Advancements in reconstructive microsurgery have evolved into supermicrosurgery; connecting vessels with diameter between 0.3 and 0.8 mm for reconstruction of lymphatic flow and vascularized tissue ...transplantation. Supermicrosurgery is limited by the precision and dexterity of the surgeon's hands. Robot assistance can help overcome these human limitations, thereby enabling a breakthrough in supermicrosurgery. We report the first-in-human study of robot-assisted supermicrosurgery using a dedicated microsurgical robotic platform. A prospective randomized pilot study is conducted comparing robot-assisted and manual supermicrosurgical lymphatico-venous anastomosis (LVA) in treating breast cancer-related lymphedema. We evaluate patient outcome at 1 and 3 months post surgery, duration of the surgery, and quality of the anastomosis. At 3 months, patient outcome improves. Furthermore, a steep decline in duration of time required to complete the anastomosis is observed in the robot-assisted group (33-16 min). Here, we report the feasibility of robot-assisted supermicrosurgical anastomosis in LVA, indicating promising results for the future of reconstructive supermicrosurgery.
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.
Muscle depletion negatively impacts treatment efficacy and survival rates in cancer. Prevention and timely treatment of muscle loss require prediction of patients at risk. We aimed to investigate the ...potential of skeletal muscle radiomic features to predict future muscle loss.
A total of 116 patients with stage IV non-small cell lung cancer included in a randomised controlled trial (NCT01171170) studying the effect of nitroglycerin added to paclitaxel-carboplatin-bevacizumab were enrolled. In this post hoc analysis, muscle cross-sectional area and radiomic features were extracted from computed tomography images obtained before initiation of chemotherapy and shortly after administration of the second cycle. For internal cross-validation, the cohort was randomly split in a training set and validation set 100 times. We used least absolute shrinkage and selection operator method to select features that were most significantly associated with muscle loss and an area under the curve (AUC) for model performance.
Sixty-nine patients (59%) exhibited loss of skeletal muscle. One hundred ninety-three features were used to construct a prediction model for muscle loss. The average AUC was 0.49 (95% confidence interval CI: 0.36, 0.62). Differences in intensity and texture radiomic features over time were seen between patients with and without muscle loss.
The present study shows that skeletal muscle radiomics did not predict future muscle loss during chemotherapy in non-small cell lung cancer. Differences in radiomic features over time might reflect myosteatosis. Future imaging analysis combined with muscle tissue analysis in patients and in experimental models is needed to unravel the biological processes linked to the radiomic features.
•This was the first attempt to evaluate the potential of muscle radiomics to predict muscle loss.•Fifty-nine percent of patients with non-small cell lung cancer exhibited loss of skeletal muscle during chemotherapy.•Skeletal muscle radiomics did not predict future muscle loss.
Loss of skeletal muscle mitochondrial oxidative capacity is well-established in patients with COPD, but the role of mitochondrial breakdown herein is largely unexplored. Currently, we studied if ...mitochondrial breakdown signalling is increased in skeletal muscle of COPD patients and associates with the loss of mitochondrial content, and whether it is affected in patients with iron deficiency (ID) or systemic inflammation. Therefore, mitophagy, autophagy, mitochondrial dynamics and content markers were analysed in vastus lateralis biopsies of COPD patients (N = 95, FEV
% predicted: 39.0 31.0-53.6) and healthy controls (N = 15, FEV
% predicted: 112.8 107.5-125.5). Sub-analyses were performed on patients stratified by ID or C-reactive protein (CRP). Compared with controls, COPD patients had lower muscle mitochondrial content, higher BNIP3L and lower FUNDC1 protein, and higher Parkin protein and gene-expression. BNIP3L and Parkin protein levels inversely correlated with mtDNA/gDNA ratio and FEV
% predicted. ID-COPD patients had lower BNIP3L protein and higher BNIP3 gene-expression, while high CRP patients had higher BNIP3 and autophagy-related protein levels. In conclusion, our data indicates that mitochondrial breakdown signalling is increased in skeletal muscle of COPD patients, and is related to disease severity and loss of mitochondrial content. Moreover, systemic inflammation is associated with higher BNIP3 and autophagy-related protein levels.
Fatigue is frequently reported in people with a non-communicable chronic disease. More insight in the nature of this symptom may enhance targeted treatment of fatigue. In this study, we aimed to gain ...more insight in the prevalence of different types of fatigue and in current prescribed treatment strategies to reduce fatigue in non-communicable chronic diseases.
People with non-communicable chronic diseases were contacted via public, non-profit, disease-specific health funds and patient associations and invited to complete a web-based survey. The survey included a general question about the experience ("Do you now or have you ever had complaints of fatigue?") and nature of fatigue (physically/mentally/combination), the Checklist Individual Strength-subscale subjective fatigue (CIS-Fatigue; 8-56 points), self-constructed questions for the distinction between physical and mental fatigue (both 3-21 points) and questions on prescribed treatments for fatigue.
In total, 4199 participants (77% females) completed the online survey. 3945 participants (94.0%) reported experiencing fatigue, of which 64.4% reported a combination of both physical and mental fatigue. Median CIS-Fatigue score was 41 (32-48) points, with 68% of the participants reporting severe fatigue (≥36 points). Median scores for physical and mental fatigue were 15 (11-18) and 12 (8-16) points, respectively. In 55% of the participants, fatigue was only occasionally or never discussed with the healthcare professional, and only 23% of the participants were prescribed a treatment for fatigue. Participants often reported no effect or even an increase in fatigue after treatment.
Findings indicate that both physical and mental fatigue are often experienced simultaneously in people with non-communicable chronic diseases, but can also occur separately. Fatigue is often only occasionally or never discussed, let alone treated, highlighting the need to raise awareness among healthcare professionals. Future studies are needed to gain more insight in underlying factors of fatigue in non-communicable chronic diseases, its impact on daily life and development and evaluation of targeted treatment strategies.
Key messages:
Both physical and mental fatigue are frequently present in people with non-communicable chronic diseases.
Fatigue is often only occasionally or never discussed during consultation with the physician, highlighting the need to raise awareness among healthcare professionals for adequate screening and evaluating of fatigue in people with non-communicable chronic diseases.
Only less than a quarter of the people with non-communicable chronic diseases who reported to experience fatigue were prescribed a treatment for fatigue, which was often experienced as ineffective.
In muscle cells, the peroxisome proliferator-activated receptor γ co-activator 1 (PGC-1) signaling network, which has been shown to be disturbed in the skeletal muscle in several chronic diseases, ...tightly controls mitochondrial biogenesis and oxidative substrate metabolism. Previously, we showed that inactivation of glycogen synthase kinase (GSK)-3β potently increased Pgc-1α abundance and oxidative metabolism in skeletal muscle cells. The current study aims to unravel the molecular mechanism driving the increase in Pgc-1α mediated by GSK-3β inactivation.
GSK-3β was inactivated genetically or pharmacologically in C2C12 myotubes and the requirement of transcription factors known to be involved in Pgc-1α transcription for increases in Pgc-1α abundance mediated by inactivation of GSK-3β was examined.
Enhanced PGC-1α promoter activation after GSK-3β inhibition suggested a transcriptionally-controlled mechanism. While myocyte enhancer factor (MEF)2 transcriptional activity was unaltered, GSK-3β inactivation increased the abundance and activity of the transcription factors estrogen-related receptor (ERR)α and ERRγ. Pharmacological inhibition or knock-down of ERRα and ERRγ however failed to prevent increases in Pgc-1α mRNA mediated by GSK-3β inactivation. Interestingly, GSK-3β inactivation activated transcription factor EB (TFEB), evidenced by decreased phosphorylation and enhanced nuclear localization of the TFEB protein. Moreover, knock-down of TFEB completely prevented increases in Pgc-1α gene expression, PGC-1α promoter activity and PGC-1α protein abundance induced by GSK-3β inactivation. Furthermore, mutation of a specific TFEB binding site on the PGC-1α promoter blocked promoter activation upon inhibition of GSK-3β.
In skeletal muscle, GSK-3β inactivation causes dephosphorylation and nuclear translocation of TFEB resulting in TFEB-dependent induction of Pgc-1α expression.
•Inactivation of GSK-3β increases PGC-1α abundance and promoter activation.•Inactivation of GSK-3β increases TFEB nuclear translocation.•Increased PGC-1α expression upon GSK-3β inhibition requires TFEB.•GSK-3 inhibition enhances PGC-1α promoter activity dependent on a TFEB binding site.
Towards Personalized Management of Sarcopenia in COPD van Bakel, Sophie I J; Gosker, Harry R; Langen, Ramon C ...
International journal of chronic obstructive pulmonary disease,
01/2021, Letnik:
16
Journal Article
Recenzirano
Odprti dostop
The awareness of the presence and consequences of sarcopenia has significantly increased over the past decade. Sarcopenia is defined as gradual loss of muscle mass and strength and ultimately loss of ...physical performance associated with aging and chronic disease. The prevalence of sarcopenia is higher in chronic obstructive pulmonary disease (COPD) compared to age-matched controls. Current literature suggests that next to physical inactivity, COPD-specific alterations in physiological processes contribute to accelerated development of sarcopenia. Sarcopenia in COPD can be assessed according to current guidelines, but during physical performance testing, ventilatory limitation should be considered. Treatment of muscle impairment can halt or even reverse sarcopenia, despite respiratory impairment. Exercise training and protein supplementation are currently at the basis of sarcopenia treatment. Furthermore, effective current and new interventions targeting the pulmonary system (eg, smoking cessation, bronchodilators and lung volume reduction surgery) may also facilitate muscle maintenance. Better understanding of disease-specific pathophysiological mechanisms involved in the accelerated development of sarcopenia in COPD will provide new leads to refine nutritional, exercise and physical activity interventions and develop pharmacological co-interventions.
Chronic obstructive pulmonary disease (COPD) and obesity are common and disabling chronic health conditions with increasing prevalence worldwide. A relationship between COPD and obesity is ...increasingly recognised, although the nature of this association remains unknown. This review focuses on the epidemiology of obesity in COPD and the impact of excessive fat mass on lung function, exercise capacity and prognosis. The evidence for altered adipose tissue functions in obesity—including reduced lipid storage capacity, altered expression and secretion of inflammatory factors, adipose tissue hypoxia and macrophage infiltration in adipose tissue—is also reviewed. The interrelationship between these factors and their contribution to the development of insulin resistance in obesity is considered. It is proposed that, in patients with COPD, reduced oxidative capacity and systemic hypoxia may amplify these disturbances, not only in obese patients but also in subjects with hidden loss of fat-free mass. The potential interaction between abnormal adipose tissue function, systemic inflammation and COPD may provide more insight into the pathogenesis and reversibility of systemic pathology in this disease.
A shift in quadriceps muscle metabolic profile toward decreased oxidative metabolism and increased glycolysis is a consistent finding in chronic obstructive pulmonary disease (COPD). Chronic ...inflammation has been proposed as a trigger of this pathological metabolic adaptation. Indeed, the proinflammatory cytokine TNF-α impairs muscle oxidative metabolism through activation of the nuclear factor-κB (NF-κB) pathway. Putative effects on muscle glycolysis, however, are unclear. We hypothesized that TNF-α-induced NF-κB signaling stimulates muscle glycolytic metabolism through activation of the glycolytic regulator hypoxia-inducible factor-1α (HIF-1α). Wild-type C2C12 and C2C12-IκBα-SR (blocked NF-κB signaling) myotubes were stimulated with TNF-α, and its effects on glycolytic metabolism and involvement of the HIF pathway herein were investigated. As proof of principle, expression of HIF signaling constituents was investigated in quadriceps muscle biopsies of a previously well-characterized cohort of clinically stable patients with severe COPD and healthy matched controls. TNF-α increased myotube glucose uptake and lactate production and enhanced the activity and expression levels of multiple effectors of muscle glycolytic metabolism in a NF-κB-dependent manner. In addition, TNF-α activated HIF signaling, which required classical NF-κB activation. Moreover, the knockdown of HIF-1α largely attenuated TNF-α-induced increases in glycolytic metabolism. Accordingly, the mRNA levels of HIF-1α and the HIF-1α target gene, vascular endothelial growth factor (VEGF), were increased in muscle biopsies of COPD patients compared with controls, which was most pronounced in the patients with high levels of muscle TNF-α. In conclusion, these data show that TNF-α-induced classical NF-κB activation enhances muscle glycolytic metabolism in a HIF-1α-dependent manner.
To date, detailed analyses of walking patterns using accelerometers during the 6-min walk test (6MWT) have not been performed in patients with chronic obstructive pulmonary disease (COPD). Therefore, ...it remains unclear whether and to what extent COPD patients have an altered walking pattern during the 6MWT compared to healthy elderly subjects.
79 COPD patients and 24 healthy elderly subjects performed the 6MWT wearing an accelerometer attached to the trunk. The accelerometer features (walking intensity, cadence, and walking variability) and subject characteristics were assessed and compared between groups. Moreover, associations were sought with 6-min walk distance (6MWD) using multiple ordinary least squares (OLS) regression models. COPD patients walked with a significantly lower walking intensity, lower cadence and increased walking variability compared to healthy subjects. Walking intensity and height were the only two significant determinants of 6MWD in healthy subjects, explaining 85% of the variance in 6MWD. In COPD patients also age, cadence, walking variability measures and their interactions were included were significant determinants of 6MWD (total variance in 6MWD explained: 88%).
COPD patients have an altered walking pattern during 6MWT compared to healthy subjects. These differences in walking pattern partially explain the lower 6MWD in patients with COPD.
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