scholarly journals Myofibril breakdown during atrophy is a delayed response requiring the transcription factor PAX4 and desmin depolymerization

2017 ◽  
Vol 114 (8) ◽  
pp. E1375-E1384 ◽  
Author(s):  
Alexandra Volodin ◽  
Idit Kosti ◽  
Alfred Lewis Goldberg ◽  
Shenhav Cohen
Keyword(s):  
Transcription Factor ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Delayed Response ◽  
Myofibrillar Proteins ◽  
Down Regulation ◽  
Two Phase ◽  
Gene Encoding ◽  
Thin Filaments ◽  
Ubiquitin Proteasome

A hallmark of muscle atrophy is the excessive degradation of myofibrillar proteins primarily by the ubiquitin proteasome system. In mice, during the rapid muscle atrophy induced by fasting, the desmin cytoskeleton and the attached Z-band–bound thin filaments are degraded after ubiquitination by the ubiquitin ligase tripartite motif-containing protein 32 (Trim32). To study the order of events leading to myofibril destruction, we investigated the slower atrophy induced by denervation (disuse). We show that myofibril breakdown is a two-phase process involving the initial disassembly of desmin filaments by Trim32, which leads to the later myofibril breakdown by enzymes, whose expression is increased by the paired box 4 (PAX4) transcription factor. After denervation of mouse tibialis anterior muscles, phosphorylation and Trim32-dependent ubiquitination of desmin filaments increased rapidly and stimulated their gradual depolymerization (unlike their rapid degradation during fasting). Trim32 down-regulation attenuated the loss of desmin and myofibrillar proteins and reduced atrophy. Although myofibrils and desmin filaments were intact at 7 d after denervation, inducing the dissociation of desmin filaments caused an accumulation of ubiquitinated proteins and rapid destruction of myofibrils. The myofibril breakdown normally observed at 14 d after denervation required not only dissociation of desmin filaments, but also gene induction by PAX4. Down-regulation of PAX4 or its target gene encoding the p97/VCP ATPase reduced myofibril disassembly and degradation on denervation or fasting. Thus, during atrophy, the initial loss of desmin is critical for the subsequent myofibril destruction, and over time, myofibrillar proteins become more susceptible to PAX4-induced enzymes that promote proteolysis.

scholarly journals Supplementation of ketoacids contributes to the up-regulation of the Wnt7a/Akt/p70S6K pathway and the down-regulation of apoptotic and ubiquitin–proteasome systems in the muscle of 5/6 nephrectomised rats

2014 ◽  
Vol 111 (9) ◽  
pp. 1536-1548 ◽  
Author(s):  
Dong-Tao Wang ◽  
Lu Lu ◽  
Ying Shi ◽  
Zhen-Bo Geng ◽  
Yi Yin ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Muscle Atrophy ◽  
Caspase 3 ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
Protein Diet ◽  
Down Regulation ◽  
Beneficial Effects ◽  
Phosphorylated Akt ◽  
Ubiquitin Proteasome

Ketoacids (KA) are known to improve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (CKD-LPD), but the mechanism of its preventive effects on muscle atrophy still remains unclear. Since muscle atrophy in CKD may be attributable to the down-regulation of the Wnt7a/Akt/p70S6K pathway and the activation of the ubiquitin–proteasome system (UPS) and the apoptotic signalling pathway, a hypothesis can readily be drawn that KA supplementation improves muscle mass by up-regulating the Wnt7a/Akt/p70S6K pathway and counteracting the activation of the UPS and caspase-3-dependent apoptosis in the muscle of CKD-LPD rats. Rats with 5/6 nephrectomy were randomly divided into three groups, and fed with either 22 % protein (normal-protein diet; NPD), 6 % protein (LPD) or 5 % protein plus 1 % KA for 24 weeks. Sham-operated rats with NPD intake were used as the control. The results demonstrated that KA supplementation improved protein synthesis and increased related mediators such as Wnt7a, phosphorylated Akt and p70S6K in the muscle of CKD-LPD rats. It also inhibited protein degradation, withheld the increase in ubiquitin and its ligases MAFbx (muscle atrophy F-box) and MuRF1 (muscle ring finger-1) as well as attenuated proteasome activity in the muscle of CKD-LPD rats. Moreover, KA supplementation gave rise to a reduction in DNA fragment, cleaved caspase-3 and 14 kDa actin fragment via the down-regulation of the Bax:Bcl-2 ratio in the muscle of CKD-LPD rats. The beneficial effects unveiled herein further consolidate that KA may be a better therapeutic strategy for muscle atrophy in CKD-LPD.

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 Increasing autophagy does not affect neurogenic muscle atrophy

2018 ◽  
Vol 28 (3) ◽  
Author(s):  
Eva Pigna ◽  
Krizia Sanna ◽  
Dario Coletti ◽  
Zhenlin Li ◽  
Ara Parlakian ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Autophagic Flux ◽  
Molecular Pathways ◽  
Muscle Loss ◽  
Relative Contribution ◽  
Ubiquitin Proteasome ◽  
Muscle Mass Loss ◽  
Kinetics Of

Physiological autophagy plays a crucial role in the regulation of muscle mass and metabolism, while the excessive induction or the inhibition of the autophagic flux contributes to the progression of several diseases. Autophagy can be activated by different stimuli, including cancer, exercise, caloric restriction and denervation. The latter leads to muscle atrophy through the activation of catabolic pathways, i.e. the ubiquitin-proteasome system and autophagy. However, the kinetics of autophagy activation and the upstream molecular pathways in denervated skeletal muscle have not been reported yet. In this study, we characterized the kinetics of autophagic induction, quickly triggered by denervation, and report the Akt/mTOR axis activation. Besides, with the aim to assess the relative contribution of autophagy in neurogenic muscle atrophy, we triggered autophagy with different stimuli along with denervation, and observed that four week-long autophagic induction, by either intermitted fasting or rapamycin treatment, did not significantly affect muscle mass loss. We conclude that: i) autophagy does not play a major role in inducing muscle loss following denervation; ii) nonetheless, autophagy may have a regulatory role in denervation induced muscle atrophy, since it is significantly upregulated as early as eight hours after denervation; iii) Akt/mTOR axis, AMPK and FoxO3a are activated consistently with the progression of muscle atrophy, further highlighting the complexity of the signaling response to the atrophying stimulus deriving from denervation.

scholarly journals Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Author(s):  
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Atrophy ◽  
Late Onset ◽  
Oral Treatment ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Functional Study ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Ubiquitin Proteasome ◽  
And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

Calpain and caspase-3 play required roles in immobilization-induced limb muscle atrophy

2013 ◽  
Vol 114 (10) ◽  
pp. 1482-1489 ◽  
Author(s):  
Erin E. Talbert ◽  
Ashley J. Smuder ◽  
Kisuk Min ◽  
Oh Sung Kwon ◽  
Scott K. Powers
Keyword(s):  
Muscle Atrophy ◽  
Caspase 3 ◽  
Respiratory Muscles ◽  
Ubiquitin Proteasome System ◽  
Type I ◽  
Disuse Atrophy ◽  
Limb Muscle ◽  
Disuse Muscle Atrophy ◽  
Ubiquitin Proteasome ◽  
Rat Soleus Muscle

Prolonged skeletal muscle inactivity results in a rapid decrease in fiber size, primarily due to accelerated proteolysis. Although several proteases are known to contribute to disuse muscle atrophy, the ubiquitin proteasome system is often considered the most important proteolytic system during many conditions that promote muscle wasting. Emerging evidence suggests that calpain and caspase-3 may also play key roles in inactivity-induced atrophy of respiratory muscles, but it remains unknown if these proteases are essential for disuse atrophy in limb skeletal muscles. Therefore, we tested the hypothesis that activation of both calpain and caspase-3 is required for locomotor muscle atrophy induced by hindlimb immobilization. Seven days of immobilization (i.e., limb casting) promoted significant atrophy in type I muscle fibers of the rat soleus muscle. Independent pharmacological inhibition of calpain or caspase-3 prevented this casting-induced atrophy. Interestingly, inhibition of calpain activity also prevented caspase-3 activation, and, conversely, inhibition of caspase-3 prevented calpain activation. These findings indicate that a regulatory cross talk exists between these proteases and provide the first evidence that the activation of calpain and caspase-3 is required for inactivity-induced limb muscle atrophy.

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

2016 ◽  
Vol 311 (3) ◽  
pp. C392-C403 ◽  
Author(s):  
Philippe A. Bilodeau ◽  
Erin S. Coyne ◽  
Simon S. Wing
Keyword(s):  
Signaling Pathways ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Clinical Problem ◽  
Ubiquitin Proteasome System ◽  
Mechanisms Of Action ◽  
Loss Of Function ◽  
Critical Determinant ◽  
Ubiquitin Proteasome

Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3β, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.

scholarly journals Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy

2012 ◽  
Vol 198 (4) ◽  
pp. 575-589 ◽  
Author(s):  
Shenhav Cohen ◽  
Bo Zhai ◽  
Steven P. Gygi ◽  
Alfred L. Goldberg
Keyword(s):  
Muscle Atrophy ◽  
Ubiquitin Ligase ◽  
Thin Filament ◽  
Thick Filament ◽  
Myofibrillar Proteins ◽  
Rapid Loss ◽  
Thin Filaments ◽  
Thin Filament Proteins ◽  
Rapid Destruction ◽  
Fiber Atrophy

During muscle atrophy, myofibrillar proteins are degraded in an ordered process in which MuRF1 catalyzes ubiquitylation of thick filament components (Cohen et al. 2009. J. Cell Biol. http://dx.doi.org/10.1083/jcb.200901052). Here, we show that another ubiquitin ligase, Trim32, ubiquitylates thin filament (actin, tropomyosin, troponins) and Z-band (α-actinin) components and promotes their degradation. Down-regulation of Trim32 during fasting reduced fiber atrophy and the rapid loss of thin filaments. Desmin filaments were proposed to maintain the integrity of thin filaments. Accordingly, we find that the rapid destruction of thin filament proteins upon fasting was accompanied by increased phosphorylation of desmin filaments, which promoted desmin ubiquitylation by Trim32 and degradation. Reducing Trim32 levels prevented the loss of both desmin and thin filament proteins. Furthermore, overexpression of an inhibitor of desmin polymerization induced disassembly of desmin filaments and destruction of thin filament components. Thus, during fasting, desmin phosphorylation increases and enhances Trim32-mediated degradation of the desmin cytoskeleton, which appears to facilitate the breakdown of Z-bands and thin filaments.

scholarly journals Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia

2020 ◽  
Vol 21 (11) ◽  
pp. 3779 ◽  
Author(s):  
Ichiro Kawahata ◽  
Kohji Fukunaga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tyrosine Hydroxylase ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
The Novel ◽  
Gene Encoding ◽  
Dopaminergic Systems ◽  
Dopamine Biosynthesis ◽  
Ubiquitin Proteasome

Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson’s disease as well as anticipate therapeutic targets and early diagnosis of these diseases.

Muscle Atrophy Classification: The Need for a Pathway-Driven Approach

2021 ◽  
Vol 27 ◽  
Author(s):  
John Zizzo
Keyword(s):  
Physical Activity ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Specific Region ◽  
Signaling Cascades ◽  
Impaired Ability ◽  
Neurogenic Atrophy ◽  
Ubiquitin Proteasome ◽  
Underlying Mechanisms

: It is well known that muscles can waste away (atrophy) due to a lack of physical activity. Muscle wasting commonly presents with reduced muscle strength and an impaired ability to perform daily tasks. Several studies have attempted to categorize muscle atrophy into three main subgroups: physiologic, pathologic, and neurogenic atrophy. Physiologic atrophy is caused by the general underuse of skeletal muscle (e.g., bedridden). Pathologic atrophy is characterized as the loss of stimulus to a specific region (e.g. aging). Neurogenic atrophy results from damage to the nerve innervating a muscle (e.g. SMA, GBS). Mechanisms have been elucidated for many of these pathways (e.g., ubiquitin-proteasome system, NF-κB, etc.). However, many causes of muscle atrophy (e.g., burns, arthritis, etc.) operate through unelucidated signaling cascades. Therefore, this review highlights the underlying mechanisms of each subtype of muscle atrophy while emphasizing the need for additional research in properly classifying and identifying muscle atrophy.

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.

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