The Ubiquitin Ligase Nedd4-1 Participates in Denervation-Induced Skeletal Muscle Atrophy in Mice

Nagpal, Preena; Plant, Pamela; Correa, Judy; Bain, A. D.; Takeda, Masaya; Kawabe, Hiroshi; Rotin, Daniela; Bain, James R.; Batt, Jane

doi:10.1371/journal.pone.0046427

Cited by 66 publications

(53 citation statements)

References 51 publications

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“…Although the detailed mechanisms are not known, muscle-specific Nedd4-1 knockout mice display some protection of fast-twitch fibers to denervation-induced atrophy (318). The protein of the RING-finger domain family that is induced by denervation the most is Fbxo32.…”

Section: Protein Degradationmentioning

confidence: 99%

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

Tintignac

Brenner

Rüegg

2015

Physiological Reviews

332

341

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The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibers. It is designed to reliably convert the action potential from the presynaptic motor neuron into the contraction of the postsynaptic muscle fiber. Diseases that affect the neuromuscular junction may cause failure of this conversion and result in loss of ambulation and respiration. The loss of motor input also causes muscle wasting as muscle mass is constantly adapted to contractile needs by the balancing of protein synthesis and protein degradation. Finally, neuromuscular activity and muscle mass have a major impact on metabolic properties of the organisms. This review discusses the mechanisms involved in the development and maintenance of the neuromuscular junction, the consequences of and the mechanisms involved in its dysfunction, and its role in maintaining muscle mass during aging. As life expectancy is increasing, loss of muscle mass during aging, called sarcopenia, has emerged as a field of high medical need. Interestingly, aging is also accompanied by structural changes at the neuromuscular junction, suggesting that the mechanisms involved in neuromuscular junction maintenance might be disturbed during aging. In addition, there is now evidence that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia.

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Section: Protein Degradationmentioning

confidence: 99%

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

Tintignac

Brenner

Rüegg

2015

Physiological Reviews

332

341

View full text Add to dashboard Cite

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“…Nedd4-1 is another ubiquitin ligase that may be involved in myofibrillar degradation but whose mechanisms of action are unclear (74). The putative substrate of Nedd4-1 appears to be the PDZ and LIM domain 7, Enigma (PDLIM7) protein (16).…”

Section: The Ups Modulates Disassembly/degradation Of Myofibrillar Prmentioning

confidence: 99%

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

Bilodeau

Coyne

Wing

2016

American Journal of Physiology-Cell Physiology

136

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Bilodeau PA, Coyne ES, Wing SS. The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. Am J Physiol Cell Physiol 311: C392-C403, 2016. First published August 10, 2016; doi:10.1152/ajpcell.00125.2016.-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 GSK3␤, 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.hormones; muscle atrophy SKELETAL MUSCLE SERVES TWO essential functions, a contractile function for locomotion/maintenance of posture and a metabolic function as the protein reservoir of the body. The myofibers that make up the muscle consist primarily of myofibrillar proteins. The ability of the body to maintain posture or to move arises from the precise organization of myofibrillar proteins into a contractile unit called the sarcomere. The sarcomere consists of thick filaments containing primarily myosin that can slide over thin filaments containing primarily actin. Both types of filaments contain additional regulatory proteins and are linked to the ␣-actinin-containing Z disk, the thin filaments directly so and the thick filaments via titin. Vimentin and desmin are intermediate filaments that serve to anchor sarcomeres properly at the Z disks. These myofibrillar proteins, as well as the sarcoplasmic proteins, also serve as the protein reservoir of the body. Upon fasting, once hepatic glycogen stores are depleted, muscle protein degradation must be activated to provide amino acids to the liver for gluconeogenesis. These amino a...

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“…It is important to understand the molecular mechanisms underlying skeletal muscle atrophy and to develop effective strategies to delay its onset (2)(3)(4). Denervation-induced muscle atrophy has received attention as it is commonly encountered in clinical practice and is very likely to cause extreme adverse effects (5,6). A number of factors that contribute to denervation-induced muscle atrophy have been identified, including neuromuscular alterations, altered protein synthesis and degradation, and apoptosis-induced muscle fiber loss (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Proteomic and bioinformatic analysis of differentially expressed proteins in denervated skeletal muscle

Sun

Qiu

Chen

et al. 2014

International Journal of Molecular Medicine

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Abstract. The aim of this study was to improve our understanding and the current treatment of denervation-induced skeletal muscle atrophy. We used isobaric tags for relative and absolute quantification (iTRAQ) coupled with two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) to identify the differentially expressed proteins in the tibialis anterior (TA) muscle of rats at 1 and 4 weeks following sciatic nerve transection. A total of 110 proteins was differentially expressed and was further classified using terms from the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases to unravel their molecular functions. Among the differentially expressed metabolic enzymes involved in glycolysis, Krebs cycle and oxidative phosphorylation, α-and β-enolase displayed an increased and decreased expression, respectively, which was further validated by western blot analysis and immunohistochemistry. These findings suggest that the enolase isozymic switch during denervation-induced muscle atrophy is the reverse of that occurring during muscle maturation. Notably, protein-protein interaction analysis using the STRING database indicated that the protein expression of tumor necrosis factor receptor-associated factor-6 (TRAF6), muscle ring-finger protein 1 (MuRF1) and muscle atrophy F-box (MAFBx) was also upregulated during denervation-induced skeletal muscle atrophy, which was confirmed by western blot analysis. TRAF6 knockdown experiments in L6 myotubes suggested that the decreased expression of TRAF6 attenuated glucocorticoid-induced myotube atrophy. Therefore, we hypothesized that the upregulation of TRAF6 may be involved in the development of denervation-induced muscle atrophy, at least in part, by regulating the expression of MAFBx and MuRF1 proteins. The data from the present study provide valuable insight into the molecular mechanisms regulating denervation-induced muscle atrophy.

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The Ubiquitin Ligase Nedd4-1 Participates in Denervation-Induced Skeletal Muscle Atrophy in Mice

Cited by 66 publications

References 51 publications

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting

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

Proteomic and bioinformatic analysis of differentially expressed proteins in denervated skeletal muscle

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