RNA-binding proteins: The next step in translating skeletal muscle adaptations?

Pelt, Douglas W. Van; Hettinger, Zachary R.; Vanderklish, Peter W.

doi:10.1152/japplphysiol.00076.2019

Cited by 16 publications

(14 citation statements)

References 91 publications

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“…The suppression of degradation during reloading may be orchestrated by the stabilizing effects of RBPs on rRNA. RBPs may represent a critical node in controlling not only translation programming but also the translational capacity of muscle 61 . As such, we have recently shown that RNA‐binding protein motif −3 induces hypertrophy and attenuates atrophy, which may be due to its role in RNA degradation 63 .…”

Section: Discussionmentioning

confidence: 99%

“…As stated above, mTORC1 is likely involved in regulating ribophagy as mTORC1 activity was rapidly restored during reloading, which coincided with suppressed ribosome degradation. Furthermore, RNA‐binding proteins (RBPs) play a key regulatory role in RNA stability and decay 61, 62 . The suppression of degradation during reloading may be orchestrated by the stabilizing effects of RBPs on rRNA.…”

Section: Discussionmentioning

confidence: 99%

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Ribosome biogenesis and degradation regulate translational capacity during muscle disuse and reloading

Figueiredo

D’Souza

Pelt

et al. 2020

J cachexia sarcopenia muscle

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Background Translational capacity (i.e. ribosomal mass) is a key determinant of protein synthesis and has been associated with skeletal muscle hypertrophy. The role of translational capacity in muscle atrophy and regrowth from disuse is largely unknown. Therefore, we investigated the effect of muscle disuse and reloading on translational capacity in middle‐aged men (Study 1) and in rats (Study 2). Methods In Study 1, 28 male participants (age 50.03 ± 3.54 years) underwent 2 weeks of knee immobilization followed by 2 weeks of ambulatory recovery and a further 2 weeks of resistance training. Muscle biopsies were obtained for measurement of total RNA and pre‐ribosomal (r)RNA expression, and vastus lateralis cross‐sectional area (CSA) was determined via peripheral quantitative computed tomography. In Study 2, male rats underwent hindlimb suspension (HS) for either 24 h (HS 24 h, n = 4) or 7 days (HS 7d, n = 5), HS for 7 days followed by 7 days of reloading (Rel, n = 5) or remained as ambulatory weight bearing (WB, n = 5) controls. Rats received deuterium oxide throughout the study to determine RNA synthesis and degradation, and mTORC1 signalling pathway was assessed. Results Two weeks of immobilization reduced total RNA concentration (20%) and CSA (4%) in men (both P ≤ 0.05). Ambulatory recovery restored total RNA concentration to baseline levels and partially restored muscle CSA. Total RNA concentration and 47S pre‐rRNA expression increased above basal levels after resistance training (P ≤ 0.05). In rats, RNA synthesis was 30% lower while degradation was ~400% higher in HS 7d in soleus and plantaris muscles compared with WB (P ≤ 0.05). mTORC1 signalling was lower in HS compared with WB as was 47S pre‐rRNA (P ≤ 0.05). With reloading, the aforementioned parameters were restored to WB levels while RNA degradation was suppressed (P ≤ 0.05). Conclusions Changes in RNA concentration following muscle disuse and reloading were associated with changes in ribosome biogenesis and degradation, indicating that both processes are important determinants of translational capacity. The pre‐clinical data help explain the reduced translational capacity after muscle immobilization in humans and demonstrate that ribosome biogenesis and degradation might be valuable therapeutic targets to maintain muscle mass during disuse.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ribosome biogenesis and degradation regulate translational capacity during muscle disuse and reloading

Figueiredo

D’Souza

Pelt

et al. 2020

J cachexia sarcopenia muscle

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“…Misregulation of ribonucleic acid (RNA) processing therefore leads to a vast collection of muscle diseases from myotonic dystrophies to cardiomyopathies [10][11][12][13]. Moreover, exercise, adaptation, aging and recovery after injury also involve changes in RNA regulation [14][15][16]. Thus, understanding normal RNA regulatory dynamics in developing muscle is foundational to understanding normal muscle physiology as well as disease.…”

Section: Introductionmentioning

confidence: 99%

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

Kao

Nikonova

Chaabane

et al. 2021

Cells

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The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability among muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing, including alternative splicing, which generates fiber-type specific isoforms of structural proteins that confer contractile sarcomeres with distinct biomechanical properties. Alternative splicing is disrupted in muscle diseases such as myotonic dystrophy and dilated cardiomyopathy and is altered after intense exercise as well as with aging. It is therefore important to understand splicing and RBP function, but currently, only a small fraction of the hundreds of annotated RBPs expressed in muscle have been characterized. Here, we demonstrate the utility of Drosophila as a genetic model system to investigate basic developmental mechanisms of RBP function in myogenesis. We find that RBPs exhibit dynamic temporal and fiber-type specific expression patterns in mRNA-Seq data and display muscle-specific phenotypes. We performed knockdown with 105 RNAi hairpins targeting 35 RBPs and report associated lethality, flight, myofiber and sarcomere defects, including flight muscle phenotypes for Doa, Rm62, mub, mbl, sbr, and clu. Knockdown phenotypes of spliceosome components, as highlighted by phenotypes for A-complex components SF1 and Hrb87F (hnRNPA1), revealed level- and temporal-dependent myofibril defects. We further show that splicing mediated by SF1 and Hrb87F is necessary for Z-disc stability and proper myofibril development, and strong knockdown of either gene results in impaired localization of kettin to the Z-disc. Our results expand the number of RBPs with a described phenotype in muscle and underscore the diversity in myofibril and transcriptomic phenotypes associated with splicing defects. Drosophila is thus a powerful model to gain disease-relevant insight into cellular and molecular phenotypes observed when expression levels of splicing factors, spliceosome components and splicing dynamics are altered.

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“…A recent surge of disease-focused reviews have highlighted the emerging clinical interest for therapeutically targeting RBPs in the setting of: neurodegenerative diseases (Hofmann et al, 2019 ; Nussbacher et al, 2019 ), pain disorders (de la Pena and Campbell, 2018 ), cancer (Pereira et al, 2017 ), immunity (Turner and Díaz-Muñoz, 2018 ), diabetes (Nutter and Kuyumcu-Martinez, 2018 ), muscle wasting (Van Pelt et al, 2019 ), reproductive pathologies (Khalaj et al, 2017 ), cardiovascular disease (de Bruin et al, 2017 ), renal injury (Ignarski et al, 2019 ) and hepatic illness (Lee et al, 2020 ). Increased awareness of RBPs as targets has accelerated efforts to develop therapies that disrupt and/or modulate their activity.…”

Section: Rna-binding Proteins As Therapeutic Targets To Modulate Tranmentioning

confidence: 99%

RNA Binding Motif 5 (RBM5) in the CNS—Moving Beyond Cancer to Harness RNA Splicing to Mitigate the Consequences of Brain Injury

Jackson

Kochanek

2020

Front. Mol. Neurosci.

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Gene splicing modulates the potency of cell death effectors, alters neuropathological disease processes, influences neuronal recovery, but may also direct distinct mechanisms of secondary brain injury. Therapeutic targeting of RNA splicing is a promising avenue for next-generation CNS treatments. RNA-binding proteins (RBPs) regulate a variety of RNA species and are prime candidates in the hunt for druggable targets to manipulate and tailor gene-splicing responses in the brain. RBPs preferentially recognize unique consensus sequences in targeted mRNAs. Also, RBPs often contain multiple RNA-binding domains (RBDs)-each having a unique consensus sequence-suggesting the possibility that drugs could be developed to block individual functional domains, increasing the precision of RBP-targeting therapies. Empirical characterization of most RBPs is lacking and represents a major barrier to advance this emerging therapeutic area. There is a paucity of data on the role of RBPs in the brain including, identification of their unique mRNA targets, defining how CNS insults affect their levels and elucidating which RBPs (and individual domains within) to target to improve neurological outcomes. This review focuses on the state-of-the-art of the RBP tumor suppressor RNA binding motif 5 (RBM5) in the CNS. We discuss its potent pro-death roles in cancer, which motivated our interest to study it in the brain. We review recent studies showing that RBM5 levels are increased after CNS trauma and that it promotes neuronal death in vitro. Finally, we conclude with recent reports on the first set of RBM5 regulated genes identified in the intact brain, and discuss how those findings provide new clues germane to its potential function(s) in the CNS, and pose new questions on its therapeutic utility to mitigate CNS injury.

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RNA-binding proteins: The next step in translating skeletal muscle adaptations?

Cited by 16 publications

References 91 publications

Ribosome biogenesis and degradation regulate translational capacity during muscle disuse and reloading

Ribosome biogenesis and degradation regulate translational capacity during muscle disuse and reloading

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

RNA Binding Motif 5 (RBM5) in the CNS—Moving Beyond Cancer to Harness RNA Splicing to Mitigate the Consequences of Brain Injury

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