Publications
139 results found
Polkey MI, Griffiths MJ, Kemp PR, 2016, Muscle regeneration after critical illness: are satellite cells the answer?, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 780-782, ISSN: 1535-4970
Mohan D, Lewis A, Patel MS, et al., 2016, Using laser capture microdissection to study fiber specific signalling in locomotor muscle in COPD: A pilot study, Muscle & Nerve, Vol: 55, Pages: 902-912, ISSN: 1097-4598
INTRODUCTION: Quadriceps dysfunction is important in chronic obstructive pulmonary disease (COPD), with an associated increased proportion of type II fibers. Investigation of protein synthesis and degradation has yielded conflicting results, possibly due to study of whole biopsy samples, whereas signalling may be fiber-specific. Our objective was to develop a method for fiber-specific gene expression analysis. METHODS: 12 COPD and 6 healthy subjects underwent quadriceps biopsy. Cryosections were immunostained for type II fibers, which were separated using laser capture microdissection (LCM). Whole muscle and different fiber populations were subject to quantitative polymerase chain reaction (qPCR). RESULTS: Muscle-RING-finger-protein-1(MURF-1) and Atrogin-1 were lower in type II fibers of COPD versus healthy subjects (P=0.02 and P=0.03, respectively), but differences were not apparent in whole muscle or type I fibers. DISCUSSION: We describe a novel method for studying fiber-specific gene expression in optimum-cutting-temperature (OCT) compound-embedded muscle specimens. LCM offers a more sensitive way to identify molecular changes in COPD muscle. This article is protected by copyright. All rights reserved.
Patel MS, Donaldson AV, Lewis A, et al., 2016, Klotho and smoking – An interplay influencing the skeletal muscle function deficits that occur in COPD, Respiratory Medicine, Vol: 113, Pages: 50-56, ISSN: 0954-6111
BackgroundKlotho is an ‘anti-ageing’ hormone and transmembrane protein; Klotho deficient mice develop a similar ageing phenotype to smokers including emphysema and muscle wasting. The objective of this study was to evaluate skeletal muscle and circulating Klotho protein in smokers and COPD patients and to relate Klotho levels to relevant skeletal muscle parameters. We sought to validate our findings by undertaking complimentary murine studies.MethodsFat free mass, quadriceps strength and spirometry were measured in 87 participants (61 COPD, 13 ‘healthy smokers’ and 13 never smoking controls) in whom serum and quadriceps Klotho protein levels were also measured. Immunohistochemistry was performed to demonstrate the location of Klotho protein in human skeletal muscle and in mouse skeletal muscle in which regeneration was occurring following injury induced by electroporation. In a separate study, gastrocnemius Klotho protein was measured in mice exposed to 77 weeks of smoke or sham air.ResultsQuadriceps Klotho levels were lower in those currently smoking (p = 0.01), irrespective of spirometry, but were not lower in patients with COPD. A regression analysis identified current smoking status as the only independent variable associated with human quadriceps Klotho levels, an observation supported by the finding that smoke exposed mice had lower gastrocnemius Klotho levels than sham exposed mice (p = 0.005). Quadriceps Klotho levels related to local oxidative stress but were paradoxically higher in patients with established muscle wasting or weakness; the unexpected relationship with low fat free mass was the only independent association. Within locomotor muscle, Klotho localized to the plasma membrane and to centralized nuclei in humans and in mice with induced muscle damage. Serum Klotho had an independent association with quadriceps strength but did not relate to quadriceps Klotho levels or to spirometric parameters.ConclusionsKlotho is expressed
Lewis A, Donaldson AV, Natanek SA, et al., 2016, Increased expression of H19/miR-675 is associated with a low fat free mass index in patients with COPD, Journal of Cachexia, Sarcopenia and Muscle, Vol: 7, Pages: 330-344, ISSN: 2190-6009
BackgroundLoss of muscle mass and strength is a significant comorbidity in patients with chronic obstructive pulmonary disease (COPD) that limits their quality of life and has prognostic implications but does not affect everyone equally. To identify mechanisms that may contribute to the susceptibility to a low muscle mass, we investigated microRNA (miRNA) expression, methylation status, and regeneration in quadriceps muscle from COPD patients and the effect of miRNAs on myoblast proliferation in vitro. The relationships of miRNA expression with muscle mass and strength was also determined in a group of healthy older men.MethodsWe identified miRNAs associated with a low fat-free mass (FFM) phenotype in a small group of patients with COPD using a PCR screen of 750 miRNAs. The expression of two differentially expressed miRNAs (miR-675 and miR-519a) was determined in an expanded group of COPD patients and their associations with FFM and strength identified. The association of these miRNAs with FFM and strength was also explored in a group of healthy community-dwelling older men. As the expression of the miRNAs associated with FFM could be regulated by methylation, the relative methylation of the H19 ICR was determined. Furthermore, the proportion of myofibres with centralized nuclei, as a marker of muscle regeneration, in the muscle of COPD patients was identified by immunofluorescence.ResultsImprinted miRNAs (miR-675 and from a cluster, C19MC which includes miR-519a) were differentially expressed in the quadriceps of patients with a low fat-free mass index (FFMI) compared to those with a normal FFMI. In larger cohorts, miR-675 and its host gene (H19) were higher in patients with a low FFMI and strength. The association of miR-519a expression with FFMI was present in male patients with severe COPD. Similar associations of miR expression with lean mass and strength were not observed in healthy community dwelling older men participating in the Hertfordshire Sarcopenia Stu
Patel MS, Lee J, Baz M, et al., 2015, Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo, Journal of Cachexia, Sarcopenia and Muscle, Vol: 7, Pages: 436-448, ISSN: 2190-6009
BackgroundLoss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor-15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD.MethodsWe determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation.ResultsGrowth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF-15 levels were associated with 8-oxo-dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over-expression of GDF-15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF-15 on muscle mass (P < 0.001).ConclusionsTogether, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD.
Bloch SAA, Donaldson AVJ, Lewis A, et al., 2015, MiR-181a: a potential biomarker of acute muscle wasting following elective high-risk cardiothoracic surgery, Critical Care, Vol: 19, ISSN: 1364-8535
Garfield B, Shao D, Crosby A, et al., 2015, THE ROLE OF GROWTH AND DIFFERENTIATION FACTOR 15 IN SMOOTH MUSCLE CELL PROLIFERATION IN PULMONARY HYPERTENSION, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A213-A214, ISSN: 0040-6376
Paul RG, Polkey MI, Kemp PR, et al., 2015, GDF-15, THE MIR-542 CLUSTER AND MIR-422A ARE ASSOCIATED WITH MUSCLE WASTING IN INTENSIVE CARE UNIT ACQUIRED PARESIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A66-A67, ISSN: 0040-6376
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Garfield B, Crosby A, Pieran Y, et al., 2015, The role of growth and differentiation factor 15 (GDF-15) in the development of skeletal muscle wasting in pulmonary arterial hypertension (PAH), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Kemp P, Lee JY, lori O, et al., 2015, FHL1 activates myostatin signalling in skeletal muscle and promotes atrophy, FEBS Open Bio, Vol: 5, Pages: 753-762, ISSN: 2211-5463
Myostatin is a TGFβ family ligand that reduces muscle mass. In cancer cells, TGFβ signalling is increased by the protein FHL1. Consequently, FHL1 may promote signalling by myostatin. We therefore tested the ability of FHL1 to regulate myostatin function. FHL1 increased the myostatin activity on a SMAD reporter and increased myostatin dependent myotube wasting. In mice, independent expression of myostatin reduced fibre diameter whereas FHL1 increased fibre diameter, both consistent with previously identified effects of these proteins. However, co-expression of FHL1 and myostatin reduced fibre diameter to a greater extent than myostatin alone. Together, these data suggest that the expression of FHL1 may exacerbate muscle wasting under the appropriate conditions.Abbreviations FHL1, four and a half LIM domain protein 1; COPD, chronic obstructive pulmonary disease; TGF-β, transforming growth factor beta; MHC, myosin heavy chain; GDF-15, growth and differentiation factor 15; PAI-1, plasminogen activator inhibitor 1; TA, tibialis anterior; VEGF-C, vascular endothelial growth factor C
Mohan D, Lewis A, Patel MS, et al., 2015, Fiber Specific Signalling In Locomotor Muscle In Chronic Obstructive Pulmonary Disease (COPD), International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bloch SAA, Lee JY, Syburra T, et al., 2014, Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs, Thorax, Vol: 70, Pages: 219-228, ISSN: 0040-6376
Rationale The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs.Objectives To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro.Methods In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined.Measurements and main results Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle.Conclusions GDF-15 may increase sensitivity to TGF-β signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.
Garfield BE, Parfitt L, Harries C, et al., 2014, QUALITY OF LIFE IN IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION IS ASSOCIATED WITH QUADRICEPS FUNCTION AND SIZE, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A76-A77, ISSN: 0040-6376
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Bloch SAA, Syburrah T, Rosendahl U, et al., 2014, A PARADOXICAL RISE IN RECTUS FEMORIS MYOSTATIN (GDF-8) AND GDF-15 IN RESPONSE TO NEUROMUSCULAR ELECTRICAL STIMULATION IN CRITICAL CARE, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A74-A74, ISSN: 0040-6376
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- Citations: 1
Bloch SAA, Lee JY, Syburrah T, et al., 2014, GDF-15 DOWN-REGULATION OF MUSCLE MICRORNA DRIVES INCREASED SENSITIVITY TO TGF-beta SIGNALLING; A NOVEL MECHANISM IN INTENSIVE CARE UNIT ACQUIRED WEAKNESS, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A75-A75, ISSN: 0040-6376
Maddocks M, Shrikrishna D, Vitoriano S, et al., 2014, Skeletal muscle adiposity is associated with physical activity, exercise capacity and fibre shift in COPD, European Respiratory Journal, Vol: 44, Pages: 1188-1198, ISSN: 1399-3003
Quadriceps muscle phenotype varies widely between patients with chronic obstructive pulmonary disease (COPD) and cannot be determined without muscle biopsy. We hypothesised that measures of skeletal muscle adiposity could provide noninvasive biomarkers of muscle quality in this population.In 101 patients and 10 age-matched healthy controls, mid-thigh cross-sectional area, percentage intramuscular fat and skeletal muscle attenuation were calculated using computed tomography images and standard tissue attenuation ranges: fat -190– -30 HU; skeletal muscle -29–150 HU.Mean±sd percentage intramuscular fat was higher in the patient group (6.7±3.5% versus 4.3±1.2%, p = 0.03). Both percentage intramuscular fat and skeletal muscle attenuation were associated with physical activity level, exercise capacity and type I fibre proportion, independent of age, mid-thigh cross-sectional area and quadriceps strength. Combined with transfer factor of the lung for carbon monoxide, these variables could identify >80% of patients with fibre type shift with >65% specificity (area under the curve 0.83, 95% CI 0.72–0.95).Skeletal muscle adiposity assessed by computed tomography reflects multiple aspects of COPD related muscle dysfunction and may help to identify patients for trials of interventions targeted at specific muscle phenotypes.
Haji G, Weigman C, Patel M, et al., 2014, Mitochondrial membrane potential in the airway and skeletal muscle compartments of smokers with and without COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Patel MS, Mohan D, Andersson YM, et al., 2014, Phenotypic Characteristics Associated With Reduced Short Physical Performance Battery Score in COPD, CHEST, Vol: 145, Pages: 1016-1024, ISSN: 0012-3692
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- Citations: 48
Shrikrishna D, Tanner RJ, Lee JY, et al., 2014, A Randomized Controlled Trial of Angiotensin-Converting Enzyme Inhibition for Skeletal Muscle Dysfunction in COPD, Chest, Vol: 146, Pages: 932-940, ISSN: 1931-3543
Bloch SA, Lee JY, Polkey MI, et al., 2014, Gdf-15 Regulation Of Micrornas: A Novel Mechanism Of Intensive Care Unit Acquired Paresis?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
Bloch SAA, Kemp PR, Griffiths MJD, et al., 2013, MIR-181: A POTENTIAL BIOMARKER OF ACUTE MUSCLE WASTING?, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A30-A31, ISSN: 0040-6376
Patel MS, Donaldson AV, Natanek SA, et al., 2013, KLOTHO IS ASSOCIATED WITH SKELETAL MUSCLE DYSFUNCTION AND OXIDATIVE STRESS IN COPD, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A28-A29, ISSN: 0040-6376
Donaldson AVJ, Tanner RJ, Davey CA, et al., 2013, MIR-181 INCREASES IN THE QUADRICEPS MUSCLE OF COPD PATIENTS AFTER AN ACUTE BOUT OF EXERCISE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A29-A29, ISSN: 0040-6376
Haji G, Wiegman C, Patel M, et al., 2013, MITOCHONDRIAL DYSFUNCTION IN MUSCLE AND AIRWAY COMPARTMENTS IN COPD: PRELIMINARY FINDINGS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A161-A162, ISSN: 0040-6376
Donaldson A, Natanek SA, Lewis A, et al., 2013, Increased skeletal muscle-specific microRNA in the blood of patients with COPD, THORAX, Vol: 68, Pages: 1140-1149, ISSN: 0040-6376
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- Citations: 93
Mohan D, Lewis A, Patel MS, et al., 2013, STUDYING FIBRE SPECIFIC GENE EXPRESSION IN COPD USING LASER CAPTURE MICRO-DISSECTION IN HUMAN SKELETAL MUSCLE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A29-A30, ISSN: 0040-6376
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- Citations: 2
Natanek SA, Gosker HR, Slot IGM, et al., 2013, HETEROGENEITY OF QUADRICEPS MUSCLE PHENOTYPE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD); IMPLICATIONS FOR STRATIFIED MEDICINE?, MUSCLE & NERVE, Vol: 48, Pages: 488-497, ISSN: 0148-639X
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- Citations: 53
Maddocks M, Shrikrishna D, Natanek S, et al., 2013, Mid-thigh intramuscular fat is associated with physical inactivity and quadriceps fibre type profile in patients with COPD, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
Patel MS, Donaldson AV, Jackson SG, et al., 2013, Smoking reduces klotho expression, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
Patel MS, Lewis A, Natanek SA, et al., 2013, Klotho expression is reduced in COPD, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
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