Background
Evidence regarding the efficacy of nutritional supplementation to enhance exercise training responses in COPD patients with low muscle mass is limited.
The objective was to study if ...nutritional supplementation targeting muscle derangements enhances outcome of exercise training in COPD patients with low muscle mass.
Methods
Eighty‐one COPD patients with low muscle mass, admitted to out‐patient pulmonary rehabilitation, randomly received oral nutritional supplementation, enriched with leucine, vitamin D, and omega‐3 fatty acids (NUTRITION) or PLACEBO as adjunct to 4 months supervised high intensity exercise training.
Results
The study population (51% males, aged 43–80) showed moderate airflow limitation, low diffusion capacity, normal protein intake, low plasma vitamin D, and docosahexaenoic acid. Intention‐to‐treat analysis revealed significant differences after 4 months favouring NUTRITION for body mass (mean difference ± SEM) (+1.5 ± 0.6 kg, P = 0.01), plasma vitamin D (+24%, P = 0.004), eicosapentaenoic acid (+91%,P < 0.001), docosahexaenoic acid (+31%, P < 0.001), and steps/day (+24%, P = 0.048). After 4 months, both groups improved skeletal muscle mass (+0.4 ± 0.1 kg, P < 0.001), quadriceps muscle strength (+12.3 ± 2.3 Nm,P < 0.001), and cycle endurance time (+191.4 ± 34.3 s, P < 0.001). Inspiratory muscle strength only improved in NUTRITION (+0.5 ± 0.1 kPa, P = 0.001) and steps/day declined in PLACEBO (−18%,P = 0.005).
Conclusions
High intensity exercise training is effective in improving lower limb muscle strength and exercise performance in COPD patients with low muscle mass and moderate airflow obstruction. Specific nutritional supplementation had additional effects on nutritional status, inspiratory muscle strength, and physical activity compared with placebo.
COVID-19 has demonstrated a highly variable disease course, from asymptomatic to severe illness and eventually death. Clinical parameters, as included in the 4C Mortality Score, can predict mortality ...accurately in COVID-19. Additionally, CT scan-derived low muscle and high adipose tissue cross-sectional areas (CSAs) have been associated with adverse outcomes in COVID-19.
Are CT scan-derived muscle and adipose tissue CSAs associated with 30-day in-hospital mortality in COVID-19, independent of 4C Mortality Score?
This was a retrospective cohort analysis of patients with COVID-19 seeking treatment at the ED of two participating hospitals during the first wave of the pandemic. Skeletal muscle and adipose tissue CSAs were collected from routine chest CT-scans at admission. Pectoralis muscle CSA was demarcated manually at the fourth thoracic vertebra, and skeletal muscle and adipose tissue CSA was demarcated at the first lumbar vertebra level. Outcome measures and 4C Mortality Score items were retrieved from medical records.
Data from 578 patients were analyzed (64.6% men; mean age, 67.7 ± 13.5 years; 18.2% 30-day in-hospital mortality). Patients who died within 30 days demonstrated lower pectoralis CSA (median, 32.6 interquartile range (IQR), 24.3-38.8 vs 35.4 IQR, 27.2-44.2; P = .002) than survivors, whereas visceral adipose tissue CSA was higher (median, 151.1 IQR, 93.6-219.7 vs 112.9 IQR, 63.7-174.1; P = .013). In multivariate analyses, low pectoralis muscle CSA remained associated with 30-day in-hospital mortality when adjusted for 4C Mortality Score (hazard ratio, 0.98; 95% CI, 0.96-1.00; P = .038).
CT scan-derived low pectoralis muscle CSA is associated significantly with higher 30-day in-hospital mortality in patients with COVID-19 independently of the 4C Mortality Score.
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•SM, SAT and RA decrease significantly after two lines of chemotherapy.•Low SM index at baseline does not significantly influence OS.•Loss of SM after two lines of chemotherapy is a poor prognostic ...factor.
To evaluate the relationship between early changes in muscle and adipose tissue during chemotherapy and overall survival (OS) in stage IV non-small cell lung cancer (NSCLC).
In this post-hoc analysis of the first line NVALT12 trial (NCT01171170) in stage IV NSCLC, skeletal muscle (SM), radiation attenuation (RA), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were assessed at the third lumbar level on CT-images obtained before initiation of chemotherapy and shortly after administration of the second cycle. The contribution of changes in different body compartments to overall survival was assessed.
CT scans of 111 patients were included. Analysis of body composition changes between the baseline and the follow-up scan, revealed that overall SM cross sectional area (CSA), radiation attenuation and SAT CSA decreased respectively by −1.2 ± 2.9 cm2/m2 (p < 0.001), −0.7 ± 3.3 HU (p = 0.026) and −1.9 ± 8.7 cm2/m2 (p = 0.026), while no significant changes in VAT tissue were observed. Longitudinally, median OS was significantly shorter among patients losing SM compared to patients with preserved SM (9.4 versus 14.2 months; HR 1.9, 95% CI: 1.23, 2.79, p = 0.003). Multivariate analyses showed that proportional loss of muscle mass was associated with poor OS (HR 0.949, 95% CI: 0.915, 0.985, p = 0.006) independent from important clinical prognostic factors including WHO-PS, gender, age and Charlson comorbidity index.
Early loss of SM during first line chemotherapy is a poor prognostic factor in stage IV NSCLC patients. Future studies have to reveal whether early supportive intervention guided by initial CT muscle response to chemotherapy can influence the wasting process and related mortality risk.
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and ...pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.
Background
Chemoradiation or bioradiation treatment (CRT/BRT) of locally advanced head and neck squamous cell carcinoma (LAHNSCC) comes with high toxicity rates, often leading to temporary tube ...feeding (TF) dependency. Cachexia is a common problem in LAHNSCC. Yet changes in body composition and muscle weakness during CRT/BRT are underexplored. Strong evidence on the effect of TF on body composition during treatment is lacking. The aim of this cohort study was to assess (i) the relationship of fat‐free mass index (FFMI) and handgrip strength (HGS) with CRT/BRT toxicity and outcome, (ii) body composition in patients treated with chemoradiation (cisplatin) vs. bioradiation (cetuximab), and (iii) the effect of the current TF regime on body composition and muscle strength.
Methods
Locally advanced head and neck squamous cell carcinoma patients treated with CRT/BRT between January 2013 and December 2016 were included (n = 137). Baseline measurements of body composition (bioelectrical impedance analysis) and HGS were performed. Toxicity grades (Common Terminology Criteria for Adverse Events) were scored. In a subset of 69 patients, weight loss, body composition, and HGS were additionally assessed during and after CRT/BRT. TF was initiated according to the Dutch guidelines for malnutrition.
Results
In this cohort (68% male, mean age 59 ± 8 years), the incidence of baseline muscle wasting, defined as FFMI < P10, was 29%. Muscle wasting was present in 23 of 100 (23%) chemoradiation patients and 17 of 37 (46%) bioradiation patients (P = 0.009). Muscle‐wasted patients required more unplanned hospitalizations during CRT (P = 0.035). In the chemoradiation subset, dose‐limiting toxicity was significantly higher in wasted vs. non‐wasted patients (57% vs. 25%, P = 0.004). Median follow‐up was 32 months. Multivariate Cox regression analysis identified muscle wasting as independent unfavourable prognostic factor for overall survival hazard ratio 2.1 (95% CI 1.1–4.1), P = 0.022 and cisplatin as favourable prognostic factor hazard ratio 0.3 (95% CI 0.2–0.6), P = 0.001. Weight and HGS significantly decreased during CRT/BRT, −3.7 ± 3.5 kg (P < 0.001) and −3.1 ± 6.0 kg (P < 0.001), respectively. Sixty‐four per cent of the patients required TF 21 days (range 0–59) after CRT/BRT initiation. Total weight loss during CRT/BRT was significantly (P = 0.007) higher in the total oral diet group (5.5 ± 3.7 kg) compared with the TF group (3.0 ± 3.2 kg). Loss of FFM and HGS was similar in both groups.
Conclusions
In LAHNSCC patients undergoing CRT/BRT, FFMI < P10 is an unfavourable prognostic factor for overall survival, treatment toxicity, and tolerance. Patients experience significant weight and FFM loss during treatment. Current TF regime attenuates weight loss but does not overcome loss of muscle mass and function during therapy. Future interventions should consider nutritional intake and additional strategies specifically targeting metabolism, loss of muscle mass, and function.
A poor dietary quality may accelerate disturbances in body composition in chronic obstructive pulmonary disease (COPD), but only limited studies have investigated dietary intake from this ...perspective. The objective of the current study was to investigate dietary intake in relation to low fat-free mass and abdominal obesity in COPD.
Dietary intake was assessed by means of a cross-check dietary history method in 564 COPD patients referred for pulmonary rehabilitation. The Dutch Food Composition Database was used to calculate nutrient intake, which was compared with the 2006 recommendations from the Dutch Health Council. Body composition was assessed by DEXA scan.
In general, the reported intake of macronutrients represented a typical western diet. With regard to micronutrients, vitamin D and calcium intakes were below the recommended levels in the majority of patients (>75%), whereas vitamin A, C and E intakes were below the recommended levels in over one-third of patients. Patients with inadequate vitamin D intake more frequently reported a low intake of protein (P=0.02) and micronutrients (P<0.001). Patients with a low fat-free mass index (FFMI) more often had low intake of protein, while abdominally obese patients more often had low intake of protein and most micronutrients (P<0.05). Patients with both low FFMI and abdominal obesity appeared most often to be consuming a poor-quality diet.
Our data indicate that dietary quality is low in COPD patients referred for pulmonary rehabilitation and differs between patients with different body composition profiles.
Summary COPD is a chronic disease of the lungs, but heterogeneous with respect to clinical manifestations and disease progression. This has consequences for health risk assessment, stratification and ...management. Heterogeneity can be driven by pulmonary events but also by systemic consequences (e.g. cachexia and muscle weakness) and co-morbidity (e.g. osteoporosis, diabetes and cardiovascular disease). This paper shows how a metabolic perspective on COPD has contributed significantly to understanding clinical heterogeneity and the need for a paradigm shift from reactive medicine towards predictive, preventive, personalized and participatory medicine. These insights have also lead to a paradigm shift in nutritional therapy for COPD from initial ignorance or focusing on putative adverse effects of carbohydrate overload on the ventilatory system to beneficial effects of nutritional intervention on body composition and physical functioning as integral part of disease management. The wider implications beyond COPD as disease have been as clinical model for translational cachexia research.
Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. ...Evidence in non-muscle cells suggests that glycogen synthase kinase-3β (GSK-3β) represses mitochondrial biogenesis and inhibits PPAR-γ co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3β in the regulation of skeletal muscle oxidative metabolism is unknown.
We hypothesized that inactivation of GSK-3β stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3β inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism.
GSK-3β was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3β knock-out (KO) mice were subjected to hind limb suspension for 14days. Key constituents of oxidative metabolism and PGC-1 signaling were investigated.
In vitro, knock-down of GSK-3β increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3β increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3β KO animals were protected against unloading-induced decrements in expression levels of these constituents.
Inactivation of GSK-3β up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3β KO protects against inactivity-induced reductions in muscle metabolic gene expression.
•Inactivation of GSK-3β increases mitochondrial metabolism in C2C12 muscle cells.•Inactivation of GSK-3β activates PGC-1 signaling in cultured C2C12 myotubes.•GSK-3β inactivation increased metabolic gene expression via PGC-1α in myotubes.•GSK-3β KO protects against HLS-induced loss of muscle oxidative gene expression.
BIA is easy, non-invasive, relatively inexpensive and can be performed in almost any subject because it is portable. Part II of these ESPEN guidelines reports results for fat-free mass (FFM), body ...fat (BF), body cell mass (BCM), total body water (TBW), extracellular water (ECW) and intracellular water (ICW) from various studies in healthy and ill subjects. The data suggests that BIA works well in healthy subjects and in patients with stable water and electrolytes balance with a validated BIA equation that is appropriate with regard to age, sex and race. Clinical use of BIA in subjects at extremes of BMI ranges or with abnormal hydration cannot be recommended for routine assessment of patients until further validation has proven for BIA algorithm to be accurate in such conditions. Multi-frequency- and segmental-BIA may have advantages over single-frequency BIA in these conditions, but further validation is necessary. Longitudinal follow-up of body composition by BIA is possible in subjects with BMI 16–34kg/m2 without abnormal hydration, but must be interpreted with caution. Further validation of BIA is necessary to understand the mechanisms for the changes observed in acute illness, altered fat/lean mass ratios, extreme heights and body shape abnormalities.
Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-alpha, are common features of chronic obstructive pulmonary disease. To investigate whether inflammation of ...the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed overexpression of a TNF-alpha transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-alpha mice exhibited increased levels of TNF-alpha in the circulation and increased endogenous TNF-alpha expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-alpha. Decreased muscle and body weights observed in SP-C/TNF-alpha mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF-alpha mouse musculature revealed a decreased muscle regenerative capacity, shown by attenuated myoblast proliferation and differentiation in response to reloading of disuse-atrophied muscle, which may contribute to skeletal muscle wasting. Importantly, incubation of cultured myoblasts with TNF-alpha also resulted in elevated TNF-alpha mRNA levels and inhibition of myoblast differentiation. Collectively, our results demonstrate that chronic pulmonary inflammation results in muscle wasting and impaired muscle regeneration in SP-C/TNF-alpha mice, possibly as a consequence of an amplificatory TNF-alpha expression circuit extending from the lung to skeletal muscle.
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