Contributions of the ubiquitin–proteasome pathway and apoptosis to human skeletal muscle wasting with age

2005 ◽  
Vol 450 (6) ◽  
pp. 437-446 ◽  
Author(s):  
Samantha A. Whitman ◽  
Michael J. Wacker ◽  
Scott R. Richmond ◽  
Michael P. Godard
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome Pathway ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins

2011 ◽  
Vol 301 (6) ◽  
pp. C1316-C1324 ◽  
Author(s):  
Sudarsanareddy Lokireddy ◽  
Vincent Mouly ◽  
Gillian Butler-Browne ◽  
Peter D. Gluckman ◽  
Mridula Sharma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Muscle Wasting ◽  
Negative Regulator ◽  
Potent Inducer ◽  
Ubiquitin Proteasome Pathway ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of “cachectic-like” muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting. Therefore, in this present study we describe in further detail the mechanisms behind myostatin regulation of human skeletal muscle wasting using an in vitro human primary myotube atrophy model. Treatment of human myotube populations with myostatin promoted dramatic myotubular atrophy. Mechanistically, myostatin-induced myotube atrophy resulted in reduced p-AKT concomitant with the accumulation of active dephosphorylated Forkhead Box-O (FOXO1) and FOXO3. We further show that addition of myostatin results in enhanced activation of atrogin-1 and muscle-specific RING finger protein 1 (MURF1) and reduced expression of both myosin light chain (MYL) and myosin heavy chain (MYH). In addition, we found that myostatin-induced loss of MYL and MYH proteins is dependent on the activity of the proteasome and mediated via SMAD3-dependent regulation of FOXO1 and atrogin-1. Therefore, these data suggest that the mechanism through which myostatin promotes muscle wasting is very well conserved between species, and that myostatin-induced human myotube atrophy is mediated through inhibition of insulin-like growth factor (IGF)/phosphoinositide 3-kinase (PI3-K)/AKT signaling and enhanced activation of the ubiquitin-proteasome pathway and elevated protein degradation.

scholarly journals High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Johanna Abrigo ◽  
Juan Carlos Rivera ◽  
Javier Aravena ◽  
Daniel Cabrera ◽  
Felipe Simon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Stem Cells ◽  
Muscle Atrophy ◽  
High Fat Diet ◽  
Muscle Wasting ◽  
High Fat ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes.

Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin–proteasome pathway, are increased in patients with lung cancer referred for thoracotomy

2002 ◽  
Vol 102 (3) ◽  
pp. 353-361 ◽  
Author(s):  
R. Thomas JAGOE ◽  
Christopher P.F. REDFERN ◽  
Russell G. ROBERTS ◽  
G. John GIBSON ◽  
Timothy H.J. GOODSHIP
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Skeletal Muscle ◽  
Cathepsin B ◽  
Muscle Wasting ◽  
Fat Free Mass ◽  
Mrna Levels ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Muscle wasting is a common and prominent feature of advanced cancer, including lung cancer. Evidence from animal experiments suggests that accelerated proteolysis via the ubiquitin-proteasome pathway is the primary cause of cancer-related cachexia. However, there are few data on the role of this pathway in determining muscle wasting in human cancer. The present study was designed to measure whether skeletal muscle gene expression of components of the ubiquitin-proteasome pathway and/or the lysosomal proteolytic pathway was increased in patients with early lung cancer. A total of 36 patients with lung cancer referred for curative resection and 10 control subjects had biopsies of latissimus dorsi muscle taken at operation. mRNA levels of four components of the ubiquitin-proteasome pathway, i.e. polyubiquitin, C2α proteasome subunit, 14kDa ubiquitin-carrier protein and ubiquitin-activating protein, and of two lysosomal proteolytic enzymes, i.e. cathepsin B and cathepsin D, were measured using quantitative Northern blotting. mRNA levels for cathepsin B, but not for components of the ubiquitin-proteasome pathway, were higher in patients with cancer compared with controls (P = 0.01). Among lung cancer patients, cathepsin B mRNA levels correlated with fat-free mass index (r =-0.57, P = 0.003) and tumour stage (rs = 0.45, P = 0.03), and were higher in smokers (P = 0.04). Thus gene expression of the lysosomal protease cathepsin B is increased in the skeletal muscle of patients with early lung cancer, and the strong inverse relationship with fat-free mass suggests that cathepsin B may have a role in inducing muscle wasting in the early stages of lung cancer.

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

Mergla K + channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway

2006 ◽  
Vol 20 (9) ◽  
pp. 1531-1533 ◽  
Author(s):  
Xun Wang ◽  
Gregory H. Hockerman ◽  
Henry W. Green ◽  
Charles F. Babbs ◽  
Sulma I. Mohammad ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
K Channel ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

scholarly journals Human skeletal muscle wasting in hypoxia: a matter of hypoxic dose?

2017 ◽  
Vol 122 (2) ◽  
pp. 406-408 ◽  
Author(s):  
Gommaar D’Hulst ◽  
Louise Deldicque
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Muscle Wasting ◽  
Skeletal Muscle Wasting

Mechanisms of Cancer Cachexia

2009 ◽  
Vol 89 (2) ◽  
pp. 381-410 ◽  
Author(s):  
Michael J. Tisdale
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Adipose Tissue ◽  
Protein Degradation ◽  
Initiation Factor ◽  
Tissue Loss ◽  
Α Subunit ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the α-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFκB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-α, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment.

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