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.

Dynamics of autophagy and ubiquitin proteasome system coordination and interplay in skeletal muscle atrophy

2021 ◽  
Vol 14 ◽  
Author(s):  
Ajay Singh ◽  
Aarti Yadav ◽  
Jatin Phogat ◽  
Rajesh Dabur
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Protein ◽  
Ubiquitin Proteasome System ◽  
The Body ◽  
Skeletal Muscle Atrophy ◽  
Protein Pool ◽  
Ubiquitin Proteasome ◽  
Muscle Protein Degradation ◽  
Loss Of Mass

: Skeletal muscles are considered the largest reservoirs of the protein pool in the body and are critical for the maintenances of body homeostasis. Skeletal muscle atrophy is supported by various physiopathological conditions that lead to loss of muscle mass and contractile capacity of the skeletal muscle. Lysosomal mediated autophagy and ubiquitin-proteasomal system (UPS) concede the major intracellular systems of muscle protein degradation that result in the loss of mass and strength. Both systems recognize ubiquitination as a signal of degradation through different mechanisms, a sign of dynamic interplay between systems. Hence, growing shreds of evidence suggest the interdependency of autophagy and UPS in the progression of skeletal muscle atrophy under various pathological conditions. Therefore, understanding the molecular dynamics as well associated factors responsible for their interdependency is a necessity for the new therapeutic insights to counteract the muscle loss. Based on current literature, the present review summarizes the factors interplay in between the autophagy and UPS in favor of enhanced proteolysis of skeletal muscle and how they affect the anabolic signaling pathways under various conditions of skeletal muscle atrophy.

scholarly journals Exercise Training Prevents Oxidative Stress and Ubiquitin-Proteasome System Overactivity and Reverse Skeletal Muscle Atrophy in Heart Failure

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e41701 ◽  
Author(s):  
Telma F. Cunha ◽  
Aline V. N. Bacurau ◽  
Jose B. N. Moreira ◽  
Nathalie A. Paixão ◽  
Juliane C. Campos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Atrophy ◽  
Ubiquitin Proteasome

scholarly journals Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2272
Author(s):  
Volker Adams ◽  
Victoria Gußen ◽  
Sergey Zozulya ◽  
André Cruz ◽  
Anselmo Moriscot ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Citrate Synthase ◽  
Malignant Tumors ◽  
Ubiquitin Proteasome System ◽  
Muscle Performance ◽  
Skeletal Muscle Atrophy ◽  
Muscle Weight ◽  
Ubiquitin Proteasome ◽  
Progressive Weakness

Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13–23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction.

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 The dependency of autophagy and ubiquitin proteasome system during skeletal muscle atrophy

2021 ◽  
Vol 13 (2) ◽  
pp. 203-219 ◽  
Author(s):  
Ajay Singh ◽  
Jatin Phogat ◽  
Aarti Yadav ◽  
Rajesh Dabur
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Atrophy ◽  
Ubiquitin Proteasome

scholarly journals Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

2015 ◽  
Vol 309 (7) ◽  
pp. E651-E662 ◽  
Author(s):  
Tatsuro Egawa ◽  
Ayumi Goto ◽  
Yoshitaka Ohno ◽  
Shingo Yokoyama ◽  
Akihiro Ikuta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Degradation ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Skeletal Muscle Mass ◽  
Ubiquitin Proteasome System ◽  
Hindlimb Unloading ◽  
Slow Twitch Muscle ◽  
Ubiquitin Proteasome ◽  
Slow Twitch

AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT ( n = 24) and AMPK-DN ( n = 24) mice were randomly divided into two groups: an untreated preexperimental control group ( n = 12 in each group) and an unloading ( n = 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ∼30% in WT mice by hindlimb unloading and by ∼20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of κBα, microRNA (miR)-1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system.

scholarly journals Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 407
Author(s):  
Dulce Peris-Moreno ◽  
Laura Cussonneau ◽  
Lydie Combaret ◽  
Cécile Polge ◽  
Daniel Taillandier
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Signaling Pathways ◽  
Muscle Atrophy ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Atrophy ◽  
Mortality And Morbidity ◽  
E3 Ligases ◽  
Ubiquitin Proteasome

Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in muscle atrophy and the E3 ligases implicated, but also the molecules potentially usable for future therapies.

Fenofibrate, a PPARα agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy

2011 ◽  
Vol 300 (5) ◽  
pp. E790-E799 ◽  
Author(s):  
Estíbaliz Castillero ◽  
María Paz Nieto-Bona ◽  
Carmen Fernández-Galaz ◽  
Ana Isabel Martín ◽  
María López-Menduiña ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Atrophy ◽  
Skeletal Muscle Wasting ◽  
Cross Section Area ◽  
Section Area ◽  
Ubiquitin Proteasome ◽  
Injection Control

Arthritis is a chronic inflammatory illness that induces cachexia, which has a direct impact on morbidity and mortality. Fenofibrate, a selective PPARα activator prescribed to treat human dyslipidemia, has been reported to decrease inflammation in rheumatoid arthritis patients. The aim of this study was to elucidate whether fenofibrate is able to ameliorate skeletal muscle wasting in adjuvant-induced arthritis, an experimental model of rheumatoid arthritis. On day 4 after adjuvant injection, control and arthritic rats were treated with 300 mg/kg fenofibrate until day 15, when all rats were euthanized. Fenofibrate decreased external signs of arthritis and liver TNFα and blocked arthritis-induced decreased in PPARα expression in the gastrocnemius muscle. Arthritis decreased gastrocnemius weight, which results from a decrease in cross-section area and myofiber size, whereas fenofibrate administration to arthritic rats attenuated the decrease in both gastrocnemius weight and fast myofiber size. Fenofibrate treatment prevented arthritis-induced increase in atrogin-1 and MuRF1 expression in the gastrocnemius. Neither arthritis nor fenofibrate administration modify Akt-FoxO3 signaling. Myostatin expression was not modified by arthritis, but fenofibrate decreased myostatin expression in the gastrocnemius of arthritic rats. Arthritis increased muscle expression of MyoD, PCNA, and myogenin in the rats treated with vehicle but not in those treated with fenofibrate. The results indicate that, in experimental arthritis, fenofibrate decreases skeletal muscle atrophy through inhibition of the ubiquitin-proteasome system and myostatin.

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.

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