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 Emerging Strategies Targeting Catabolic Muscle Stress Relief

2020 ◽  
Vol 21 (13) ◽  
pp. 4681 ◽  
Author(s):  
Mattia Scalabrin ◽  
Volker Adams ◽  
Siegfried Labeit ◽  
T. Scott Bowen
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Treatment Strategies ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
Functional Mobility ◽  
Skeletal Muscle Wasting ◽  
Therapeutic Concepts ◽  
Ubiquitin Proteasome

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitors, myostatin antibodies, β2 adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting.

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 An UBR-box from a non-N-recognin: Crystal Structure of the UBR domain of UBR6

2014 ◽  
Vol 70 (a1) ◽  
pp. C306-C306
Author(s):  
Juliana Muñoz-Escobar ◽  
Guennadi Kozlov ◽  
Jean-François Trempe ◽  
Kalle Gehring
Keyword(s):  
Crystal Structure ◽  
Ubiquitin Proteasome System ◽  
Zinc Binding ◽  
Binding Motifs ◽  
Clear Explanation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Binding Pockets ◽  
F Box Protein

The degradation of many short-lived proteins in eukaryotic cells is carried out by the Ubiquitin Proteasome System. The N-end rule pathway links the half-life of proteins to the identity of its N-terminal residue, also called N-degron. Destabilizing N-degrons, are recognized by E3 ubiquitin ligases termed N-recognins. N-degrons are grouped into type 1, composed of basic residues, and type 2, composed of bulky hydrophobic residues. In mammals, four N-recognins mediate the N-end rule pathway: UBR1, UBR2, UBR4 and UBR5. These proteins share a ~70-residue zinc finger-like motif termed the Ubiquitin Recognin (UBR) box, responsible for their specificity. The mammalian genome encodes at least three more UBR-box proteins: UBR3, UBR6/FBXO11 and UBR7. However, these UBRs cannot recognize any type of N-degrons. Our lab reported the crystal structures of the UBR boxes from the human UBR1 and UBR2, rationalizing the empirical rules for the classification of type 1 N-degrons. Despite the valuable information obtained from those structures there is not a clear explanation for the no recognition of N-degrons by other UBR-box proteins. Here we report the crystal structure of the UBR-box domain from UBR6 also known as FBXO11. UBR6 is a F-box protein of the SKP1-Cullin1-F-box (SCF) ubiquitin ligase complex and does not recognize any type of N-degrons. We crystallized a 77-residue fragment of the UBR-box of UBR6 and determined its structure at 1.7 Å resolution. Unexpectedly, this domain adopts an open conformation compared to UBR1-box, without any N-degron binding pockets. Its zinc-binding residues are conserved as in the N-recognins, but they are arranged in different zinc-binding motifs. Molecules form dimmers stabilized by zinc ions. The crystal had 4 molecules per asymmetric unit and space group P212121. For phasing we used Zn-SAD. With this structure we hope to obtain clues that explain the absence of N-degron recognition in some members of the UBR family.

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 p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting

2010 ◽  
Vol 298 (3) ◽  
pp. C542-C549 ◽  
Author(s):  
J. M. McClung ◽  
A. R. Judge ◽  
S. K. Powers ◽  
Z. Yan
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Protein Modification ◽  
Muscle Wasting ◽  
Ring Finger ◽  
Mitogen Activated Protein Kinase ◽  
C2c12 Myotubes ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome ◽  
F Box Protein

Oxidative stress is a primary trigger of cachectic muscle wasting, but the signaling pathway(s) that links it to the muscle wasting processes remains to be defined. Here, we report that activation of p38 mitogen-activated protein kinase (MAPK) (phosphorylation) and increased oxidative stress ( trans-4-hydroxy-2-nonenal protein modification) in skeletal muscle occur as early as 8 h after lipopolysaccharide (1 mg/kg) and 24 h after dexamethasone (25 mg/kg) injection (intraperitoneal) in mice, concurrent with upregulation of autophagy-related genes, Atg6, Atg7, and Atg12. Treating cultured C2C12 myotubes with oxidant hydrogen peroxide (4 h) resulted in increased p38 phosphorylation and reduced FoxO3 phosphorylation along with induced Atg7 mRNA expression without activation of NF-κ B or FoxO3a transcriptional activities. Furthermore, inhibition of p38α/β by SB202190 blocked hydrogen peroxide-induced atrophy with diminished upregulation of Atg7 and atrogenes [muscle atrophy F-box protein ( MAFbx/Atrogin-1) , muscle ring finger protein 1 ( MuRF-1), and Nedd4]. These findings provide direct evidence for p38α/β MAPK in mediating oxidative stress-induced autophagy-related genes, suggesting that p38α/β MAPK regulates both the ubiquitin-proteasome and the autophagy-lysosome systems in muscle wasting.

Amyloid Beta

2019 ◽  
pp. 235-251
Author(s):  
Abhinav Anand ◽  
Neha Sharma ◽  
Monica Gulati ◽  
Navneet Khurana
Keyword(s):  
Amyloid Beta ◽  
Cognitive Abilities ◽  
Neurodegenerative Disorder ◽  
Proteolytic Enzymes ◽  
Ubiquitin Proteasome System ◽  
The Novel ◽  
Ubiquitin Proteasome ◽  
Causes Of Deaths ◽  
Brain Acetylcholine ◽  
The Brain

Alzheimer's disease (AD), exhibiting accumulation of amyloid beta (Aβ) peptide as a foremost protagonist, is one of the top five causes of deaths. It is a neurodegenerative disorder (ND) that causes a progressive decline in memory and cognitive abilities. It is characterized by deposition of Aβ plaques and neurofibrillary tangles (NFTs) in the neurons, which in turn causes a decline in the brain acetylcholine levels. Aβ hypothesis is the most accepted hypothesis pertaining to the pathogenesis of AD. Amyloid Precursor Protein (APP) is constitutively present in brain and it is cleaved by three proteolytic enzymes (i.e., alpha, beta, and gamma secretases). Beta and gamma secretases cleave APP to form Aβ. Ubiquitin Proteasome System (UPS) is involved in the clearing of Aβ plaques. AD also involves impairment in UPS. The novel disease-modifying approaches involve inhibition of beta and gamma secretases. A number of clinical trials are going on worldwide with moieties targeting beta and gamma secretases. This chapter deals with an overview of APP and its enzymatic cleavage leading to AD.

Amyloid Beta

2021 ◽  
pp. 1-17
Author(s):  
Abhinav Anand ◽  
Neha Sharma ◽  
Monica Gulati ◽  
Navneet Khurana
Keyword(s):  
Amyloid Beta ◽  
Cognitive Abilities ◽  
Neurodegenerative Disorder ◽  
Proteolytic Enzymes ◽  
Ubiquitin Proteasome System ◽  
The Novel ◽  
Ubiquitin Proteasome ◽  
Causes Of Deaths ◽  
Brain Acetylcholine ◽  
The Brain

Alzheimer's disease (AD), exhibiting accumulation of amyloid beta (Aβ) peptide as a foremost protagonist, is one of the top five causes of deaths. It is a neurodegenerative disorder (ND) that causes a progressive decline in memory and cognitive abilities. It is characterized by deposition of Aβ plaques and neurofibrillary tangles (NFTs) in the neurons, which in turn causes a decline in the brain acetylcholine levels. Aβ hypothesis is the most accepted hypothesis pertaining to the pathogenesis of AD. Amyloid Precursor Protein (APP) is constitutively present in brain and it is cleaved by three proteolytic enzymes (i.e., alpha, beta, and gamma secretases). Beta and gamma secretases cleave APP to form Aβ. Ubiquitin Proteasome System (UPS) is involved in the clearing of Aβ plaques. AD also involves impairment in UPS. The novel disease-modifying approaches involve inhibition of beta and gamma secretases. A number of clinical trials are going on worldwide with moieties targeting beta and gamma secretases. This chapter deals with an overview of APP and its enzymatic cleavage leading to AD.

scholarly journals The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1

2011 ◽  
Vol 194 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Rachel Lander ◽  
Kara Nordin ◽  
Carole LaBonne
Keyword(s):  
Structural Diversity ◽  
Ubiquitin Proteasome System ◽  
Common Mechanism ◽  
Rich Domain ◽  
Transcriptional Regulatory ◽  
Snail Family ◽  
Ubiquitin Proteasome ◽  
Snail Proteins ◽  
The Stability ◽  
F Box Protein

A small group of core transcription factors, including Twist, Snail, Slug, and Sip1, control epithelial–mesenchymal transitions (EMTs) during both embryonic development and tumor metastasis. However, little is known about how these factors are coordinately regulated to mediate the requisite behavioral and fate changes. It was recently shown that a key mechanism for regulating Snail proteins is by modulating their stability. In this paper, we report that the stability of Twist is also regulated by the ubiquitin–proteasome system. We found that the same E3 ubiquitin ligase known to regulate Snail family proteins, Partner of paired (Ppa), also controlled Twist stability and did so in a manner dependent on the Twist WR-rich domain. Surprisingly, Ppa could also target the third core EMT regulatory factor Sip1 for proteasomal degradation. Together, these results indicate that despite the structural diversity of the core transcriptional regulatory factors implicated in EMT, a common mechanism has evolved for controlling their stability and therefore their function.

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