11ß-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD.

Muscle atrophy is an extrapulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) activates GCs and contributes toward GC-induced muscle wasting. To explore the potential of 11ßHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 11ßHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intratracheal (IT) instillation of elastase to model COPD in WT and 11ßHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. µCT scans were obtained prior and at study endpoint 48 h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were determined by ELISA. In vitro, myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-11ßHSD1/KO animals compared with WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11ßHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11ßHSD1/KO animals, whereas C2C12 myotubes treated with LPS-11ßHSD1/KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11ß-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11ß-HSD1 may not be appropriate to prevent muscle wasting in this setting.

Tooth extractions prior to chemoradiation or bioradiation are associated with weight loss during treatment for locally advanced oropharyngeal cancer.

PURPOSE: Prior to radiotherapy combined with chemotherapy (CRT) or biotherapy (BRT) for oropharyngeal squamous cell carcinoma (OPSCC), teeth with poor prognosis that pose a risk for post-RT osteoradionecrosis (ORN) are removed. The effect of tooth loss on body weight loss and tube feeding (TF) dependency during CRT/BRT is unknown. This study aimed to evaluate the effect of incomplete dentition, tooth extractions prior to CRT/BRT, and the subsequent loss of functional units on (1) weight loss during CRT/BRT and (2) the need for TF during CRT/BRT for OPSCC. METHODS: OPSCC patients treated with CRT/BRT between 2013 and 2016 were included in this retrospective cohort study. Dental status was determined during the dental assessment at first visit and after tooth extractions prior to the start of CRT/BRT. Weight loss during CRT/BRT was scored dichotomously, comparing weight loss > 5% to stable or increased weight. Potential factors associated with weight loss were identified, including patient, tumor, and treatment characteristics. RESULTS: Seventy-seven OPSCC patients were included. Forty patients (52%) experienced weight loss > 5% during CRT/BRT. Extractions were performed in 66% of the OPSCC patients. The mean number of extracted teeth was 4.1 ± 5.6 per patient. Tooth extractions prior to CRT/BRT were associated with weight loss > 5% during CRT/BRT (HR 1.130 (95% CI 1.011-1.262), p = 0.031). None of the dental status-related parameters showed any significant associative value for TF during CRT/BRT. CONCLUSIONS: Pre-CRT/BRT tooth extractions intended to reduce the risk of ORN, are a risk factor for weight loss during CRT/BRT for OPSCC. TRIAL REGISTRATION NUMBER: This study was approved by the medical ethics committee of the MUMC + (METC 2020-1589) on July 28, 2020.

Frequency and functional translation of low muscle mass in overweight and obese patients with COPD.

BACKGROUND: Cut offs for fat-free mass index (FFMI) and appendicular skeletal muscle mass index (ASMI) are available for diagnosing low muscle mass in patients with COPD. This study aimed to investigate: (1) the frequency of low muscle mass (FFMI and ASMI) applying different cut-offs and (2) the functional translation (clinical impact) of low muscle mass, in patients with COPD stratified into BMI categories. METHODS: Patients with COPD were assessed regarding body composition, exercise capacity, quadriceps muscle strength, symptoms of anxiety and depression, dyspnea and quality of life upon referral to pulmonary rehabilitation. The proportion of patients with low muscle mass was compared among BMI categories. Clinical outcomes between patients with normal and low muscle mass within each BMI category were compared. RESULTS: 469 patients with COPD were included for analyses. The frequency of patients classified as low FFMI varied significantly according to the choice of cut-off (32 to 54%; P < 0.05), whereas the frequency of patients with low ASMI was 62%. When applying age-gender-BMI-specific cut-offs, 254 patients (54%) were classified as low FFMI. The choice of the cut-off affected the frequency of patients with low muscle mass in all BMI categories. Overweight and obese patients with low muscle mass were more frequently males and presented worse pulmonary function, exercise capacity and muscle strength compared with overweight and obese patients with normal muscle mass. CONCLUSIONS: Approximately half of the overweight and obese patients with COPD have low muscle mass when applying age-gender-BMI-specific cut-offs. Low muscle mass is associated with worse functional outcomes in overweight and obese COPD patients.

Iron deficiency-induced loss of skeletal muscle mitochondrial proteins and respiratory capacity; the role of mitophagy and secretion of mitochondria-containing vesicles.

Iron homeostasis is essential for mitochondrial function, and iron deficiency has been associated with skeletal muscle weakness and decreased exercise capacity in patients with different chronic disorders. We hypothesized that iron deficiency-induced loss of skeletal muscle mitochondria is caused by increased mitochondrial clearance. To study this, C2C12 myotubes were subjected to the iron chelator deferiprone. Mitochondrial parameters and key constituents of mitophagy pathways were studied in presence or absence of pharmacological autophagy inhibition or knockdown of mitophagy-related proteins. Furthermore, it was explored if mitochondria were present in extracellular vesicles (EV). Iron chelation resulted in an increase in BCL2/Adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and BNIP3-like gene and protein levels, and the appearance of mitochondria encapsulated by lysosome-like vesicular structures in myotubes. Moreover, mitochondria were secreted via EV. These changes were associated with cellular mitochondrial impairments. These impairments were unaltered by autophagy inhibition, knockdown of mitophagy-related proteins BNIP3 and BNIP3L, or knockdown of their upstream regulator hypoxia-inducible factor 1 alpha. In conclusion, mitophagy is not essential for development of iron deficiency-induced reductions in mitochondrial proteins or respiratory capacity. The secretion of mitochondria-containing EV could present an additional pathway via which mitochondria can be cleared from iron chelation-exposed myotubes.

Effect of Bronchoscopic Lung Volume Reduction in Advanced Emphysema on Energy Balance Regulation.

BACKGROUND: Hypermetabolism and muscle wasting frequently occur in patients with severe emphysema. Improving respiratory mechanics by bronchoscopic lung volume reduction (BLVR) might contribute to muscle maintenance by decreasing energy requirements and alleviating eating-related dyspnoea. OBJECTIVE: The goal was to assess the impact of BLVR on energy balance regulation. DESIGN: Twenty emphysematous subjects participated in a controlled clinical experiment before and 6 months after BLVR. Energy requirements were assessed: basal metabolic rate (BMR) by ventilated hood, total daily energy expenditure (TDEE) by doubly labelled water, whole body fat-free mass (FFM) by deuterium dilution, and physical activity by accelerometry. Oxygen saturation, breathing rate, and heart rate were monitored before, during, and after a standardized meal via pulse oximetry and dyspnoea was rated. RESULTS: Sixteen patients completed follow-up, and among those, 10 patients exceeded the minimal clinically important difference of residual volume (RV) reduction. RV was reduced with median (range) 1,285 mL (-2,430, -540). Before BLVR, 90% of patients was FFM-depleted despite a normal BMI (24.3 ± 4.3 kg/m2). BMR was elevated by 130%. TDEE/BMR was 1.4 ± 0.2 despite a very low median (range) daily step count of 2,188 (739, 7,110). Following BLVR, the components of energy metabolism did not change significantly after intervention compared to before intervention, but BLVR treatment decreased meal-related dyspnoea (4.1 vs. 1.7, p = 0.019). CONCLUSIONS: Impaired respiratory mechanics in hyperinflated emphysematous patients did not explain hypermetabolism. Clinical Trial Registry Number: NCT02500004 at www.clinicaltrial.gov.

European white paper: oropharyngeal dysphagia in head and neck cancer.

PURPOSE: To develop a European White Paper document on oropharyngeal dysphagia (OD) in head and neck cancer (HNC). There are wide variations in the management of OD associated with HNC across Europe. METHODS: Experts in the management of specific aspects of OD in HNC across Europe were delegated by their professional medical and multidisciplinary societies to contribute to this document. Evidence is based on systematic reviews, consensus-based position statements, and expert opinion. RESULTS: Twenty-four sections on HNC-specific OD topics. CONCLUSION: This European White Paper summarizes current best practice on management of OD in HNC, providing recommendations to support patients and health professionals. The body of literature and its level of evidence on diagnostics and treatment for OD in HNC remain poor. This is in the context of an expected increase in the prevalence of OD due to HNC in the near future. Contributing factors to increased prevalence include aging of our European population (including HNC patients) and an increase in human papillomavirus (HPV) related cancer, despite the introduction of HPV vaccination in various countries. We recommend timely implementation of OD screening in HNC patients while emphasizing the need for robust scientific research on the treatment of OD in HNC. Meanwhile, its management remains a challenge for European professional associations and policymakers.

Pulmonary Rehabilitation in the Management of Chronic Obstructive Pulmonary Disease among Asian Indians- Current Status and Moving Forward.

Chronic Obstructive Pulmonary Disease (COPD) is a significant public health concern in India with high prevalence and associated disability, morbidity, mortality. The progression of COPD is not confined to the lungs but includes extrapulmonary involvement that reduces the functional capacity and quality of life. Pulmonary Rehabilitation (PR) is an evidence-based intervention, targeting multiple domains of pulmonary and extrapulmonary manifestations, and therefore, is recommended as an integral part of COPD management. The practical implementation of PR in India is poor. In this review, we have summarized the latest pieces of evidence in support of PR and highlight the challenges and potential solutions for PR implementation in India.

Gut microbial dysbiosis as a limiting factor in the management of primary and secondary sarcopenia: an Asian Indian perspective.

PURPOSE OF REVIEW: The article summarizes recent research advances on the role of gut microbiome in primary and secondary sarcopenia. This article also explores the potential contribution of gut dysbiosis to suboptimal sarcopenia management with special focus on factors contributing to gut dysbiosis among Asian Indians. RECENT FINDINGS: Aging and chronic diseases contribute to gut dysbiosis and intestinal barrier dysfunction allowing enhanced microbial translocation that may negatively affect muscle strength, physical function, and frailty. Gut microbiome of Asian Indians has shown a unique composition that is affected by multiple factors, such as socioeconomic status, poor hygiene, high rate of infection and infestations, antibiotic overuse and transition towards a westernized eating pattern. Current management approach for sarcopenia (exercise and/or protein supplementation) fails to address gut dysbiosis and intestinal barrier dysfunction. Incorporating a prebiotic or probiotic element to the intervention strategy may improve gut dysbiosis, inflammation and muscle function. SUMMARY: Gut dysbiosis and intestinal barrier dysfunction appear to be a significant limitation in sarcopenia management, thus gut centric intervention may be perceived as a (co)intervention strategy to be tested in appropriate clinical trials.

Safety and Tolerability of Targeted Medical Nutrition for Cachexia in Non-Small-Cell Lung Cancer: A Randomized, Double-Blind, Controlled Pilot Trial.

Background: This pilot, double-blind, comparator-controlled trial evaluated the safety and tolerability of an oral targeted medical nutrition (TMN) supplement for the management of cachexia in patients with non-small-cell lung cancer (NSCLC).Methods: Patients receiving first-line chemotherapy for NSCLC with weight loss or low BMI were randomized 1:1 to receive juice-based TMN (∼200 kcal; 10 g whey protein; ≥2.0 g eicosapentaenoic acid/docosahexaenoic acid in fish oil; and 10 µg 25-hydroxy-vitamin D3) or a milk-based isocaloric comparator twice daily for 12 weeks (ClinicalTrials.gov: NCT02515032). Primary endpoints included number/type of adverse events and changes in vital signs/laboratory parameters. Secondary endpoints included measures of clinical relevance. Survival was an exploratory endpoint.Results: The TMN group (n = 26; mean 64.4 years) experienced fewer adverse events (64 vs. 87) than the comparator group (n = 29; mean 66.0 years), including fewer cases of neutropenia (0 vs. 4). Compliance was slightly lower in the TMN (58.5%) vs. comparator group (73.6%). There were no statistically significant between-group differences in efficacy endpoints. Fewer (4 vs. 10) patients who received TMN than comparator had died by 1-year post baseline.Conclusions: TMN was well tolerated. Trends for improved clinical outcomes with TMN identified in this study warrant further investigation.

Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle.

BACKGROUND: Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation. METHODS: We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle. RESULTS: Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found. CONCLUSIONS: These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.

CT-derived muscle remodelling after bronchoscopic lung volume reduction in advanced emphysema.

Muscle wasting frequently occurs in severe emphysema. Improving respiratory mechanics by bronchoscopic lung volume reduction using endobronchial valves (EBV) might prevent further loss or even increase in muscle mass. CT-derived skeletal muscle mass gain was observed in 39/49 patients 6 months after EBV. Multiple linear regression showed that gain in muscle (ß=2.4; 95% CI 0.2 to 4.6; p=0.036) and intramuscular fat (ß=3.1; 95% CI 0.2 to 5.9; p=0.035) is associated with improved 6 min walk distance independent of the change in residual volume. Skeletal muscle remodelling associates with improved exercise capacity after EBV, independent of hyperinflation reduction. TRIAL REGISTRATION NUMBER: Clinical trial registered with the Dutch trial register www.trialregister.nl (NTR2876), Results.

Pulmonary rehabilitation, physical activity, respiratory failure and palliative respiratory care.

The CIRO Academy in Horn (the Netherlands) organised a 2-day meeting to present and discuss the studies published in 2017 pertaining to key priority areas of respiratory and critical care medicine. This review summarises studies focussing on pulmonary rehabilitation and exercise training, physical activity, chronic respiratory failure and palliative respiratory care published in 2017.

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation.

INTRODUCTION: Physical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading. METHODS: We analyzed a comprehensive set of molecular markers involved in mitochondrial-autophagy, -biogenesis, -dynamics, and -content, in the gastrocnemius muscle of C57BL/6J mice subjected to 0- and 3-days hind limb suspension, and in biopsies from human vastus lateralis muscle obtained before and after 7 days of one-leg immobilization. RESULTS: In both mice and men, short-term skeletal muscle unloading results in molecular marker patterns indicative of increased receptor-mediated mitophagy and decreased mitochondrial biogenesis regulation, before apparent loss of mitochondrial content. DISCUSSION: These results emphasize the early-onset of skeletal muscle disuse-induced mitochondrial remodeling.

Pulmonary inflammation-induced loss and subsequent recovery of skeletal muscle mass require functional poly-ubiquitin conjugation.

BACKGROUND: Pulmonary inflammation in response to respiratory infections can evoke muscle wasting. Increased activity of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Since poly-Ub conjugation is required for UPS-mediated proteolysis and has been implicated in the ALP, we assessed the effect of impaired ubiquitin conjugation on muscle atrophy and recovery following pulmonary inflammation, and compared activation and suppression of these proteolytic systems to protein synthesis regulation. METHODS: Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS. Proteolysis (UPS and ALP) and synthesis signaling were examined in gastrocnemius muscle homogenates. Ub-conjugation-dependency of muscle atrophy and recovery was addressed using Ub-K48R (K48R) mice with attenuated poly-ubiquitin conjugation, and compared to UBWT control mice. RESULTS: Pulmonary inflammation caused a decrease in skeletal muscle mass which was accompanied by a rapid increase in expression of UPS and ALP constituents and reduction in protein synthesis signaling acutely after LPS. Muscle atrophy was attenuated in K48R mice, while ALP and protein synthesis signaling were not affected. Muscle mass recovery starting 72 h post LPS, correlated with reduced expression of UPS and ALP constituents and restoration of protein synthesis signaling. K48R mice however displayed impaired recovery of muscle mass. CONCLUSION: Pulmonary inflammation-induced muscle atrophy is in part attributable to UPS-mediated proteolysis, as activation of ALP- and suppression of protein synthesis signaling occur independently of poly-Ub conjugation during muscle atrophy. Recovery of muscle mass following pulmonary inflammation involves inverse regulation of proteolysis and protein synthesis signaling, and requires a functional poly-Ub conjugation.

Resveratrol for patients with chronic obstructive pulmonary disease: hype or hope?

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with a high prevalence of extrapulmonary manifestations and, frequently, cardiovascular comorbidity. Resveratrol is a food-derived compound with anti-inflammatory, antioxidant, metabolic and cardioprotective potential. Therefore, resveratrol might improve the pulmonary as well as extrapulmonary pathology in COPD. In this review, we will evaluate knowledge on the effects of resveratrol on lung injury, muscle metabolism and cardiovascular risk profile and discuss if resveratrol is a hype or hope for patients with COPD. RECENT FINDINGS: Experimental models of COPD consistently show decreased inflammation and oxidative stress in the lungs after resveratrol treatment. These beneficial anti-inflammatory and antioxidant properties of resveratrol can indirectly also improve both skeletal and respiratory muscle impairment in COPD. Recent clinical studies in non-COPD populations show improved mitochondrial oxidative metabolism after resveratrol treatment, which could be beneficial for both lung and muscle impairment in COPD. Moreover, preclinical studies suggest cardioprotective effects of resveratrol but results of clinical studies are inconclusive. SUMMARY: Resveratrol might be an interesting therapeutic candidate to counteract lung and muscle impairments characteristic to COPD. However, there is no convincing evidence that resveratrol will significantly decrease the cardiovascular risk in patients with COPD.

Differential regulation of muscle protein turnover in response to emphysema and acute pulmonary inflammation.

BACKGROUND: Exacerbations in COPD are often accompanied by pulmonary and systemic inflammation, and associated with increased susceptibility to and prevalence of weight loss and muscle wasting. Muscle mass loss during disease exacerbations may contribute to emphysema-associated muscle atrophy. However, whether pulmonary inflammation in presence of emphysema differentially affects skeletal muscle, including protein synthesis and degradation signaling pathways has not previously been addressed. The aims of this study were to 1) develop a mouse model of disease exacerbation-associated muscle wasting, 2) evaluate whether emphysema and muscle wasting can be monitored non-invasively and 3) assess alterations in muscle protein turnover regulation. METHODS: Emphysema was induced by three, weekly intra-tracheal (IT) elastase (E) or vehicle control (vc) instillations, followed by one single IT-LPS bolus (L) or vc instillation to mimic pulmonary inflammation-driven disease exacerbation. Consequently, four experimental groups were defined: vc/vc ('C'), E/vc ('E'), vc/LPS ('L'), E/LPS ('E + L'). Using micro cone-beam CT-scans, emphysema development and muscle mass changes were monitored, and correlated to muscle weight 48 h after LPS instillation. Protein turnover signaling was assessed in muscle tissue collected 24 h post LPS instillation. RESULTS: Micro-CT imaging correlated strongly with established invasive measurements of emphysema and muscle atrophy. Pulmonary inflammation following LPS instillation developed irrespective of emphysema and body and muscle weight were similarly reduced in the 'L' and 'E + L' groups. Accordingly, mRNA and protein expression levels of genes of the ubiquitin-proteasome pathway (UPS) and the autophagy-lysosomal pathway (ALP) were upregulated in skeletal muscle following IT-LPS ('L' and 'E + L'). In contrast, mTOR signaling, which controls ALP and protein synthesis, was reduced by pulmonary inflammation ('L' and 'E + L') as well as emphysema as a single insult ('E') compared to control. CONCLUSION: Changes in lung tissue density and muscle mass can be monitored non-invasively to evaluate emphysema and muscle atrophy longitudinally. Acute loss of muscle mass evoked by pulmonary inflammation is similar in control and emphysematous mice. Although muscle atrophy cues in response to pulmonary inflammation are not altered by emphysema, emphysema itself affects protein synthesis and ALP signaling, which may interfere with muscle mass recovery and impair maintenance of muscle mass in emphysema.

Muscle-specific GSK-3ß ablation accelerates regeneration of disuse-atrophied skeletal muscle.

Muscle wasting impairs physical performance, increases mortality and reduces medical intervention efficacy in chronic diseases and cancer. Developing proficient intervention strategies requires improved understanding of the molecular mechanisms governing muscle mass wasting and recovery. Involvement of muscle protein- and myonuclear turnover during recovery from muscle atrophy has received limited attention. The insulin-like growth factor (IGF)-I signaling pathway has been implicated in muscle mass regulation. As glycogen synthase kinase 3 (GSK-3) is inhibited by IGF-I signaling, we hypothesized that muscle-specific GSK-3ß deletion facilitates the recovery of disuse-atrophied skeletal muscle. Wild-type mice and mice lacking muscle GSK-3ß (MGSK-3ß KO) were subjected to a hindlimb suspension model of reversible disuse-induced muscle atrophy and followed during recovery. Indices of muscle mass, protein synthesis and proteolysis, and post-natal myogenesis which contribute to myonuclear accretion, were monitored during the reloading of atrophied muscle. Early muscle mass recovery occurred more rapidly in MGSK-3ß KO muscle. Reloading-associated changes in muscle protein turnover were not affected by GSK-3ß ablation. However, coherent effects were observed in the extent and kinetics of satellite cell activation, proliferation and myogenic differentiation observed during reloading, suggestive of increased myonuclear accretion in regenerating skeletal muscle lacking GSK-3ß. This study demonstrates that muscle mass recovery and post-natal myogenesis from disuse-atrophy are accelerated in the absence of GSK-3ß.

Alterations in Skeletal Muscle Oxidative Phenotype in Mice Exposed to 3 Weeks of Normobaric Hypoxia.

Skeletal muscle of patients with chronic respiratory failure is prone to loss of muscle mass and oxidative phenotype. Tissue hypoxia has been associated with cachexia and emphysema in humans. Experimental research on the role of hypoxia in loss of muscle oxidative phenotype, however, has yielded inconsistent results. Animal studies are frequently performed in young animals, which may hinder translation to generally older aged patients. Therefore, in this study, we tested the hypothesis that hypoxia induces loss of skeletal muscle oxidative phenotype in a model of aged (52 weeks) mice exposed to 3 weeks of hypoxia. Additional groups of young (4 weeks) and adult (12 weeks) mice were included to examine age effects. To verify hypoxia-induced cachexia, fat pad and muscle weights as well as muscle fiber cross-sectional areas were determined. Muscle oxidative phenotype was assessed by expression and activity of markers of mitochondrial metabolism and fiber-type distribution. A profound loss of muscle and fat was indeed accompanied by a slightly lower expression of markers of muscle oxidative capacity in the aged hypoxic mice. In contrast, hypoxia-associated changes of fiber-type composition were more prominent in the young mice. The differential response of the muscle of young, adult, and aged mice to hypoxia suggests that age matters and that the aged mouse is a better model for translation of findings to elderly patients with chronic respiratory disease. Furthermore, the findings warrant further mechanistic research into putative accelerating effects of hypoxia-induced loss of oxidative phenotype on the cachexia process in chronic respiratory disease.

Towards a multidimensional healthy ageing phenotype.

PURPOSE OF REVIEW: There is great interest in developing tools to measure healthy ageing and to identify early stages of health impairment, which may guide the implementation of interventions to prevent or delay the development of disease, disability, and mortality. Here, we review the most recent developments directed to operationalize, and test, definitions of healthy ageing. RECENT FINDINGS: There is lack of consensus about how to define healthy ageing and, unsurprisingly, diversity in the instruments for its measurement. However, progress is being made in describing and in devising tools to capture the healthy ageing phenotype. Attempts to measure healthy ageing have relied primarily on cross-sectional data collected in older people. More recent studies have assessed the healthy ageing phenotype using markers of multiple functional domains and have used longitudinal data to model the dynamics and trajectories of healthy ageing. SUMMARY: Given the complexity of the ageing process, no single measure is able to predict the ageing trajectory. Current attempts to operationalize the healthy ageing phenotype have relied on markers and data from earlier cohort studies and are limited by the tools used to collect data in those studies. Such data are often unsuitable to detect early subtle declines in function and/or are inappropriate for use in younger old adults. Future studies employing more objective and novel markers of healthy ageing are likely to offer opportunities to define and operationalize the healthy ageing phenotype.

Modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses.

Each year, 430,000 people are diagnosed with bladder cancer. Due to the high recurrence rate of the disease, primary prevention is paramount. Therefore, we reviewed all meta-analyses on modifiable risk factors of primary bladder cancer. PubMed, Embase and Cochrane database were systematically searched for meta-analyses on modifiable risk factors published between 1995 and 2015. When appropriate, meta-analyses (MA) were combined in meta-meta-analysis (MMA). If not, the most comprehensive MA was selected based on the number of primary studies included. Probability of causation was calculated for individual factors and a subset of lifestyle factors combined. Of 1496 articles identified, 5 were combined in MMA and 21 were most comprehensive on a single risk factor. Statistically significant associations were found for current (RR 3.14) or former (RR 1.83) cigarette smoking, pipe (RR 1.9) or cigar (RR 2.3) smoking, antioxidant supplementation (RR 1.52), obesity (RR 1.10), higher physical activity levels (RR 0.86), higher body levels of selenium (RR 0.61) and vitamin D (RR 0.75), and higher intakes of: processed meat (RR 1.22), vitamin A (RR 0.82), vitamin E (RR 0.82), folate (RR 0.84), fruit (RR 0.77), vegetables (RR 0.83), citrus fruit (RR 0.85), and cruciferous vegetables (RR 0.84). Finally, three occupations with the highest risk were tobacco workers (RR 1.72), dye workers (RR 1.58), and chimney sweeps (RR 1.53). The probability of causation for individual factors ranged from 4 to 68 %. The combined probability of causation was 81.8 %. Modification of lifestyle and occupational exposures can considerably reduce the bladder cancer burden. While smoking remains one of the key risk factors, also several diet-related and occupational factors are very relevant.