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Summary: Iron is central to multiple biological pathways, and treatment of non‐anaemic absolute iron deficiency (NAID) is beneficial in certain conditions. However, it is unknown if NAID is associated with increased mortality in older adults. A nationally representative sample of 4451 older adults from the English Longitudinal Study of Ageing was used. NAID was defined as serum ferritin < 30 μg/l and haemoglobin ≥ 120 g/l (women) or ≥ 130 g/l (men). Cumulative mortality was estimated by Kaplan–Meier method. Unadjusted and adjusted hazard ratios (HRs) of mortality were calculated using Cox proportional hazards regression models. Baseline NAID prevalence was 8·8% (95% confidence interval [CI] 8·0–9·7%); 10·9% (95% CI 9·7–12·3%) for women and 6·35% for men (95% CI 5·3–7·5%). The HR for mortality for individuals with NAID compared with non‐anaemic individuals without iron deficiency over the 14‐year follow‐up was 1·58 (95% CI 1·29–1·93). This association was independent of all identified demographic, health‐related and biological covariates, and robust in multiple sensitivity analyses. In older adults in England, NAID is common and associated with an increased mortality rate compared to non‐anaemic individuals with normal serum ferritin. The association is principally driven by an excess mortality in women. [ABSTRACT FROM AUTHOR]

Background: Cachexia is an important extra‐pulmonary manifestation of chronic obstructive pulmonary disease (COPD) presenting as unintentional weight loss and altered body composition. Previous studies have focused on the relative importance of body composition compared with body mass rather than the relative importance of dynamic compared with static measures. We aimed to determine the prevalence of cachexia and pre‐cachexia phenotypes in COPD and examine the associations between cachexia and its component features with all‐cause mortality. Methods: We enrolled 1755 consecutive outpatients with stable COPD from two London centres between 2012 and 2017, stratified according to European Respiratory Society Task Force defined cachexia [unintentional weight loss >5% and low fat‐free mass index (FFMI)], pre‐cachexia (weight loss >5% but preserved FFMI), or no cachexia. The primary outcome was all‐cause mortality. We calculated hazard ratios (HRs) using Cox proportional hazards regression for cachexia classifications (cachexia, pre‐cachexia, and no cachexia) and component features (weight loss and FFMI) and mortality, adjusting for age, sex, body mass index, and disease‐specific prognostic markers. Results: The prevalence of cachexia was 4.6% [95% confidence interval (CI): 3.6–5.6] and pre‐cachexia 1.6% (95% CI: 1.0–2.2). Prevalence was similar across sexes but increased with worsening Global Initiative for Chronic Obstructive Pulmonary Disease spirometric stage and Medical Research Council dyspnoea score (all P < 0.001). There were 313 (17.8%) deaths over a median (interquartile range) follow‐up duration 1089 (547–1704) days. Both cachexia [HR 1.98 (95% CI: 1.31–2.99), P = 0.002] and pre‐cachexia [HR 2.79 (95% CI: 1.48–5.29), P = 0.001] were associated with increased mortality. In multivariable analysis, the unintentional weight loss feature of cachexia was independently associated with mortality [HR 2.16 (95% CI: 1.31–3.08), P < 0.001], whereas low FFMI was not [HR 0.88 (95% CI: 0.64–1.20), P = 0.402]. Sensitivity analyses using body mass index‐specific, age‐specific, and gender‐specific low FFMI values found consistent findings. Conclusions: Despite the low prevalence of cachexia and pre‐cachexia, both confer increased mortality risk in COPD, driven by the unintentional weight loss component. Our data suggest that low FFMI without concurrent weight loss may not confer the poor prognosis as previously reported for this group. Weight loss should be regularly monitored in practice and may represent an important target in COPD management. We propose the incorporation of weight monitoring into national and international COPD guidance. [ABSTRACT FROM AUTHOR]

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 reduced protein synthesis and increased protein breakdown, thereby freeing amino acids from the muscle. We argue that the variability in muscle loss observed in the human population arises from at least two sources. The first is from pre‐existing or disease‐induced variation in the expression of microRNAs controlling the sensitivity of muscle to the atrophic signal and the second is from the expression of microRNAs from imprinted loci (i.e. only expressed from the maternally or paternally inherited allele) and may control the rate of myonuclear recruitment. In the absence of disease, these factors do not correlate with muscle mass, since there is no challenge to the established balance. However, in the presence of such a challenge, these microRNAs determine the rate of decline for a given disease severity. Together these mechanisms provide novel insight into the loss of muscle mass and its variation in the human population. The involvement of imprinted loci also suggests that genes that regulate early development also contribute to the ability of individuals to resist muscle loss in response to disease. [ABSTRACT FROM AUTHOR]

Abstract: 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 are potential contributors 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 Argonaute2 pull down, and the effects of the miRNA on RNA and protein expression were determined by quantitative polymerase chain reaction 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 quantitative polymerase chain reaction in patients with COPD and intensive care unit (ICU)‐acquired weakness 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 messenger RNAs encoding proteins associated with muscle protein synthesis. The most highly enriched messenger RNAs encoded proteins required for the Pol I RNA pre‐initiation complex required for ribosomal RNA (rRNA) transcription, (PolR1A and upstream binding transcription factor). In vitro, miR‐424‐5p reduced the 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 upstream binding transcription factor expression and rRNA levels. In humans, elevated miR‐424‐5p associated with markers of disease severity in COPD (FEV1%), in patients undergoing aortic surgery (LVEF%), and in patients with ICU‐acquired weakness (days in ICU). In patients undergoing aortic surgery, preoperative miR‐424‐5p expression in skeletal muscle was associated with muscle loss over the following 7 days. Conclusions: These data suggest that miR‐424‐5p regulates rRNA synthesis by inhibiting Pol I pre‐initiation complex formation. Increased miR‐424‐5p expression in patients with conditions associated with muscle wasting is likely to contribute to the inhibition of protein synthesis and loss of muscle mass. [ABSTRACT FROM AUTHOR]

Abstract: Background: Loss 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. Methods: The 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). Results: miR‐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). Conclusions: These 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. [ABSTRACT FROM AUTHOR]

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 signaling 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.Results: Levels of muscle-RING-finger-protein-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.Conclusions: We describe a novel method for studying fiber-specific gene expression in optimum cutting temperature compound-embedded muscle specimens. LCM offers a more sensitive way to identify molecular changes in COPD muscle. Muscle Nerve 55: 902-912, 2017. [ABSTRACT FROM AUTHOR]

Background Loss 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. Methods We 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. Results Growth 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). Conclusions Together, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD. [ABSTRACT FROM AUTHOR]

Background Loss 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. Methods We 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. Results Imprinted 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 Study. Relative methylation of the H19 ICR was reduced in COPD patients with muscle weakness but was not associated with FFM. In vitro, miR-675 inhibited myoblast proliferation and patients with a low FFMI had fewer centralized nuclei suggesting miR-675 represses regeneration. Conclusions The data suggest that increased expression of miR-675/H19 and altered methylation of the H19 imprinting control region are associated with a low FFMI in patients with COPD but not in healthy community dwelling older men suggesting that epigenetic control of this loci may contribute to a susceptibility to a low FFMI. [ABSTRACT FROM AUTHOR]

Background and objective Quadriceps weakness is seen across all GOLD stages of COPD and is associated with increased morbidity and mortality. As quadriceps weakness is only weakly associated with FEV1, mechanisms other than airflow obstruction are implicated. We tested the hypothesis that insulin resistance contributes to skeletal muscle weakness in people with stable COPD. Methods Fifty-one COPD patients (no exacerbations preceding 6 weeks, no rehabilitation preceding 3 months) without known diabetes mellitus underwent assessment of skeletal muscle, including measurement of quadriceps maximal voluntary contraction ( QMVC). Physical activity was measured for 7 days using a multisensory biaxial accelerometer armband. Insulin resistance ( HOMA2 IR) was calculated from fasting blood glucose and insulin concentrations. Results QMVC was 30 ± 13 kg (74 ± 25% predicted) and 16 (31%) participants had quadriceps weakness. There was a negative univariate correlation between HOMA2 IR and QMVC (r = −0.446, P = 0.002). HOMA2 IR was greater in people with quadriceps weakness (1.59 ± 0.99) than in those without (1.11 ± 0.55, P = 0.032). On multivariate analysis, with age, sex, weight, BODE index and step count per day included in the model, a one-unit increase in insulin resistance was associated with a 5.9 (2.0-9.8)-kg decrease in QMVC ( P = 0.004) and a 4.2 (1.3-14.3)-fold increased risk of quadriceps weakness ( P = 0.02). Conclusion Insulin resistance is associated with skeletal muscle weakness in COPD, independent of potential confounders. Further studies are required to explore underlying mechanisms and determine whether insulin-sensitizing drugs could augment pulmonary rehabilitation in building skeletal muscle strength in COPD. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Chronic obstructive pulmonary disease (COPD) is associated with metabolic abnormalities in muscles of the lower limbs, but it is not known whether these abnormalities are generalized or limited to specific muscle groups, nor is there an easy way of predicting their presence. Methods: Metabolism in the quadriceps and biceps of 14 COPD patients and controls was assessed during sustained contraction using 31-phosphorus magnetic resonance spectroscopy (31P MRS). T1 MRI was used to measure quadriceps intermuscular adipose tissue (IMAT). Results: COPD patients had prolonged quadriceps phosphocreatine time (patients: 38.8 ± 12.7 s; controls: 25.2 ± 10.6 s; P = 0.006) and a lower pH (patents: 6.88 ± 0.1; controls: 6.99 ± 0.06; P = 0.002). Biceps measures were not significantly different. IMAT was associated with a nadir pH <7.0 (area under the curve = 0.84). Conclusions: Anaerobic metabolism during contraction was characteristic of quadriceps, but not biceps, muscles of patients with COPD and was associated with increased IMAT. Because IMAT can be assessed quickly by conventional MRI, it may be a useful approach for identifying patients with abnormal muscle bioenergetics. Muscle Nerve 51: 214-221, 2015 [ABSTRACT FROM AUTHOR]

Background and objective Quadriceps muscle dysfunction is an important contributor to exercise limitation in chronic obstructive pulmonary disease, but little is known about skeletal muscle function and its impact on exercise capacity in patients with fibrotic idiopathic interstitial pneumonia ( IIP). The aim of the study was to compare quadriceps strength and endurance in patients with fibrotic IIP and healthy controls, and relate it to exercise capacity. Methods Quadriceps strength and endurance, as well as respiratory muscle strength, and 6-min walk distance were compared among 25 patients with fibrotic IIP, forced vital capacity mean (standard deviation) 78.7 (14.0) %predicted, carbon monoxide transfer factor 40.3 (10.9) %predicted and 33 age-matched healthy controls using non-volitional measures. Quadriceps strength was assessed using magnetic femoral nerve stimulation (quadriceps twitch force), and endurance using the decay in force in response to repetitive magnetic stimulation of the quadriceps over 5 min. Results Both groups had comparable anthropometrics, gender proportion and respiratory muscle strength. Patients were significantly weaker than controls; quadriceps twitch force 10.1 (3.0) kg versus 8.0 (2.4) kg ( P = 0.013). Quadriceps force in response to repetitive magnetic stimulation declined significantly more rapidly in patients during the endurance protocol ( P < 0.001). In controls, there was a significant relationship between 6-min walk distance and quadriceps twitch force ( r 0.40, P = 0.038), and quadriceps endurance ( r 0.59, P = 0.016). In patients, only PaO2 and inspiratory muscle strength were retained as independent correlates of 6-min walk distance ( r2 = 0.3 P = 0.022). Conclusions Quadriceps strength and endurance are reduced in patients with fibrotic IIP compared with healthy controls, but are less tightly correlated with exercise performance. [ABSTRACT FROM AUTHOR]

Introduction: Quadriceps muscle dysfunction is common in COPD. Determining, and, if possible, predicting quadriceps phenotype in COPD is important for patient stratification for therapeutic trials.Methods: In biopsies from 114 COPD patients and 30 controls, we measured fiber size and proportion and assessed the relationship with quadriceps function (strength and endurance), clinical phenotype (lung function, physical activity, fat-free mass) and exercise performance. In a subset (n = 40) we measured muscle mid-thigh cross-sectional area by computed tomography.Results: Normal ranges for fiber proportions and fiber cross-sectional area were defined from controls; we found isolated fiber shift in 31% of patients, isolated fiber (predominantly type II) atrophy in 20%, both shift and atrophy in 25%, and normal fiber parameters in 24%. Clinical parameters related poorly to muscle biopsy appearances.Conclusions: Quadriceps morphology is heterogeneous in COPD and cannot be predicted without biopsy, underlining the need for biomarkers. [ABSTRACT FROM AUTHOR]

Background and objective The COPD Assessment Test ( CAT) is a recently introduced, simple-to-use health status instrument that takes less time to complete than better-established health status instruments. In chronic obstructive pulmonary disease ( COPD) patients, the CAT improves with pulmonary rehabilitation ( PR), and changes correlate with improvements in longer-established health status instruments such as the Chronic Respiratory Questionnaire ( CRQ). Increasing numbers of non- COPD patients are referred for PR, but it is not known whether the CAT is responsive to PR in these populations. Methods The CAT score was prospectively measured in 365 consecutive patients (255 COPD, 110 non- COPD) before and after an 8-week PR programme. Pre to post change in CAT was calculated for COPD and non- COPD patients, and correlated with change in the CRQ. Results For both non- COPD and COPD patients, there was a similar and significant improvement in the mean (95% confidence interval) CAT score following PR (non- COPD: −2.1 (−1.0, −3.2) vs COPD: −3.0 (−2.2, −3.8); P = 0.19). Change in CAT was significantly correlated with all domains of the CRQ in non- COPD patients (all P < 0.01). Conclusions As in COPD patients, the CAT is immediately responsive to PR in non- COPD patients. Even in unselected chronic respiratory disease patients undergoing PR, the CAT is a practical alternative to longer-established health status questionnaires. [ABSTRACT FROM AUTHOR]

Introduction: Quadriceps strength and size are commonly reduced in chronic obstructive pulmonary disease (COPD). We wished to assess volitional and nonvolitional ankle dorsiflexor strength in COPD. Methods: Quadriceps and ankle dorsiflexor strength were measured by maximum voluntary contraction (MVC) and by twitch responses to supramaximal femoral and fibular nerve stimulation. Cross-sectional areas of the tibialis anterior (TACSA) and rectus femoris muscles (RFCSA) were measured by ultrasound. Results: Eighteen elderly subjects and 20 COPD patients [mean(SD) %predictedFEV1 50(20)%] participated. No significant difference in fat-free mass index, ankle dorsiflexor strength, or TACSA were observed in the presence of reduced quadriceps strength and size in COPD [mean MVC difference: −10.9 kg (95% confidence interval {CI}: −17.1 kg to −4.8 kg, P < 0.01; mean RFCSA difference −119 mm2, 95% CI: −180 mm2 to −58 mm2, P < 0.01)]. Conclusions: Ankle dorsiflexor strength is less attenuated than quadriceps strength in COPD patients with moderate airflow obstruction. Direct quadriceps assessment may be more relevant than measurement of lower limb fat-free mass. Muscle Nerve 46: 548-554, 2012 [ABSTRACT FROM AUTHOR]

The contractile and actomyosin ATPase properties of single fibres were examined in human diaphragm muscle obtained from patients with and without chronic obstructive pulmonary disease (COPD). Costal diaphragm biopsies were taken from five patients without evidence of COPD and from 11 age-matched individuals with varying degrees of the disease. Our aim was to establish whether changes in contractile properties of COPD diaphragm could be fully explained by the previously documented shift towards a greater proportion of type I myosin heavy chain isoform in COPD. The relative proportion of type I diaphragm fibres from non-COPD and COPD patients was measured by gel electrophoresis, and was negatively correlated with FEV1 over the full range of values investigated. There was also significant atrophy of the type I fibre population in COPD diaphragms. Isometric tension was similar among the fibre types and between the COPD and non-COPD patients. The intrinsic energetic properties of diaphragm fibres were examined by monitoring the time-resolved actomyosin ATPase activity in COPD and non-COPD fibres that produced similar isometric forces. The isometric ATPase rate in COPD fibres was reduced to 50% of the rate in non-COPD fibres; hence, the cost of isometric contraction in type I and type IIA COPD fibres was reduced to between one-third and one-half of the tension cost calculated for non-COPD fibres. The rate of force development in type I COPD fibres was reduced to 50% of the rate seen in non-COPD type-I fibres. No difference in the rate of ATP consumption between COPD and non-COPD fibres was evident during isovelocity shortening. These data extend previous findings showing that aspects of breathing mechanics during progressive COPD are associated with remodelling of the diaphragm fibre-type distribution; on top of the increase in type I fibres there are fibre-specific reductions in force development rate (type I fibres) and ATPase rate that are consistent with the impairment of cross-bridge cycling kinetics. [ABSTRACT FROM AUTHOR]

Abstract: Background: Reduced diaphragm contractility occurs in some healthy subjects when they exercise to exhaustion. This indicates low frequency fatigue, which may contribute to task failure. We hypothesised that patients with congestive heart failure (CHF) might be especially vulnerable to the development of low frequency diaphragm fatigue after exhaustive exercise. Aims: To study the effect of exhaustive incremental cycle exercise on diaphragm contractility in patients with CHF. Methods: 12 patients with CHF with an ejection fraction of 36.5±7.3% and 12 healthy age-matched control subjects performed an incremental cycle test to exhaustion. The unpotentiated twitch transdiaphragmatic pressure (twitch Pdi) in response to bilateral anterolateral magnetic phrenic nerve stimulation (BAMPS) was measured before and after exercise. Results: Twitch Pdi at baseline was 20.2±6.7 cmH2O in the CHF group and 20.3±.3 cmH2O in the controls (p =0.957). 25 and 35 min post exercise the values were 19.9±5.4 and 20.0±5.1 cmH2O in the CHF group and 20.6±4.3 and 21.2±3.4 cmH2O in the control group; neither change was significant (F(2,27)=0.007, p =0.993; F(2,33)=0.144, p =0.866, respectively). Conclusion: When patients with CHF cycle to exhaustion, low frequency fatigue of the diaphragm does not occur, and this is unlikely to be an important factor limiting exercise capacity of such patients. [Copyright &y& Elsevier]

Functional imaging studies in normal humans have shown that the supplementary motor area (SMA) and the primary motor cortex (PMC) are coactivated during various breathing tasks. It is not known whether a direct pathway from the SMA to the diaphragm exists, and if so what properties it has. Using transcranial magnetic stimulation (TMS) a site at the vertex, representing the diaphragm primary motor cortex, has been identified. TMS mapping revealed a second area 3 cm anterior to the vertex overlying the SMA, which had a rapidly conducting pathway to the diaphragm (mean latency 16.7 ± 2.4 ms). In comparison to the vertex, the anterior position was characterized by a higher diaphragm motor threshold, a greater proportional increase in motor-evoked potential (MEP) amplitude with voluntary facilitation and a shorter silent period. Stimulus-response curves did not differ significantly between the vertex and anterior positions. Using paired TMS, we also compared intracortical inhibition/facilitation (ICI/ICF) curves. In comparison to the vertex, the MEP elicited from the anterior position was not inhibited at short interstimulus intervals (1-5 ms) and was more facilitated at long interstimulus intervals (9-20 ms). The patterns of response were identical for the costal and crural diaphragms. We conclude that the two coil positions represent discrete areas that are likely to be the PMC and SMA, with the latter wielding a more excitatory effect on the diaphragm. [ABSTRACT FROM AUTHOR]

Magnetic stimulation of the femoral nerve is a new technique for assessment of quadriceps strength by measurement of twitch tension (TwQ), a test that is independent of subject motivation. In this study, we sought to establish better define normal values by measurement of TwQ in 45 normal subjects. Supramaximal stimulation, as judged by TwQ, was achieved in 43 of 45 subjects at a mean of 90% of maximum stimulator output. The mean TwQ was 7·3 kilograms force (kgf) (SD 2·3) for women and 9·8 kgf (SD 2·5) for men. The mean maximal voluntary contraction (MVC) force was 48·0 kgf (SD 9·2) for women and 70·1 kgf (15·2) for men. The mean TwQ/MVC ratio was 0·15 for both women and men. Significant correlations were observed between TwQ and weight (r = 0·33,P<0·03) and height (r = 0·32,P<0·03) but these were weak and only partially explained observed variance. Our data confirm that magnetic femoral nerve stimulation is generally acceptable to naive subjects. Values are provided as a function of weight in normal subjects. [ABSTRACT FROM AUTHOR]

The authors comment on whether respiratory muscle training (RMT) improves exercise tolerance. According to the authors, there is a tendency for RMT to enhance aspects of respiratory muscle performance that are inherent to the training. They point out the methodological difficulties involved in evaluating RMT. The authors also cite the poor correlation between changes in respiratory muscle function and performance as another argument against RMT in disease.

See article, page 1089 [ABSTRACT FROM AUTHOR]

A response by Mehul S. Patel and colleagues to a commentary on the idea that respiratory muscle training (RMT) can improve exercise tolerance. According to Patel and colleagues, there is insufficient data supporting the RMT case. They point out that RMT in the case of chronic obstructive pulmonary disease may involve an opportunity cost for physical training. They argue that mechanistic studies are not enough to address the questions posed by the RMT case.

A correction to the "CrossTalk" article by Patel and colleagues, published in the 2012 issue is presented.