Annemie M. W. J. Schols

Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics"

Chronic diseases as well as aging are frequently associated with deterioration of nutritional status, loss muscle mass and function (i.e. sarcopenia), impaired quality of life and increased risk for morbidity and mortality. Although simple and effective tools for the accurate screening, diagnosis and treatment of malnutrition have been developed during the recent years, its prevalence still remains disappointingly high and its impact on morbidity, mortality and quality of life clinically significant. Based on these premises, the Special Interest Group (SIG) on cachexia-anorexia in chronic wasting diseases was created within ESPEN with the aim of developing and spreading the knowledge on the basic and clinical aspects of cachexia and anorexia as well as of increasing the awareness of cachexia among health professionals and care givers. The definition, the assessment and the staging of cachexia, were identified as a priority by the SIG. This consensus paper reports the definition of cachexia, pre-cachexia and sarcopenia as well as the criteria for the differentiation between cachexia and other conditions associated with sarcopenia, which have been developed in cooperation with the ESPEN SIG on nutrition in geriatrics.

Body composition and mortality in chronic obstructive pulmonary disease

BACKGROUND Survival studies have consistently shown significantly greater mortality rates in underweight and normal-weight patients with chronic obstructive pulmonary disease (COPD) than in overweight and obese COPD patients. OBJECTIVE To compare the contributions of low fat-free mass and low fat mass to mortality, we assessed the association between body composition and mortality in COPD. DESIGN We studied 412 patients with moderate-to-severe COPD [Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stages II-IV, forced expiratory volume in 1 s of 36 +/- 14% of predicted (range: 19-70%). Body composition was assessed by using single-frequency bioelectrical impedance. Body mass index, fat-free mass index, fat mass index, and skeletal muscle index were calculated and related to recently developed reference values. COPD patients were stratified into defined categories of tissue-depletion pattern. Overall mortality was assessed at the end of follow-up. RESULTS Semistarvation and muscle atrophy were equally distributed among disease stages, but the highest prevalence of cachexia was seen in GOLD stage IV. Forty-six percent of the patients (n = 189) died during a maximum follow-up of 5 y. Cox regression models, with and without adjustment for disease severity, showed that fat-free mass index (relative risk: 0.90; 95% CI: 0.84, 0.96; P = 0.003) was an independent predictor of survival, but fat mass index was not. Kaplan-Meier and Cox regression plots for cachexia and muscle atrophy did not differ significantly. CONCLUSIONS Fat-free mass is an independent predictor of mortality irrespective of fat mass. This study supports the inclusion of body-composition assessment as a systemic marker of disease severity in COPD staging.

Recommendations on the use of exercise testing in clinical practice

Evidence-based recommendations on the clinical use of cardiopulmonary exercise testing (CPET) in lung and heart disease are presented, with reference to the assessment of exercise intolerance, prognostic assessment and the evaluation of therapeutic interventions (e.g. drugs, supplemental oxygen, exercise training). A commonly used grading system for recommendations in evidence-based guidelines was applied, with the grade of recommendation ranging from A, the highest, to D, the lowest. For symptom-limited incremental exercise, CPET indices, such as peak O2 uptake (V′O2), V′O2 at lactate threshold, the slope of the ventilation–CO2 output relationship and the presence of arterial O2 desaturation, have all been shown to have power in prognostic evaluation. In addition, for assessment of interventions, the tolerable duration of symptom-limited high-intensity constant-load exercise often provides greater sensitivity to discriminate change than the classical incremental test. Field-testing paradigms (e.g. timed and shuttle walking tests) also prove valuable. In turn, these considerations allow the resolution of practical questions that often confront the clinician, such as: 1) “When should an evaluation of exercise intolerance be sought?”; 2) “Which particular form of test should be asked for?”; and 3) “What cluster of variables should be selected when evaluating prognosis for a particular disease or the effect of a particular intervention?”

Raised CRP levels mark metabolic and functional impairment in advanced COPD

Background: C-reactive protein (CRP) is often used as a clinical marker of acute systemic inflammation. Since low grade inflammation is evident in chronic diseases such as chronic obstructive pulmonary disease (COPD), new methods have been developed to enhance the sensitivity of CRP assays in the lower range. A study was undertaken to investigate the discriminative value of high sensitivity CRP in COPD with respect to markers of local and systemic impairment, disability, and handicap. Methods: Plasma CRP levels, interleukin 6 (IL-6) levels, body composition, resting energy expenditure (REE), exercise capacity, health status, and lung function were determined in 102 patients with clinically stable COPD (GOLD stage II–IV). The cut off point for normal versus raised CRP levels was 4.21 mg/l. Results: CRP levels were raised in 48 of 102 patients. In these patients, IL-6 (p<0.001) and REE (adjusted for fat-free mass, p = 0.002) were higher while maximal (p = 0.040) and submaximal exercise capacity (p = 0.017) and 6 minute walking distance (p = 0.014) were lower. The SGRQ symptom score (p = 0.003) was lower in patients with raised CRP levels, as were post-bronchodilator FEV1 (p = 0.031) and reversibility (p = 0.001). Regression analysis also showed that, when adjusted for FEV1, age and sex, CRP was a significant predictor for body mass index (p = 0.044) and fat mass index (p = 0.016). Conclusions: High sensitivity CRP is a marker for impaired energy metabolism, functional capacity, and distress due to respiratory symptoms in COPD.

Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor-kappaB.

Muscle wasting is often associated with chronic inflammation. Because tumor necrosis factor α (TNF‐α) has been implicated as a major mediator of cachexia, its effects on C2C12 myocytes were examined. TNF‐α activated nuclear factor‐κΒ (NF‐κΒ) and interfered with the expression of muscle proteins in differentiating myoblasts. Introduction of a mutant form of inhibitory protein κΒα (IκBα) restored myogenic differentiation in myoblasts treated with TNF‐α or interleukin 1β. Conversely, activation of NF‐KBby overexpression of IΚB kinase was sufficient to block myogenesis, illustrating the causal link between NF‐ΚB activation and inhibition of myogenic differentiation. The inhibitory effects of TNF‐α on myogenic differentiation were reversible, indicating that the effects of the cytokine were not due to nonspecific toxicity. Treatment of differentiated myotubes with TNF‐α did not result in a striking loss of muscle‐specific proteins, which shows that myogenesis was selectively affected in the myoblast stage by TNF‐α. An important finding was that NF‐ΚB was activated to the same extent in differentiating and differentiated cells, illustrating that once myocytes have differentiated they become refractory to the effects of NF‐ΚB activation. These results demonstrate that inflammatory cytokines may contribute to muscle wasting through the inhibition of myogenic differentiation via a NF‐κB‐dependent pathway.—Langen, R. C. J., Schols, A. M. W. J., Kelders, M. C. J. M., Wouters, E. F. M., Janssen‐Heininger, Y. M. W. Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor‐KB. FASEB J. 15, 1169–1180 (2001)

Nutritional recommendations for the management of sarcopenia.

The Society for Sarcopenia, Cachexia, and Wasting Disease convened an expert panel to develop nutritional recommendations for prevention and management of sarcopenia. Exercise (both resistance and aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement.

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

BACKGROUND Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

Skeletal muscle fibre-type shifting and metabolic profile in patients with chronic obstructive pulmonary disease

The aim of this study was to examine the nature of fibre-type redistribution in relation to fibre metabolic profile in the vastus lateralis in chronic obstructive pulmonary disease (COPD) and COPD subtypes. Fifteen COPD patients (eight with emphysema stratified by high-resolution computed tomography) and 15 healthy control subjects were studied. A combination of myofibrillar adenosine triphosphatase staining and immunohistochemistry was used to identify pure, as well as hybrid fibre types. For oxidative capacity, fibres were stained for cytochrome c oxidase and succinate dehydrogenase activities, and glycogen phosphorylase for glycolytic capacity. The proportion of type‐I fibres in COPD patients was markedly lower (16% versus 42%), especially in emphysema, and the proportion of hybrid fibres was higher (29% versus 16%) compared to controls. The proportion of fibres staining positive for oxidative enzymes was lower in COPD patients, which correlated with the proportion of type‐I fibres. In COPD oxidative capacity was lower within IIA fibres. The authors conclude that fibre-type transitions are involved in the fibre-type redistribution in chronic obstructive pulmonary disease. Low oxidative capacity is closely related to the proportion of type‐I fibres, but an additional reduction of oxidative enzyme activity is present within IIA fibres. Fibre-type abnormalities may be aggravated in emphysema.

Tumor necrosis factor-alpha inhibits myogenic differentiation through MyoD protein destabilization

Tumor necrosis factor α (TNFα) has been implicated as a mediator of muscle wasting through nuclear factor kappa B (NF‐ΚB) ‐dependent inhibition of myogenic differentiation. The aim of the present study was to identify the regulatory molecule(s) of myogenesis targeted by TNFα/NF‐κΒ signaling. TNFα interfered with cell cycle exit and repressed the accumulation of transcripts encoding muscle‐specific genes in differentiating C2C12 myoblasts. Overexpression of a p65 (RelA) mutant lacking the transcriptional activation domain attenuated the TNFα‐mediated inhibition of muscle‐specific gene transcription. The ability of muscle regulatory factor MyoD to induce muscle‐specific transcription in 10T1/2 fibroblasts was also disrupted by wild‐type p65, demonstrating that NF‐KB transcriptional activity interferes with the function of MyoD. Inhibition of muscle‐specific gene expression by TNFα was restored by overexpression of MyoD, whereas endogenous MyoD protein abundance and stability were reduced by TNFα through increased proteolysis of MyoD by the ubiquitin proteasome pathway. Last, the inhibitory effects of TNFα on myogenic differentiation were demonstrated in a mouse model of skeletal muscle regeneration, in which TNFα caused a delay in myoblast cell cycle exit. These results implicate that TNFα inhibits myogenic differentiation through destabilizing MyoD protein in a NF‐κB‐dependent manner, which interferes with skeletal muscle regeneration and may contribute to muscle wasting.—Langen, R. C. J., van der Velden, J. L. J., Schols, A. M. W. J., Kelders, M. C. J. M., Wouters, E. F. M., Janssen‐Heininger, Y. M. W. Tumor necrosis factor‐alpha inhibits myogenic differentiation through MyoD protein destabilization. FASEB J. 18, 227–237 (2004)

Body composition and exercise performance in patients with chronic obstructive pulmonary disease.

To investigate whether a compromised nutritional state may limit exercise performance in patients with chronic obstructive pulmonary disease we studied 54 such patients (FEV1 less than 50% and arterial oxygen tension (PaO2) greater than 7.3 kPa) whose clinical condition was stable and who were admitted to a pulmonary rehabilitation centre. Fat free mass was assessed anthropometrically (from skinfold measurements at four sites) and by bioelectrical impedance; creatinine height index and arm muscle circumference were also assessed. The mean (SD) distance walked in 12 minutes was 845 (178) m. No association was established between the distance walked and spirometric measures. A good correlation was found between the distance walked and fat free mass in the whole group (r = 0.73 for impedance measurements and 0.65 for skinfold thickness) and in a subgroup of 23 lean patients (body weight less than 90% of ideal weight; r = 0.66 for impedance measurements and 0.46 for skinfold thickness). Body weight correlated with the distance walked only in the whole group (r = 0.61). On stepwise regression analysis fat free mass measured by bioelectrical impedance, maximal inspiratory mouth pressure, and PaO2 accounted for 60% of the variation in the distance walked in 12 minutes. We conclude that fat free mass, independently of airflow obstruction, is an important determinant of exercise performance in patients with severe chronic obstructive pulmonary disease.