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.

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 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.

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.

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 Angiotensin (1-7) Decreases Myostatin-Induced NF-κB Signaling and Skeletal Muscle Atrophy

2020 ◽  
Vol 21 (3) ◽  
pp. 1167 ◽  
Author(s):  
Javier Aravena ◽  
Johanna Abrigo ◽  
Francisco Gonzalez ◽  
Francisco Aguirre ◽  
Andrea Gonzalez ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Renin Angiotensin System ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Atrophy ◽  
Gene Expressions ◽  
Protein Levels ◽  
Mas Receptor ◽  
Signaling Activation ◽  
Species Production

Myostatin is a myokine that regulates muscle function and mass, producing muscle atrophy. Myostatin induces the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. The main pathway that mediates protein degradation during muscle atrophy is the ubiquitin proteasome system, by increasing the expression of atrogin-1 and MuRF-1. In addition, myostatin activates the NF-κB signaling pathway. Renin–angiotensin system (RAS) also regulates muscle mass. Angiotensin (1-7) (Ang-(1-7)) has anti-atrophic properties in skeletal muscle. In this paper, we evaluated the effect of Ang-(1-7) on muscle atrophy and signaling induced by myostatin. The results show that Ang-(1-7) prevented the decrease of the myotube diameter and myofibrillar protein levels induced by myostatin. Ang-(1-7) also abolished the increase of myostatin-induced reactive oxygen species production, atrogin-1, MuRF-1, and TNF-α gene expressions and NF-κB signaling activation. Ang-(1-7) inhibited the activity mediated by myostatin through Mas receptor, as is demonstrated by the loss of all Ang-(1-7)-induced effects when the Mas receptor antagonist A779 was used. Our results show that the effects of Ang-(1-7) on the myostatin-dependent muscle atrophy and signaling are blocked by MK-2206, an inhibitor of Akt/PKB. Together, these data indicate that Ang-(1-7) inhibited muscle atrophy and signaling induced by myostatin through a mechanism dependent on Mas receptor and Akt/PKB.

scholarly journals Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Li Wang ◽  
Xin-Feng Jiao ◽  
Cheng Wu ◽  
Xiao-Qing Li ◽  
Hui-Xian Sun ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Performance ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
High Dose ◽  
Protective Effects ◽  
Akt Inhibitor ◽  
Caspase 1

AbstractSkeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.

scholarly journals UBE2L3, a Partner of MuRF1/TRIM63, Is Involved in the Degradation of Myofibrillar Actin and Myosin

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1974
Author(s):  
Dulce Peris-Moreno ◽  
Mélodie Malige ◽  
Agnès Claustre ◽  
Andrea Armani ◽  
Cécile Coudy-Gandilhon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Contractile Proteins ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Skeletal Muscle Wasting ◽  
Life Prognosis ◽  
Ubiquitin Conjugating Enzymes ◽  
Alpha Actin

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (KD = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (KD = 46.7 nM) over monomeric G-actin (KD = 450 nM). By contrast with actin that did not alter MuRF1–UBE2L3 affinity, binding of MHC to MuRF1 (KD = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy.

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