Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting

Bédard, Nathalie; Jammoul, Samer; Moore, Tamara J.; Wykes, Linda; Hallauer, Patricia L.; Hastings, Kenneth E.M.; Stretch, Cynthia; Baracos, Vickie E.; Chevalier, Stéphanie; Plourde, Marie; Coyne, Erin; Wing, Simon S.

doi:10.1096/fj.15-270579

Cited by 41 publications

(33 citation statements)

References 33 publications

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“…MURF1 is ROS sensitive autophagy related ubiquitin ligase that is greatly increased in atrophying muscles (Bedard et al, 2015; Gomes et al, 2012; Smith et al, 2014; Tanner et al, 2015). ROS, and in sarcopenic muscles from old rats (Alway et al, 2014a; Alway et al, 2015; Hao et al, 2011; Ziaaldini et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

Takahashi

Suzuki

Mohamed

et al. 2017

Experimental Gerontology

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We have previously found that Epigallocatechin-3-gallate (EGCg), an abundant catechin in green tea, reduced apoptotic signaling and improved muscle recovery in response to reloading after hindlimb suspension (HS). In this study, we investigated if EGCg altered autophagy signaling in skeletal muscle of old rats in response to HS or reloading after HS. Fischer 344 x Brown Norway inbred rats (age 34 mo.) were given 1 ml/day of purified EGCg (50 mg/kg body weight), or the same sample volume of the vehicle by gavage. One group of animals received HS for 14 days and the second group of rats received 14 days of HS, then the HS was removed and they were allowed to recover by ambulating normally around the cage for two weeks. EGCg decreased a small number of autophagy genes in control muscles, but it increased the expression of other autophagy genes (e.g., ATG16L2, SNCA, TM9SF1, Pink1, PIM-2) and HS did not attenuate these increases. HS increased Beclin1, ATG7 and LC3-II/I protein abundance in hindlimb muscles. Relative to vehicle treatment, EGCg treatment had greater ATG12 protein abundance (35.8%, P<0.05), but decreased Beclin1 protein levels (−101.1%, P<0.05) after HS. However, in reloaded muscles, EGCg suppressed Beclin1 and LC3-II/I protein abundance as compared to vehicle treated muscles. EGCg appeared to “prime” autophagy signaling before and enhance autophagy gene expression and protein levels during unloading in muscles of aged rats, perhaps to improve the clearance of damaged organelles. However, EGCg suppressed autophagy signaling after reloading, potentially to increase the recovery of hindlimb muscles mass and function after loading is restored.

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Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

Takahashi

Suzuki

Mohamed

et al. 2017

Experimental Gerontology

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“…TRAF6 may also interact with p62, a protein that plays a role in clearance of protein aggregates, and its inactivation in muscle leads to suppressed autophagy (83). Moreover, knocking out the deubiquitinating enzyme USP19 results in downregulation of autophagy-promoting genes in muscle, indicating that USP19 may promote autophagy (2). A recent report indicates that USP19 can deubiquitinate and stabilize Beclin-1, thereby promoting autophagy (39).…”

Section: The Ups Interacts With Autophagymentioning

confidence: 99%

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

Bilodeau

Coyne

Wing

2016

American Journal of Physiology-Cell Physiology

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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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“…However, it is unlikely that the enhanced physical activity explains all the beneficial metabolic effects observed in the Usp19 −/− mice, as cell autonomous effects of USP19 have also been observed. We have previously shown that silencing Usp19 in skeletal muscle of WT mice leads to protection from muscle wasting due to alterations in protein turnover [14]. In addition, silencing or gene inactivation of Usp19 in muscle cells has been shown to promote their differentiation in vitro [11] or enhance insulin signalling [15], respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Most notably, USP19 plays an important role in muscle; USP19 regulates myogenic differentiation [11], and female muscle mass through oestrogen receptor-dependent mechanisms [12]. Importantly, Usp19 expression is induced in muscle under catabolic stimuli [13] and the inactivation of the gene in mice is protective against muscle wasting [14,15].…”

Section: Introductionmentioning

confidence: 99%

The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice

et al. 2018

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Aims/hypothesis Elucidating the molecular mechanisms of fat accumulation and its metabolic consequences is crucial to understanding and treating obesity, an epidemic disease. We have previously observed that Usp19 deubiquitinating enzyme-null mice (Usp19 −/− ) have significantly lower fat mass than wild-type (WT) mice. Thus, this study aimed to provide further understanding of the role of ubiquitin-specific peptidase 19 (USP19) in fat development, obesity and diabetes. Methods In this study, the metabolic phenotypes of WT and Usp19 −/− mice were compared. The stromal vascular fractions (SVFs) of inguinal fat pads from WT and Usp19 −/− mice were isolated and cells were differentiated into adipocytes in culture to assess their adipogenic capacity. Mice were fed a high-fat diet (HFD) for 18 weeks. Body composition, glucose metabolism and metabolic variables were assessed. In addition, following insulin injection, signalling activity was analysed in the muscle, liver and adipose tissue. Finally, the correlation between the expression of Usp19 mRNA and adipocyte function genes in human adipose tissue was analysed. Result Upon adipogenic differentiation, SVF cells from Usp19 −/− failed to accumulate lipid and upregulate adipogenic genes, unlike cells from WT mice. Usp19 −/− mice were also found to have smaller fat pads throughout the lifespan and a higher percentage of lean mass, compared with WT mice. When fed an HFD, Usp19 −/− mice were more glucose tolerant, pyruvate tolerant and insulin sensitive than WT mice. Moreover, HFD-fed Usp19 −/− mice had enhanced insulin signalling in the muscle and the liver, but not in adipose tissue. Finally, USP19 mRNA expression in human adipose tissue was positively correlated with the expression of important adipocyte genes in abdominal fat depots, but not subcutaneous fat depots. Conclusions/interpretation USP19 is an important regulator of fat development. Its inactivation in mice exerts effects on multiple tissues, which may protect against the negative metabolic effects of high-fat feeding. These findings suggest that inhibition of USP19 could have therapeutic potential to protect from the deleterious consequences of obesity and diabetes.

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Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting

Cited by 41 publications

References 33 publications

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

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

The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice

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