A Novel Feed-Forward Loop between ARIH2 E3-Ligase and PABPN1 Regulates Aging-Associated Muscle Degeneration

Raz, Vered; Buijze, Hellen; Raz, Yotam; Verwey, Nisha; Anvar, Seyed Yahya; Aartsma‐Rus, Annemieke; Maarel, Silvère M. van der

doi:10.1016/j.ajpath.2013.12.011

Cited by 28 publications

(31 citation statements)

References 48 publications

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“…We then assessed LWA300 fluorescence in adherent and fused C2C12 cell cultures using the Cellomics imaging system. In previous studies, we demonstrated that this imaging system is highly suitable for high‐throughput of fused muscle cell cultures 24, 30. In agreement with the flow cytometry experiments, also with the Cellomics, we measured the reduced LWA300 signal by Epox pre‐incubation (Figure 4D–4E).…”

Section: Resultssupporting

confidence: 84%

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Proteasomal activity‐based probes mark protein homeostasis in muscles

Raz¹,

Raz²,

Soriano

et al. 2017

J cachexia sarcopenia muscle

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BackgroundProtein homeostasis, primarily regulated by the ubiquitin–proteasome system is crucial for proper function of cells. In tissues of post‐mitotic cells, the impaired ubiquitin–proteasome system is found in a wide range of neuromuscular disorders. Activity‐based probes (ABPs) measure proteasomal proteolytic subunits and can be used to report protein homeostasis. Despite the crucial role of the proteasome in neuromuscular pathologies, ABPs were not employed in muscle cells and tissues, and measurement of proteasomal activity was carried out in vitro using low‐throughput procedures.MethodsWe screened six ABPs for specific application in muscle cell culture using high throughput call‐based imaging procedures. We then determined an in situ proteasomal activity in myofibers of muscle cryosections.ResultsWe demonstrate that LWA300, a pan‐reactive proteasomal probe, is most suitable to report proteasomal activity in muscle cells using cell‐based bio‐imaging. We found that proteasomal activity is two‐fold and three‐fold enhanced in fused muscle cell culture compared with non‐fused cells. Moreover, we found that proteasomal activity can discriminate between muscles. Across muscles, a relative higher proteasomal activity was found in hybrid myofibers whereas fast‐twitch myofibers displayed lower activity.ConclusionsOur study demonstrates that proteasomal activity differ between muscles and between myofiber types. We suggest that ABPs can be used to report disease progression and treatment efficacy.

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Section: Resultssupporting

confidence: 84%

“…The immortalized human muscle cells (7304.1) exhibit a high fusion index and are more suitable for analyses of fused cells as compared with C2C12 cells 30. We compared proteasomal activity in fused cultures and found a higher LWA300 signal in fused human muscle cells compared with non‐fused cultures (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

Proteasomal activity‐based probes mark protein homeostasis in muscles

Raz¹,

Raz²,

Soriano

et al. 2017

J cachexia sarcopenia muscle

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“…PABPN1 mRNA is less stable in muscles compared with other tissues (Apponi et al, 2013). PABPN1 mRNA binds to PABPN1 protein (Raz et al, 2014), which potentially affects PABPN1 mRNA stability, nuclear export, and translation (Figure 1). As yet, regulators of mRNA stability in muscles and aging-associated changes are poorly understood.…”

Section: Why Are Skeletal Muscles Primarily Affected In Opmd?mentioning

confidence: 99%

“…Since PABPN1 is prone to aggregation, higher protein accumulation leads to aggregate formation and reduced availability of the functional protein. PABPN1 protein accumulation is regulated by ARIH2 E3-ligase, whose level also declines from midlife onward in skeletal muscles (Raz et al, 2014). In OPMD muscles, ARIH2 level is lower compared to age-matching controls, which in part could result by the alternative PAS utilization in ARIH2 3′-UTR that is directly regulated by PABPN1 level.…”

Section: Why Are Skeletal Muscles Primarily Affected In Opmd?mentioning

confidence: 99%

“…In OPMD muscles, ARIH2 level is lower compared to age-matching controls, which in part could result by the alternative PAS utilization in ARIH2 3′-UTR that is directly regulated by PABPN1 level. In addition, as ARIH2 protein is entrapped in expPABPN1 aggregates, functional protein levels would be depleted (Raz et al, 2014). Protein entrapment in PABPN1 aggregates was reported for other E3 ligases and the proteasome (Corbeil-Girard et al, 2005; Tavanez et al, 2005; Anvar et al, 2011), suggesting that the UPS machinery is dysregulated in OPMD.…”

Section: Why Are Skeletal Muscles Primarily Affected In Opmd?mentioning

confidence: 99%

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Oculopharyngeal Muscular Dystrophy as a Paradigm for Muscle Aging

Raz

2014

Front. Aging Neurosci.

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Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1). The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onward. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly. Molecular signatures of OPMD muscles are similar to those of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging.

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Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1–Arih2 axis

Jiang

Yuan

et al. 2022

J cachexia sarcopenia muscle

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Background Sarcopenia, the age-related decline in skeletal muscle mass and function, diminishes life quality in elderly people. Improving the capacity of skeletal muscle differentiation is expected to counteract sarcopenia. However, the mechanisms underlying skeletal muscle differentiation are complex, and effective therapeutic targets are largely unknown. Methods The human Gene Expression Omnibus database, aged mice and primary skeletal muscle cells were used to assess the expression level of pyruvate dehydrogenase B (PDHB) in human and mouse aged state. D-Galactose (D-gal)-induced sarcopenia mouse model and two classic cell models (C2C12 and HSkMC) were used to assess the myogenic effect of PDHB and the underlying mechanisms via immunocytochemistry, western blotting, quantitative real-time polymerase chain reaction, RNA interference or overexpression, dual-luciferase reporter assay, RNA sequencing and untargeted metabolomics. ResultsWe identified that a novel target PDHB promoted myogenic differentiation. PDHB expression decreased in aged mouse muscle relative to the young state (À50% of mRNA level, P < 0.01) and increased during mouse and primary human muscle cell differentiation (+3.97-fold, P < 0.001 and +3.79-fold, P < 0.001). Knockdown or overexpression of PDHB modulated the expression of genes related to muscle differentiation, namely, myogenic factor 5 (Myf5) (À46%, P < 0.01 and À27%, P < 0.05; +1.8-fold, P < 0.01), myogenic differentiation (MyoD) (À55%, P < 0.001 and À34%, P < 0.01; +2.27-fold, P < 0.001), myogenin (MyoG) (À60%, P < 0.001 and À70%, P < 0.001; +5.46-fold, P < 0.001) and myosin heavy chain (MyHC) (À70%, P < 0.001 and À69%, P < 0.001; +3.44-fold, P < 0.001) in both C2C12 cells and HSkMC. Metabolomic and transcriptomic analyses revealed that PDHB knockdown suppressed pyruvate metabolism (P < 0.001) and up-regulated ariadne RBR E3 ubiquitin protein ligase 2 (Arih2) (+7.23-fold, P < 0.001) in cellular catabolic pathways. The role of forkhead box P1 (FoxP1) (+4.18-fold, P < 0.001)-mediated Arih2 transcription was the key downstream regulator of PDHB in muscle differentiation. PDHB overexpression improved D-gal-induced muscle atrophy in mice, which was characterized by significant increases in grip strength, muscle mass and mean muscle cross-sectional area (1.19-fold to 1.5-fold, P < 0.01, P < 0.05 and P < 0.001). Conclusions The comprehensive results show that PDHB plays a sarcoprotective role by suppressing the FoxP1-Arih2 axis and may serve as a therapeutic target in sarcopenia.

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A Novel Feed-Forward Loop between ARIH2 E3-Ligase and PABPN1 Regulates Aging-Associated Muscle Degeneration

Cited by 28 publications

References 48 publications

Proteasomal activity‐based probes mark protein homeostasis in muscles

Proteasomal activity‐based probes mark protein homeostasis in muscles

Oculopharyngeal Muscular Dystrophy as a Paradigm for Muscle Aging

Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1–Arih2 axis

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