Muscle wasting: the role of the ubiquitin-proteasome pathway in muscle atrophy and remodelling

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.

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The Critical Role of the Ubiquitin-Proteasome Pathway in Muscle Wasting in Comparison to Lysosomal and Ca2+-Dependent Systems

Intracellular Protein Decradation - Advances in Molecular and Cell Biology ◽

10.1016/s1569-2558(08)60463-4 ◽

1998 ◽

pp. 235-266 ◽

Cited By ~ 35

Author(s):

Didier Attaix ◽

Daniel Taillandier

Keyword(s):

Muscle Wasting ◽

Critical Role ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

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

The FASEB Journal ◽

10.1096/fj.05-5350fje ◽

2006 ◽

Vol 20 (9) ◽

pp. 1531-1533 ◽

Cited By ~ 16

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

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Abstract 44: TAK1 Regulates Caspase 8 Activation and Necroptotic Signaling via Multiple Cell Death Checkpoints

Circulation Research ◽

10.1161/res.119.suppl_1.44 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Xaioyun Guo ◽

Haifeng Yin ◽

Yi Chen ◽

Lei Li ◽

Jing Li ◽

...

Keyword(s):

Cell Death ◽

Adaptor Protein ◽

Regulatory Mechanisms ◽

Caspase 8 ◽

Ubiquitin Proteasome Pathway ◽

Pathological Conditions ◽

Ubiquitin Proteasome ◽

Multiple Cell ◽

Proteasome Pathway

Necroptosis has emerged as a new form of programmed cell death implicated in a number of pathological conditions such as ischemic injury, neurodegenerative disease, and viral infection. Recent studies indicate that TGFβ-activated kinase 1 (TAK1) is nodal regulator of necroptotic cell death, but the underlying molecular regulatory mechanisms remain elusive. Here we reported that TAK1 regulates necroptotic signaling as well as caspase 8 activation through both NFκB-dependent and -independent mechanisms. Inhibition of TAK1 promoted TNFα-induced necroptosis through the induction of RIP1 phosphorylation/activation and necrosome formation, in the presence of ongoing caspase activation. Further, inhibition of TAK1 triggered two caspase 8 activation pathways through the induction of RIP1-FADD-caspase 8 complex as well as FLIP cleavage/degradation. Mechanistically, our data uncovered an essential role of the adaptor protein TRADD in caspase 8 activation and necrosome formation triggered by TAK1 inhibition. Moreover, ablation of the deubiqutinase CYLD prevented both apoptotic and necroptotic signaling induced by TAK1 inhibition, whereas deletion of the E3 ubiquitin ligase TRAF2 had the opposite effect. Finally, blocking the ubiquitin-proteasome pathway prevented the degradation of key necroptotic signaling proteins and necrosome formation. Thus we identified novel regulatory mechanisms underling the critical role of TAK1 in necroptotic signaling through regulation of multiple cell death checkpoints. Targeting key components of the necroptotic pathway (e.g., TRADD and CYLD) and the ubiquitin-proteasome pathway may represent novel therapeutic strategies for pathological conditions driven by necroptosis.

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The Role of the Ubiquitin–Proteasome Pathway in the Regulation of the Cellular Hypoxia Response

Protein Degradation Series ◽

10.1002/9783527619320.ch6b ◽

2008 ◽

pp. 132-148

Author(s):

Koh Nakayama ◽

Ze'ev Ronai

Keyword(s):

Hypoxia Response ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Cellular Hypoxia ◽

Proteasome Pathway

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Participation of the ubiquitin-proteasome pathway in rat oocyte activation

Zygote ◽

10.1017/s0967199405003114 ◽

2005 ◽

Vol 13 (1) ◽

pp. 87-95 ◽

Cited By ~ 2

Author(s):

Xin Tan ◽

An Peng ◽

Yong-Chao Wang ◽

Yue Wang ◽

Qing-Yuan Sun

Keyword(s):

Meiotic Division ◽

Polar Body ◽

Meiotic Spindle ◽

Oocyte Activation ◽

Parthenogenetic Activation ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Second Polar Body

The role of the ubiquitin-proteasome pathway (UPP) in mitosis is well known. However, its role in meiotic division is still poorly documented, especially in the activation of mammalian oocytes. In this study, the role of proteasome in the spontaneous and parthenogenetic activation of rat oocytes was investigated. We found that ALLN, an inhibitor of proteasome, when applied to metaphase II oocytes, inhibited spontaneous activation, blocked extrusion of the second polar body (PB) and caused the withdrawal of the partially extruded second PB. ALLN also inhibited the parthenogenetic activation induced by cycloheximide, but had no effect on the formation of pronuclei in activated eggs. In metaphase and anaphase, ubiquitin and proteasome localized to the meiotic spindle, concentrating on both sides of the oocyte–second PB boundary during PB extrusion. This pattern of cellular distribution suggests that UPP may have a role in regulating nuclear division and cytokinesis. Ubiquitin was seen to form a ring around the pronucleus, whereas proteasome was evenly distributed in the pronuclear region. Taken together, our results indicate that (1) UPP is required for the transitions of oocytes from metaphase II to anaphase II and from anaphase II to the end of meiosis; and (2) the UPP plays a role in cytokinesis of the second meiotic division.

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