Publications
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Kemp P, Bradshaw J, Pandya B, et al., 2023, The validity of Engagement and Feedback Assessments (EFAs): identifying students at risk of failing, BMC Medical Education, Vol: 23, ISSN: 1472-6920
Background:Imperial College School of Medicine, London UK, introduced a new curriculum in 2019, with a focus on the GMC outcomes for graduates, and pedagogy best practice. The new curriculum included formative assessments, named engagement and feedback assessments (EFAs), to support learning, and attainment in the summative examinations. The aims of this study were to assess the validity of EFAs and to determine whether they have utility as a modified form of programmatic assessment to inform decision-making regarding possible interventions by measuring and analysing attendance at and performance in these formative events.Methods:Seven hundred and sixty-one students were included in the study and assessment results were included for academic years 2019/20 to 2020/21. Forty-one data points per student, (27 in Year 1 and 14 in Year 2) were used, to compare EFA scores with the summativeperformance. Attendance was monitored through engagement with the EFAs.Results:Cohort 1 (enrolled 2019): In year 1, EFAs were associated with summative exam scores (overall r =0.63, p<0.001). Year 2, EFA scores were also associated with summative scores (overall r=0.57, p<0.001), including the clinical practical assessment (r=0.45, p<0.001).Missing two or more EFAs was associated with a significant increase in the likelihood of failing one or more summative examinations in the first year (OR: 7.97, 95% CI 2.65-34.39) and second year (OR: 3.20, 95% CI 1.74-5.95). Missing more than two EFAs in their first year was also associated with a higher risk of failing a summative examination in the second year (OR: 2.47, 95% CI 1.33-4.71). Students who increased their attendance between year 1 and 2 fared better in summative assessment than those who maintained38poor attendance, whereas those that reduced their attendance fared worse than those that maintained high attendance.Cohort 2 (enrolled 2020): Analysis of cohort 2 supported these findings and in this cohort missing two or more EFAs
Kemp P, Bashir T, Achison M, et al., 2023, Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia – analyses from the LACE randomised controlled trial, PLoS One, Vol: 18, ISSN: 1932-6203
BackgroundAgeing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia.MethodsWe compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial.ResultsNeither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone.ConclusionThese data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older in
Kemp P, Rossios C, Bashir T, et al., 2023, ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial, PLoS One, Vol: 18, ISSN: 1932-6203
AbstractBackgroundAngiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study.MethodsSarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n=130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months’ treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables.ResultsAllele frequencies for the normal UK population were extracted from 13 previous studies (I=0.473, D=0.527). In the LACE cohort the D allele was over-represented (I=0.412, D=0.588, p=0.046). This over-representation was present in men (I=0.353, D=0.647, p=0.010) but not women (I=0.458, D=0.532, p=0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID= 18.00 kg (14.50, 21.60) vs DD=13.20 kg (10.50, 15.90), p=0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle stren
Shrestha A, Dani M, Kemp P, et al., 2022, Acute sarcopenia after elective and emergency surgery, Aging and Disease, Vol: 13, Pages: 1759-1769, ISSN: 2152-5250
AbstractSarcopenia is an increasingly recognised condition of loss of muscle mass and function. The European Working Group on Sarcopenia in Older People 2 (EWSOP2) updated their definition in 2018, emphasising the importance of low muscle strength in diagnosis. Acute sarcopenia has been arbitrarily defined as sarcopenia lasting less than 6 months. This review highlights the pathophysiology involved in muscle wasting following surgery, focussing on hormonal factors, inflammation, microRNAs, and oxidative stress. Biomarkers such as GDF-15, IGF-1 and various microRNAs may predict post-surgical muscle loss. The impact of existing sarcopenia on various types of surgery and incident muscle wasting following surgery is also described. The gaps in research found include the need for longitudinal studies looking in changes in muscle strength and quantity following surgery. Further work is needed to examine if biomarkers are replicated in other surgery to consolidate existing theories on the pathophysiology of muscle wasting
Witham MD, Adamson S, Avenell A, et al., 2022, Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT, Efficacy and Mechanism Evaluation, Vol: 9, Pages: 1-82, ISSN: 2050-4365
<jats:sec id="abs1-1"> <jats:title>Background</jats:title> <jats:p>Angiotensin-converting enzyme inhibitors and leucine are promising potential treatments for sarcopenia. Neither has yet been tested in adequately powered randomised trials in patients with sarcopenia.</jats:p> </jats:sec> <jats:sec id="abs1-2"> <jats:title>Objectives</jats:title> <jats:p>To determine the efficacy of leucine and perindopril in improving physical function in older people with sarcopenia, to evaluate the effect of leucine and perindopril on muscle mass and to evaluate the predictive biomarkers of sarcopenia.</jats:p> </jats:sec> <jats:sec id="abs1-3"> <jats:title>Design</jats:title> <jats:p>A placebo-controlled, parallel group, double-blind, randomised 2 × 2 factorial trial.</jats:p> </jats:sec> <jats:sec id="abs1-4"> <jats:title>Setting</jats:title> <jats:p>Primary care and geriatric medicine secondary care departments in 14 UK centres.</jats:p> </jats:sec> <jats:sec id="abs1-5"> <jats:title>Participants</jats:title> <jats:p>Adults aged ≥ 70 years with low muscle strength and mass, without contraindications to angiotensin-converting enzyme inhibitors and without known diagnosis-specific skeletal myopathy.</jats:p> </jats:sec> <jats:sec id="abs1-6"> <jats:title>Interventions</jats:title> <jats:p>Eligible participants were randomised 1 : 1 to recei
Achison M, Adamson S, Akpan A, et al., 2022, Effect of Perindopril or Leucine on physical performance in older people with sarcopenia: the LACE randomised controlled trial, Journal of Cachexia, Sarcopenia and Muscle, Vol: 13, Pages: 858-871, ISSN: 2190-6009
Background:This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia.Methods:Placebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. We recruited adults aged ≥70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4m walk) and/or low handgrip strength (women <20kg, men <30kg) plus low muscle mass (using sex and BMI category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomised to perindopril 4mg or placebo, and to oral leucine powder 2.5g or placebo thrice daily. The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy.Results:We screened 320 people and randomised 145 participants compared to an original target of 440 participants. For perindopril (n=73, mean age 79 [SD 6], female sex 39 [53%], mean SPPB 7.1 [SD 2.3]) vs no perindopril (n=72, mean age 79 [SD 6], female sex 39 [54%], mean SPPB 6.9 [SD 2.4]), medianadherence to perindopril was lower (76% vs 96%; p<0.001). Perindopril did not improve the primary outcome (adjusted treatment effect -0.1 points [95%CI -1.2 to 1.0], p=0.89). No significant treatmentbenefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.4kg [95%CI -1.1 to 0.3], p=0.27). More adverse events occurred in the perindopril group (218 vs 165) butfalls rates were similar. For leucine (n=72, mean age 78 [SD 6], female sex 38 [53%], mean SPPB 7.0 [SD 2.1]) vs no leucine (n=72, mean age 79 [SD 6], female sex 40 [55%], mean SPPB 7.0 [SD 2.5]), 5 median adherence was the same in both groups (76% vs 76%; p=0.99). Leucine did not improve the primary outcome (adjusted treatme
Witham MD, Adamson S, Avenell A, et al., 2022, 666 EFFECT OF PERINDOPRIL ON PHYSICAL PERFORMANCE, MUSCLE MASS AND QUALITY OF LIFE IN OLDER PEOPLE WITH SARCOPENIA: RESULTS: FROM THE, Publisher: OXFORD UNIV PRESS, ISSN: 0002-0729
Witham MD, Adamson S, Avenell A, et al., 2022, 667 EFFECT OF LEUCINE SUPPLEMENTATION ON PHYSICAL PERFORMANCE, MUSCLE MASS AND QUALITY OF LIFE IN OLDER PEOPLE WITH SARCOPENIA, Publisher: OXFORD UNIV PRESS, ISSN: 0002-0729
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Davies DJ, McLean PF, Kemp PR, et al., 2022, Assessment of factual recall and higher-order cognitive domains in an open-book medical school examination, Advances in Health Sciences Education, Vol: 27, Pages: 147-165, ISSN: 1382-4996
Open-book examinations (OBEs) will likely become increasingly important assessment tools. We investigated how access to open-book resources affected questions testing factual recall, which might be easy to look-up, versus questions testing higher-order cognitive domains. Few studies have investigated OBEs using modern Internet resources or as summative assessments. We compared performance on an examination conducted as a traditional closed-book exam (CBE) in 2019 (N = 320) and a remote OBE with free access to Internet resources in 2020 (N = 337) due to COVID-19. This summative, end-of-year assessment focused on basic science for second-year medical students. We categorized questions by Bloom’s taxonomy (‘Remember’, versus ‘Understand/Apply’). We predicted higher performance on the OBE, driven by higher performance on ‘Remember’ questions. We used an item-centric analysis by using performance per item over all examinees as the outcome variable in logistic regression, with terms ‘Open-Book, ‘Bloom Category’ and their interaction. Performance was higher on OBE questions than CBE questions (OR 2.2, 95% CI: 2.14–2.39), and higher on ‘Remember’ than ‘Understand/Apply’ questions (OR 1.13, 95% CI: 1.09–1.19). The difference in performance between ‘Remember’ and ‘Understand/Apply’ questions was greater in the OBE than the CBE (‘Open-Book’ * ‘Bloom Category’ interaction: OR 1.2, 95% CI: 1.19–1.37). Access to open-book resources had a greater effect on performance on factual recall questions than higher-order questions, though performance was higher in the OBE overall. OBE design must consider how searching for information affects performance, particularly on questions measuring different domains of knowledge.
Witham M, Achison M, Aspray T, et al., 2021, Recruitment strategies for sarcopenia trials: lessons from the LACE randomised controlled trial, JCSM Rapid Communications, Vol: 4, Pages: 93-102, ISSN: 2617-1619
Background:Sarcopenia is rarely diagnosed and is not recorded electronically in routine clinical care, posing challenges to trial recruitment. We describe the performance of four components of a strategy to efficiently recruit participants with sarcopenia to a trial of perindopril and/or leucine for sarcopenia: primary care vs. hospital recruitment, a comparison of central vs. local telephone pre-screening, performance of a questionnaire on physical function conducted as part of the pre-screening telephone call, and performance of bioimpedance measurement to identify low muscle mass.Methods:Hospital-based recruitment took place through inpatient and outpatient geriatric medicine services. Local research nurses reviewed medical notes and approached potentially eligible patients. Primary care recruitment reviewed primary care lists from collaborating practices, sending mailshots to patients aged 70 and over who were not taking angiotensin-converting enzyme inhibitors. Telephone pre-screening was conducted either by research nurses at each site or centrally by Tayside Clinical Trials Unit. The 10-point SARC-F questionnaire was used for pre-screening. De-identified recruitment information was held on a central electronic tracking system and analysed using SPSS. Bioimpedance was measured using the Akern BIA 101 system, with the Sergi equation used to estimate lean mass.Results:Fourteen UK sites recruited to the trial. The 1202 sets of notes in hospital-based care were reviewed at these sites; 7 participants (0.6% of total notes screened) were randomized. From primary care, 13 808 invitations were sent; 138 (1.0% of total invited) were randomized. 633/2987 primary care respondents were pre-screened centrally; the mean number of calls per respondent was 2.3. For 10 sites where central and local pre-screening could be compared, the conversion rate from pre-screening to randomization was 18/588 (3.1%) for centralized calls, compared with 73/1814 (4.0%) for local pre-screenin
Kemp P, Paul R, Neil D, et al., 2020, Metabolic profiling shows pre-existing mitochondrial dysfunction contributes to muscle loss in a model of ICU acquired weakness, Journal of Cachexia, Sarcopenia and Muscle, Vol: 11, Pages: 1321-1335, ISSN: 2190-6009
Background:Surgery can lead to significant muscle loss,which increasesrecovery time and associateswith increased mortality. Muscle lossis not uniform,with some patients losing significant muscle mass and others losing relatively little, andis likely to be accompanied by marked changes in circulating metabolitesand proteins. Determining these changes may help understand the variability and identify novel therapeutic approachesor markers of muscle wasting.Methods:To determine the association between muscle loss and circulating metabolites we studied 20 male patients (median age,70.5, inter-quartile range,62.5-75)undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3 and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SOMAlogic). Results:Ten patients lost more than 10% of the cross-sectional area of the rectus femoris (RFCSA) and were defined as wasting. Metabolomic analysisshowed 557 circulatingmetabolites were altered following surgery (q<0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q<0.05).Weighted genome co-expression network analysis,identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function(r=-0.72, p=6x10-4with RFCSAon day 0, p=3x10-4with RFCSAon day 7 and r=-0.73, p=5x10-4with hand-grip strength on day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisolto the same extent in wasting and non-wasting patients but the cortisol:cortisone ratio was higher in the wasting patients (day 3 p=0.043 and day 7 p=0.016).Wasting patients also showed a greater increase in circulating nucleotides3 days after surgery. Comparison of the metabolome with inflammatory markers
Connolly M, Garfield B, Crosby A, et al., 2020, miR-1-5p targets TGF-βR1 and is suppressed in the hypertrophying hearts of rats with pulmonary arterial hypertension, PLoS One, Vol: 15, ISSN: 1932-6203
The microRNA miR-1 is an important regulator of muscle phenotype including cardiac muscle. Down-regulation of miR-1 has been shown to occur in left ventricular hypertrophy but its contribution to right ventricular hypertrophy in pulmonary arterial hypertension are not known. Previous studies have suggested that miR-1 may suppress transforming growth factor-beta (TGF-β) signalling, an important pro-hypertrophic pathway but only indirect mechanisms of regulation have been identified. We identified the TGF-β type 1 receptor (TGF-βR1) as a putative miR-1 target. We therefore hypothesized that miR-1 and TGF-βR1 expression would be inversely correlated in hypertrophying right ventricle of rats with pulmonary arterial hypertension and that miR-1 would inhibit TGF-β signalling by targeting TGF-βR1 expression. Quantification of miR-1 and TGF-βR1 in rats treated with monocrotaline to induce pulmonary arterial hypertension showed appropriate changes in miR-1 and TGF-βR1 expression in the hypertrophying right ventricle. A miR-1-mimic reduced enhanced green fluorescent protein expression from a reporter vector containing the TGF-βR1 3’- untranslated region and knocked down endogenous TGF-βR1. Lastly, miR-1 reduced TGF-β activation of a (mothers against decapentaplegic homolog) SMAD2/3-dependent reporter. Taken together, these data suggest that miR-1 targets TGF-βR1 and reduces TGF-β signalling, so a reduction in miR-1 expression may increase TGF-β signalling and contribute to cardiac hypertrophy.
McAuley H, Donaldson A, Hussain SF, et al., 2020, Serum MyomiR Levels Are Associated with Increased Risk of Readmission Following a Severe Acute Exacerbation of COPD, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Sathyapala SA, Rochester A, Kemp PR, et al., 2019, P126 Female COPD patients have a greater prevalence of a low muscle mass and weaker quadriceps muscles than male patients, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A159-A159, ISSN: 0040-6376
Band M, Hume C, Pilvynte K, et al., 2019, Recruitment methods for sarcopenia trials - lessons from the LACE randomised controlled trial, Publisher: BMC
Connolly M, Wort S, Garfield B, et al., 2019, MiR-1-5p targets TGF-βR1 and is suppressed in the hypertrophying hearts of rats with pulmonary arterial hypertension, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Ciano M, Mantellato G, Connolly M, et al., 2019, EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype, Scientific Reports, Vol: 9, ISSN: 2045-2322
A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.
Farre-Garros R, Lee J, Natanek S, et al., 2019, Quadriceps miR-542-3p and 5p are elevated in COPD and reduce function by inhibiting ribosomal and protein synthesis, Journal of Applied Physiology, Vol: 126, Pages: 1514-1524, ISSN: 8750-7587
Reduced physical performance reduces quality of life in patients with COPD. Impaired physical performance is, in part, a consequence of reduced muscle mass and function, which is accompanied by mitochondrial dysfunction. We recently showed that miR-542-3p and miR-542-5p were elevated in a small cohort of COPD patients and more markedly in critical care patients. In mice these miRNAs promoted mitochondrial dysfunction suggesting that they would affect physical performance in patients with COPD but we did not explore the association of these miRNAs with disease severity or physical performance further. We therefore quantified miR-542-3p/5p and mitochondrial rRNA expression in RNA extracted from quadriceps muscle of patients with COPD and determined their association with physical performance. As miR-542-3p inhibits ribosomal protein synthesis its ability to inhibit protein synthesis was also determined in vitro.Both miR-542-3p and -5p expression were elevated in patients with COPD (5-fold p<0.001) and the degree of elevation associated with impaired lung function (TLCO% and FEV1%) and physical performance (6-minute walk distance %). In COPD patients, the ratio of 12S rRNA to 16S rRNA was suppressed suggesting mitochondrial ribosomal stress and mitochondrial dysfunction and miR-542-3p/5p expression was inversely associated with mitochondrial gene expression and positively associated with p53 activity. miR-542-3p suppressed RPS23 expression and maximal protein synthesis in vitro. Our data show that miR-542-3p and -5p expression is elevated in COPD patients and may suppress physical performance at least in part by inhibiting mitochondrial and cytoplasmic ribosome synthesis and suppressing protein synthesis.
Sharanya A, Ciano M, Withana S, et al., 2019, Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities, Chronic Respiratory Disease, Vol: 16, Pages: 1-13, ISSN: 1479-9723
Background: In COPD, lower limb dysfunction is associated with reduced exercise capacity, increased hospitalisations and mortality. We investigated sex differences in the prevalence of quadriceps dysfunction and fibre abnormalities in a large COPD cohort, controlling for the normal sex differences in health. Methods: We compared existing data from 76 male and 38 female COPD patients where each variable was expressed as a function of gender-specific normal values (obtained from 16 male and 14 female controls). Results: Female COPD patients had lower quadriceps muscle strength and peak workload on a maximal incremental cycle ergometry protocol compared to male patients. Female patients had a smaller type II fibre cross-sectional area (CSA) compared to male patients, suggesting a greater female preponderance to fibre atrophy, although this result was largely driven by a few male patients with increased type II fibre CSA. Female patients had significantly higher concentrations of a number of plasma pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα) and interleukin 8 (IL8), but not lower levels of physical activity or arterial oxygenation, compared to males. Conclusions: Our data confirms results from a previous small study and suggests that female COPD patients have a greater prevalence of muscle wasting and weakness. Larger studies investigating sex differences in COPD-related muscle atrophy and weakness are needed, as the results will have implications for monitoring in clinical practice and for design of clinical trials evaluating novel muscle anabolic agents.
Kemp P, Griffiths M, Polkey M, 2019, Muscle wasting in the presence of disease, why is it so variable?, Biological Reviews, Vol: 94, Pages: 1038-105, ISSN: 1464-7931
Skeletal muscle wasting is a common clinical feature of many chronic diseases and also occurs in response to single acute events. The accompanying loss of strength can lead to significant disability, increased care needs and have profound negative effects on quality of life. As muscle is the most abundant source of amino acids in the body, it appears to function as a buffer for fuel and substrates that can be used to repair damage elsewhere and to feed the immune system. In essence, the fundamentals of muscle wasting are simple: less muscle is made than is broken down. However, although well‐described mechanisms modulate muscle protein turnover, significant individual differences in the amount of muscle lost in the presence of a given severity of disease complicate the understanding of underlying mechanisms and suggest that individuals have different sensitivities to signals for muscle loss. Furthermore, the rate at which muscle protein is turned over under normal conditions means that clinically significant muscle loss can occur with changes in the rate of protein synthesis and/or breakdown that are too small to be measurable. Consequently, the changes in expression of factors regulating muscle turnover required to cause a decline in muscle mass are small and, except in cases of rapid wasting, there is no consistent pattern of change in the expression of factors that regulate muscle mass. MicroRNAs are fine tuners of cell phenotype and are therefore ideally suited to cause the subtle changes in proteome required to tilt the balance between synthesis and degradation in a way that causes clinically significant wasting. Herein we present a model in which muscle loss as a consequence of disease in non‐muscle tissue is modulated by a set of microRNAs, the muscle expression of which is associated with severity of disease in the non‐muscle tissue. These microRNAs alter fundamental biological processes including the synthesis of ribosomes and mitochondria leading to reduce
Garfield B, Crosby A, Shao D, et al., 2019, Growth/differentiation factor 15 causes TGFβ activated kinase 1 dependent muscle atrophy in pulmonary arterial hypertension, Thorax, Vol: 74, Pages: 164-176, ISSN: 1468-3296
Introduction Skeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target.Methods GDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo.Results Circulating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment.Conclusions Circulating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH.
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.
Band MM, Sumukadas D, Struthers AD, et al., 2018, Leucine and ACE inhibitors as therapies for sarcopenia (LACE trial): study protocol for a randomised controlled trial, Trials, Vol: 19, ISSN: 1745-6215
Background:Sarcopenia (the age-related loss of muscle mass and function) is a major contributor to loss of mobility, falls, loss of independence, morbidity and mortality in older people. Although resistance training is effective in preventing and reversing sarcopenia, many older people are sedentary and either cannot or do not want to exercise. This trial examines the efficacy of supplementation with the amino acid leucine and/or angiotensin converting enzyme inhibition to potentially improve muscle mass and function in people with sarcopenia. Promising preliminary data exist from small studies for both interventions, but neither has yet been tested in adequately powered randomised trials in patients with sarcopenia.Methods:Leucine and ACE inhibitors in sarcopenia (LACE) is a multicentre, masked, placebo-controlled, 2 × 2 factorial randomised trial evaluating the efficacy of leucine and perindopril (angiotensin converting enzyme inhibitor (ACEi)) in patients with sarcopenia. The trial will recruit 440 patients from primary and secondary care services across the UK. Male and female patients aged 70 years and over with sarcopenia as defined by the European Working Group on Sarcopenia (based on low total skeletal muscle mass on bioimpedance analysis and either low gait speed or low handgrip strength) will be eligible for participation. Participants will be excluded if they have a contraindication to, or are already taking, an ACEi, angiotensin receptor blocker or leucine. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at all points between baseline and 12 months. Secondary outcomes include appendicular muscle mass measured using dual-energy X-ray absorptiometry, muscle strength, activities of daily living, quality of life, activity using pedometer step counts and falls. Participants, clinical teams, outcomes assessors and trial analysts are masked to treatment allocation. A
Connolly M, Garfield B, Crosby A, et al., 2017, miR-322-5p targets IGF-1 and is suppressed in the heart of rats with pulmonary hypertension, FEBS Open Bio, Vol: 8, Pages: 339-348, ISSN: 2211-5463
Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here we show that miR-322-5p (the rodent orthologue of miR-424-5p) expression is decreased in the right ventricle of monocrotaline-treated rats, a model of PAH, whereas a putative target insulin-like growth factor 1 (IGF-1) is increased. IGF-1 mRNA was enriched 16-fold in RNA immunoprecipitated with Ago2, indicating binding to miR-322-5p. In cell transfection experiments, miR-322-5p suppressed the activity of a luciferase reporter containing a section of the IGF-1 3′ untranslated region (UTR) as well as IGF-1 mRNA and protein levels. Taken together, these data suggest that miR-322 targets IGF-1, a process downregulated in PAH-related RV hypertrophy.
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
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.
farre garros, paul R, connolly M, et al., 2017, miR-542 promotes mitochondrial dysfunction and SMAD activity and is raised in ICU Acquired Weakness, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 1-12, ISSN: 1073-449X
Rationale: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear. Objectives: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo. Measurements and main results: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
Lee J, Donaldson AV, Lewis A, et al., 2017, Circulating miRNAs from imprinted genomic regions are associated with peripheral muscle strength in COPD patients, European Respiratory Journal, Vol: 49, Pages: 1-4, ISSN: 1399-3003
Kemp P, Natanek A, 2017, Epigenetics and susceptibility to muscle wasting in COPD, Archivos de Bronconeumología, Vol: 53, Pages: 364-365, ISSN: 0300-2896
Garfield BE, Shao D, Parfitt L, et al., 2016, LOW SKELETAL MUSCLE STRENGTH AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH POOR OUTCOMES IN PULMONARY ARTERIAL HYPERTENSION, THORAX, Vol: 71, Pages: A64-A64, ISSN: 0040-6376
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