Objectives: To evaluate exercise related changes in laryngeal aperture on ventilation, pulmonary mechanics and respiratory neural drive. Methods: We prospectively evaluated 12 subjects (six with EILO and six healthy age- and gender-matched controls). Subjects underwent baseline spirometry and a symptom-limited incremental exercise test with simultaneous and synchronized recording of endoscopic video, gastric-, esophageal- and transdiaphragmatic pressures, diaphragm electromyography and respiratory airflow. Results: The EILO and control groups had similar peak work rates and minute ventilation (V̇E) (work rate: 227±35 vs. 237±35W; V̇E: 103±20 vs. 98±23 L/min; p>0.05). At submaximal work rates (140-240W) subjects with EILO demonstrated increased work of breathing (p<0.05) and respiratory neural drive (p<0.05), developing in close temporal association with onset of endoscopic evidence of laryngeal closure (p<0.05). Unexpectedly, a ventilatory increase (p<0.05), driven by augmented tidal volume (p<0.05), was seen in subjects with EILO, before the onset of laryngeal closure; there were however no differences in dyspnea intensity between groups. Conclusion: Using simultaneous measurements of respiratory mechanics and diaphragm electromyography with endoscopic video we demonstrate, for the first time, increased work of breathing and respiratory neural drive in association with the development of EILO. Future detailed investigations are now needed to understand the role of upper airway closure in causing exertional dyspnea and exercise limitation.
Nolan CM, Maddocks M, Canavan JL, et al., 2018, Are All Steps Created Equal? Revisiting Pedometer Use during Pulmonary Rehabilitation for Individuals Living with Chronic Obstructive Pulmonary Disease Reply, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 197, Pages: 406-+, ISSN: 1073-449X
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Cassiman D, Cappellini MD, Mabe P, et al., 2018, Disease severity scoring system for acid sphingomyelinase deficiency: Severity score domains and components, We're Organizing Research for Lysosomal Diseases (WORLD) Symposium, Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE, Pages: S29-S29, ISSN: 1096-7192
Demeyer H, Costilla-Frias M, Louvaris Z, et al., 2018, Both moderate and severe exacerbations accelerate physical activity decline in COPD patients, European Respiratory Journal, Vol: 51, ISSN: 0903-1936
Fisk M, McEniery CM, Gale N, et al., 2018, Surrogate Markers of Cardiovascular Risk and Chronic Obstructive Pulmonary Disease: A Large Case-Controlled Study., Hypertension, Vol: 71, Pages: 499-506, ISSN: 0194-911X
Cardiovascular disease is a common comorbidity and cause of mortality in chronic obstructive pulmonary disease. A better understanding of mechanisms of cardiovascular risk in chronic obstructive pulmonary disease patients is needed to improve clinical outcomes. We hypothesized that such patients have increased arterial stiffness, wave reflections, and subclinical atherosclerosis compared with controls and that these findings would be independent of smoking status and other confounding factors. A total of 458 patients with a diagnosis of chronic obstructive pulmonary disease and 1657 controls (43% were current or ex-smokers) with no airflow limitation were matched for age, sex, and body mass index. All individuals underwent assessments of carotid-femoral (aortic) pulse wave velocity, augmentation index, and carotid intima-media thickness. The mean age of the cohort was 67±8 years and 58% were men. Patients with chronic obstructive pulmonary disease had increased aortic pulse wave velocity (9.95±2.54 versus 9.27±2.41 m/s; P<0.001), augmentation index (28±10% versus 25±10%; P<0.001), and carotid intima-media thickness (0.83±0.19 versus 0.74±0.14 mm; P<0.001) compared with controls. Chronic obstructive pulmonary disease was associated with increased levels of each vascular biomarker independently of physiological confounders, smoking, and other cardiovascular risk factors. In this large case-controlled study, chronic obstructive pulmonary disease was associated with increased arterial stiffness, wave reflections, and subclinical atherosclerosis, independently of traditional cardiovascular risk factors. These findings suggest that the cardiovascular burden observed in this condition may be mediated through these mechanisms and supports the concept that chronic obstructive pulmonary disease is an independent risk factor for cardiovascular disease.
Mandal S, Suh E-S, Harding R, et al., 2018, Nutrition and Exercise Rehabilitation in Obesity hypoventilation syndrome (NERO): a pilot randomised controlled trial, THORAX, Vol: 73, Pages: 62-69, ISSN: 0040-6376
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- Citations: 22
Ritchie AI, Polkey MI, Donaldson GC, et al., 2018, Is Peer Review Still Anonymous?, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kemp P, Connolly, Paul R, et al., 2017, miR-424-5p reduces ribosomal RNA and protein synthesis in muscle wasting, Journal of Cachexia, Sarcopenia and Muscle, Vol: 9, Pages: 400-416, ISSN: 2190-6009
Background: A loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis so changes in the control of ribosome synthesis is a potential contributor to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR-424-5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD).Methods: Targets of miR-424-5p were identified by Ago2 pull-down and the effects of the miRNA on RNA and protein expression were determined by qPCR and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over-expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by qPCR in patients with COPD, intensive care unit acquired weakness (ICUAW), and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study.Results: Pull-down assays showed that miR-424-5p bound to mRNAs encoding proteins associated with muscle protein synthesis. The most highly enriched mRNAs encoded proteins required for the Pol I RNA pre-initiation complex (PIC) required for rRNA transcription, (PolR1A and Upstream binding transcription factor, UBTF). In vitro, miR-424-5p reduced expression of these RNAs, reduced rRNA levels and inhibited protein synthesis. In mice, over-expression of miR-322 (rodent miR-424 orthologue) caused fibre atrophy and reduced UBTF expression and rRNA levels. In humans elevated miR-424-5p as
Pavitt MJ, Nevett J, Swanton LL, et al., 2017, London Ambulance source data on choking incidence for the calendar year 2016 – an observational study., BMJ Open Respiratory Research, Vol: 4, ISSN: 2052-4439
Introduction Complete foreign body airway obstruction is a life-threatening emergency, but there are limited data on its epidemiology.Methods We conducted a retrospective analysis of data collected routinely from London Ambulance Service calls coded as being for choking was undertaken for the calendar year of 2016.Results There were 1916 choking episodes of significant severity to call for emergency assessment in London during 2016, 0.2% of total calls requiring an ambulance response, an average of 5.2 per day. The incidence increased at the extremes of age. Calls coded as choking occurred at times consistent with lunch and dinner and less frequently at breakfast. Peak incidence occurred at Sunday lunchtimes and on Wednesday evenings.Conclusions Choking is a substantial health problem for Londoners to seek emergency assistance. Choking is more frequent at the extremes of age with a higher incidence at lunch and dinner time. Greater public awareness of choking and its management could help to prevent avoidable deaths.
Buss L, McKeever TM, Mohan D, et al., 2017, CARDIORESPIRATORY PHYSIOLOGY IN PATIENTS WITH COPD ACCORDING TO BLOOD EOSINOPHILIA: DATA FROM THE ERICA COHORT, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A134-A134, ISSN: 0040-6376
Ward K, Rao P, Reilly CC, et al., 2017, Poor cough flow in acute stroke patients is associated with reduced functional residual capacity and low cough inspired volume, BMJ OPEN RESPIRATORY RESEARCH, Vol: 4
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- Citations: 13
Abdulai RM, Jellesmark Jensen T, Patel NR, et al., 2017, Deterioration of limb muscle function during acute exacerbation of chronic obstructive pulmonary disease, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 433-449, ISSN: 1073-449X
Important features of both stable and acute exacerbation of COPD are skeletal muscle weakness and wasting. Limb muscle dysfunction during an exacerbation has been linked to various adverse outcomes, including prolonged hospitalization, readmission, and mortality. The contributing factors leading to muscle dysfunction are similar to those seen in stable COPD: disuse, nutrition/energy balance, hypercapnia, hypoxemia, electrolyte derangements, inflammation, and drugs (i.e., glucocorticoids). These factors may be the trigger for a downstream cascade of local inflammatory changes, pathway process alterations, and structural degradation. Ultimately, the clinical effects can be wide ranging and include reduced limb muscle strength. Current therapies, such as pulmonary/physical rehabilitation have limited impact due to low participation rates. Recently, novel drugs have been developed in similar disorders and learnings from these studies can be used as a foundation to facilitate discovery in patients hospitalized with a COPD exacerbation. Nevertheless, investigators should approach this patient population with knowledge of the limitations of each intervention. In this concise clinical review, we provide an overview of acute muscle dysfunction in patients hospitalized with acute exacerbation of COPD (AECOPD) and a strategic approach to drug development in this setting.
Kemp P, paul R, lee J, et al., 2017, miR-422a suppresses SMAD4 protein expression and promotes resistance to muscle loss, Journal of Cachexia Sarcopenia and Muscle, Vol: 9, Pages: 119-128, ISSN: 2190-5991
BackgroundLoss of muscle mass and strength are important sequelae of chronic disease, but the response of individuals is remarkably variable, suggesting important genetic and epigenetic modulators of muscle homeostasis. Such factors are likely to modify the activity of pathways that regulate wasting, but to date, few such factors have been identified.MethodsThe effect of miR-422a on SMAD4 expression and transforming growth factor (TGF)-β signalling were determined by western blotting and luciferase assay. miRNA expression was determined by qPCR in plasma and muscle biopsy samples from a cross-sectional study of patients with chronic obstructive pulmonary disease (COPD) and a longitudinal study of patients undergoing aortic surgery, who were subsequently admitted to the intensive care unit (ICU).ResultsmiR-422a was identified, by a screen, as a microRNA that was present in the plasma of patients with COPD and negatively associated with muscle strength as well as being readily detectable in the muscle of patients. In vitro, miR-422a suppressed SMAD4 expression and inhibited TGF-beta and bone morphogenetic protein-dependent luciferase activity in muscle cells. In male patients with COPD and those undergoing aortic surgery and on the ICU, a model of ICU-associated muscle weakness, quadriceps expression of miR-422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively). Furthermore, pre-surgery levels of miR-422a were inversely associated with the amount of muscle that would be lost in the first post-operative week (r = −0.57, P < 0.001).ConclusionsThese data suggest that differences in miR-422a expression contribute to the susceptibility to muscle wasting associated with chronic and acute disease and that at least part of this activity may be mediated by reduced TGF-beta signalling in skeletal muscle.
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