scholarly journals The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia

2020 ◽  
Vol 111 (3) ◽  
pp. 570-579 ◽  
Author(s):  
Ying Zhang ◽  
Jiwei Wang ◽  
Xulin Wang ◽  
Tingting Gao ◽  
Hao Tian ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Muscle Fiber ◽  
Cancer Cachexia ◽  
Ubiquitin Proteasome System ◽  
Muscle Loss ◽  
Fiber Morphology ◽  
Cross Sectional ◽  
Ubiquitin Proteasome

ABSTRACT Background Cancer cachexia is characterized by weight loss, especially ongoing skeletal muscle loss, and is associated with poor patient outcomes. However, the molecular mechanism of skeletal muscle wasting is not fully understood. Objectives We aimed to investigate muscle fiber morphology and proteolysis system activity changes that may account for cancer cachexia and to relate these changes to patients’ clinical phenotypes. Methods We divided 39 patients with resectable gastric cancer into 4 groups based on the presence of cachexia (weight loss) and/or sarcopenia (low muscularity), including a noncachexia/nonsarcopenia group (N, n = 10), a cachexia/sarcopenia group (CS, n = 13), a cachexia/nonsarcopenia group (C, n = 9), and a noncachexia/sarcopenia group (S, n = 7). Rectus abdominis muscle biopsy specimens were obtained intraoperatively. Muscle fiber size, ultrastructural architecture, and the expression of autophagic-lysosomal system (ALS) and ubiquitin proteasome system (UPS) markers were assayed. Results Mean ± SD muscle fiber cross-sectional areas were significantly decreased in the CS (460 ± 120 μm2) and S groups (480 ± 135 μm2) compared with the N (1615 ± 388 μm2, both P < 0.05) and C groups (1219 ± 302 μm2, both P < 0.05). In the C, S, and CS groups, the muscle exhibited tissue disorganization and autophagosome formation to different degrees. The levels of ALS and UPS markers were significantly increased in the CS, C, and S groups compared with the N group. Alterations in muscle fiber morphology and increased ALS and UPS activity were related to severe muscle loss, but not weight loss. Conclusions The ALS and UPS are simultaneously activated in cancer cachexia and may play coordinated roles in cachexia-induced muscle loss.

Inclusion criteria for cancer cachexia clinical trials: CT-defined skeletal muscle loss versus body weight loss.

2015 ◽  
Vol 33 (29_suppl) ◽  
pp. 67-67
Author(s):  
Eric Roeland ◽  
Sandahl H Nelson ◽  
Ashleigh Campillo ◽  
Sean Heavey ◽  
Joseph D. Ma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Cancer Cachexia ◽  
Ct Scans ◽  
Muscle Loss ◽  
Inclusion Criteria ◽  
Cross Sectional ◽  
Skeletal Muscle Loss ◽  
Visceral Adipose ◽  
Over Time

67 Background: Cancer cachexia is defined by skeletal muscle loss, with or without fat loss (Fearon et al 2011); however, inclusion criteria for cachexia clinical trials requires a defined weight loss over time rather than muscle loss. We hypothesized that cross sectional imaging may reveal the presence of cachexia otherwise obscured by fat mass changes. Methods: A retrospective analysis of longitudinal CT scans was performed in metastatic colorectal cancer (mCRC) patients screened for a cancer cachexia trial, which required ≥5% weight loss in the prior 6 mos. De-identified CT images were analyzed for total muscle, subcutaneous, and visceral fat cross-sectional areas (cm2) at the 3rd lumbar vertebra at baseline and up to 12 mos prior (Lieffers et al 2009). Logistic regression was used to test differences between patients with <5% vs ≥5% weight loss. Random intercept regression was used to evaluate significant trends in CT measures over time. Results: 42 mCRC patients were screened and 3(7%) enrolled. Patients were excluded for comorbidity/contraindication 14 (33%), excessive [>20%] weight loss 4 (9.5%), and insufficient [<5%] weight loss 19 (45%). For the <5% weight loss subset, there was a mean of 6.7 CT scans (SD=2.67) and of 9% (SD=5.4, min=0%, 25th percentile=4.9%) mean max muscle loss. Notably this group was simultaneously losing muscle (p=0.002) and gaining visceral adipose (p=0.007). For the ≥5% weight loss subset, there was a mean of 7.5 CT scans (SD=4.5) and 20% (SD=10.0, min=5.2%, 25th percentile =10.6) mean max muscle loss. Greater max muscle loss increased the odds of being in the ≥5% weight loss subset (OR=1.19, 95% CI: 1.06,1.33). This group also had a significant decrease in visceral adipose over time (p<0.001). Redefined inclusion criteria of ≥5% muscle loss would have included 14 of the 19 patients excluded because of <5% weight loss. Conclusions: Defining cancer cachexia as weight loss over time may be limited as it does not capture body composition changes and hinders trial accrual. Cross-sectional CT body composition analysis may improve early detection of muscle loss and improve trial accrual.

Gene expression and muscle fiber function in a porcine ICU model

2009 ◽  
Vol 39 (3) ◽  
pp. 141-159 ◽  
Author(s):  
Varuna C. Banduseela ◽  
Julien Ochala ◽  
Yi-Wen Chen ◽  
Hanna Göransson ◽  
Holly Norman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mechanical Ventilation ◽  
Muscle Fiber ◽  
Ubiquitin Proteasome System ◽  
Molecular Networks ◽  
Protective Mechanism ◽  
Mrna Levels ◽  
Single Muscle ◽  
Cross Sectional ◽  
Single Muscle Fiber

Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to 1) the poorly understood intricate cellular and molecular networks and 2) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a 5-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric and LIM protein mRNA levels were downregulated, while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were upregulated. Despite 5 days of immobilization and mechanical ventilation single muscle fiber cross-sectional areas as well as the maximum force generating capacity at the single muscle fiber level were preserved. It is proposed that HSP induction in skeletal muscle is an inherent, primary, but temporary protective mechanism against protein degradation. To our knowledge, this is the first study that isolates the effect of immobilization and mechanical ventilation in an ICU condition from various other cofactors.

scholarly journals IL-6 Trans-Signaling and Crosstalk Among Tumor, Muscle and Fat Mediate Pancreatic Cancer Cachexia

2020 ◽  
Author(s):  
Joseph E. Rupert ◽  
Andrea Bonetto ◽  
Ashok Narasimhan ◽  
Yunlong Liu ◽  
Thomas M. O’Connell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Fatty Acids ◽  
Weight Loss ◽  
Tumor Cell ◽  
Cancer Cachexia ◽  
Muscle Loss ◽  
Peripheral Tissues ◽  
Patient Morbidity ◽  
Main Driver

ABSTRACTMost patients with pancreatic adenocarcinoma (PDAC) suffer unintentional weight loss, or cachexia. Interleukin-6 causes cachexia in mice and associates with mortality in PDAC. Here we show that tumor cell-derived IL-6 mediates crosstalk between tumor and peripheral tissues to promote cachexia. Tumor-cell IL-6 elicits expression of IL-6 in fat and IL-6 and IL-6 receptor (IL6R) in muscle, concomitantly raising both in blood. Inflammation-induced adipose lipolysis elevates circulating fatty acids, which cooperate with IL-6 to induce skeletal muscle dysmetabolism and wasting. Thus, PDAC induces crosstalk among tumor, fat and muscle via a feed-forward, IL-6 signaling loop. Tumor talks to muscle and fat through IL-6, and muscle to fat via IL6R trans-signaling, and fat to muscle through lipids and fatty acids. Disruption of this crosstalk by depletion of tumor-derived IL-6 halved fat wasting and abolished muscle loss, supporting IL-6, IL-6R and lipids as causal nodes for tissue crosstalk in PDAC cachexia.SignificancePDAC-associated cachexia significantly increases patient morbidity and mortality. This study identifies muscle and fat crosstalk via IL6R trans-signaling in concert with muscle steatosis as a main driver of PDAC-associated cachexia.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 ◽  
pp. 173-186 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Proteolytic Enzymes ◽  
Cathepsin L ◽  
Ubiquitin Proteasome System ◽  
Complete Breakdown ◽  
Skeletal Muscle Proteins ◽  
Ubiquitin Proteasome ◽  
Tripeptidyl Peptidase Ii ◽  
F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 (1) ◽  
pp. 173 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome

scholarly journals Identification of the MuRF1 skeletal muscle ubiquitylome through quantitative proteomics

Function ◽  
2021 ◽  
Author(s):  
Leslie M Baehr ◽  
David C Hughes ◽  
Sarah A Lynch ◽  
Delphi Van Haver ◽  
Teresa Mendes Maia ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Potential Role ◽  
Ubiquitin Proteasome System ◽  
In Vivo Electroporation ◽  
Adult Mice ◽  
Expression Of Genes ◽  
Regulation Of Metabolism ◽  
Ubiquitin Proteasome

Abstract MuRF1 (TRIM63) is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Overexpression of MuRF1 in adult mice increases ubiquitination of myofibrillar and sarcoplasmic proteins, increases expression of genes associated with neuromuscular junction instability, and causes muscle atrophy. A total of 169 ubiquitination sites on 56 proteins were found to be regulated by MuRF1. MuRF1-mediated ubiquitination targeted both thick and thin filament contractile proteins, as well as, glycolytic enzymes, deubiquitinases, p62, and VCP. These data reveal a potential role for MuRF1 in not only the breakdown of the sarcomere, but also the regulation of metabolism and other proteolytic pathways in skeletal muscle.

scholarly journals Skeletal muscle fiber size and fiber type distribution in human cancer: Effects of weight loss and relationship to physical function

2016 ◽  
Vol 35 (6) ◽  
pp. 1359-1365 ◽  
Author(s):  
Michael J. Toth ◽  
Damien M. Callahan ◽  
Mark S. Miller ◽  
Timothy W. Tourville ◽  
Sarah B. Hackett ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Physical Function ◽  
Muscle Fiber ◽  
Human Cancer ◽  
Fiber Type ◽  
Skeletal Muscle Fiber ◽  
Type Distribution ◽  
Fiber Size ◽  
Fiber Type Distribution

scholarly journals Denervation-Induced Activation of the Ubiquitin-Proteasome System Reduces Skeletal Muscle Quantity Not Quality

PLoS ONE ◽  
2016 ◽  
Vol 11 (8) ◽  
pp. e0160839 ◽  
Author(s):  
Cory W. Baumann ◽  
Haiming M. Liu ◽  
LaDora V. Thompson
Keyword(s):  
Skeletal Muscle ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals Increasing autophagy does not affect neurogenic muscle atrophy

2018 ◽  
Vol 28 (3) ◽  
Author(s):  
Eva Pigna ◽  
Krizia Sanna ◽  
Dario Coletti ◽  
Zhenlin Li ◽  
Ara Parlakian ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Autophagic Flux ◽  
Molecular Pathways ◽  
Muscle Loss ◽  
Relative Contribution ◽  
Ubiquitin Proteasome ◽  
Muscle Mass Loss ◽  
Kinetics Of

Physiological autophagy plays a crucial role in the regulation of muscle mass and metabolism, while the excessive induction or the inhibition of the autophagic flux contributes to the progression of several diseases. Autophagy can be activated by different stimuli, including cancer, exercise, caloric restriction and denervation. The latter leads to muscle atrophy through the activation of catabolic pathways, i.e. the ubiquitin-proteasome system and autophagy. However, the kinetics of autophagy activation and the upstream molecular pathways in denervated skeletal muscle have not been reported yet. In this study, we characterized the kinetics of autophagic induction, quickly triggered by denervation, and report the Akt/mTOR axis activation. Besides, with the aim to assess the relative contribution of autophagy in neurogenic muscle atrophy, we triggered autophagy with different stimuli along with denervation, and observed that four week-long autophagic induction, by either intermitted fasting or rapamycin treatment, did not significantly affect muscle mass loss. We conclude that: i) autophagy does not play a major role in inducing muscle loss following denervation; ii) nonetheless, autophagy may have a regulatory role in denervation induced muscle atrophy, since it is significantly upregulated as early as eight hours after denervation; iii) Akt/mTOR axis, AMPK and FoxO3a are activated consistently with the progression of muscle atrophy, further highlighting the complexity of the signaling response to the atrophying stimulus deriving from denervation.

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