<scp>hnRNP L</scp> is essential for myogenic differentiation and modulates myotonic dystrophy pathologies

Alexander, Matthew S.; Hightower, Rylie M; Reid, Andrea L.; Bennett, Alexis H; Iyer, Lakshmanan K.; Slonim, Donna K.; Saha, Madhurima; Kawahara, Genri; Kunkel, Louis M.; Kopin, Alan S.; Gupta, Vandana; Kang, Peter B.; Draper, Isabelle

doi:10.1002/mus.27216

Cited by 10 publications

(7 citation statements)

References 74 publications

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“…DDX5 may directly interact with hnRNP F/H and facilitate its binding to highly structured G-quadruplex-enriched regions, thus initiating myoblast-specific splicing programs and regulating myogenic differentiation ( Dardenne et al, 2014 ). In DM1 muscles, hnRNP L may regulate the same targets as MBNL1, which is consistent with the their physical interaction ( Alexander et al, 2021 ). It is also of note that RBM24 interacts with several RBPs of the cytoplasmic polyadenylation complex, including PABPC1 and CPEB4, to regulate poly(A) tail length ( Shao et al, 2020 ).…”

Section: Functional Interactions Between Rna-binding Proteins Coordinate Gene Expression During Myogenesissupporting

confidence: 70%

“…Its expression level increases during myogenic differentiation in normal human myoblasts. Knockdown of hnRNP L in zebrafish and human cell lines reduces muscle birefringence and impairs myoblast fusion, respectively ( Alexander et al, 2021 ). Moreover, hnRNP L may be also involved in maintaining muscle homeostasis and in modulating DM1 pathologies because it complexes with MBNL1 and forms nuclear protein aggregates in DM1 myoblasts, which partially colocalize with toxic CUG repeats.…”

Section: Rna-binding Proteins Involved In Skeletal Muscle Development Regeneration and Diseasementioning

confidence: 99%

“…Moreover, hnRNP L may be also involved in maintaining muscle homeostasis and in modulating DM1 pathologies because it complexes with MBNL1 and forms nuclear protein aggregates in DM1 myoblasts, which partially colocalize with toxic CUG repeats. Bioinformatic analysis reveals that hnRNP L may regulate the expression of multiple target genes that are aberrantly spliced due to loss of MBNL1 activity in DM1 muscle ( Alexander et al, 2021 ), but these in silico data need experimental validation.…”

Section: Rna-binding Proteins Involved In Skeletal Muscle Development Regeneration and Diseasementioning

confidence: 99%

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RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Shi

Grifone

2021

Front. Cell Dev. Biol.

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Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations.

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Section: Functional Interactions Between Rna-binding Proteins Coordinate Gene Expression During Myogenesissupporting

confidence: 70%

Section: Rna-binding Proteins Involved In Skeletal Muscle Development Regeneration and Diseasementioning

confidence: 99%

Section: Rna-binding Proteins Involved In Skeletal Muscle Development Regeneration and Diseasementioning

confidence: 99%

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RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Shi

Grifone

2021

Front. Cell Dev. Biol.

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“…Previous studies indicated that MBNL1 is downregulated in DM1 models and patients, and the overexpression of MBNL1 is beneficial in murine disease models [ 5 , 12 ]. Various drugs and epigenetic approaches have been found to promote endogenous MBNL1 expression and ameliorate the disease phenotypes in different experimental models [ 31 – 34 ]. In the current study, we identified that calcitriol (active form of vitamin D3) elevated MBNL1 expression in mouse myogenic cells and in skeletal muscles of HSA LR mouse model via enhancing the Mbnl1 promoter activity.…”

Section: Discussionmentioning

confidence: 99%

Calcitriol increases MBNL1 expression and alleviates myotonic dystrophy phenotypes in HSALR mouse models

Huang

Wang

et al. 2022

J Transl Med

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Background Myotonic dystrophy type 1 (DM1), one of the most common forms of adult-onset muscular dystrophy, is caused by abnormally expanded CTG repeats in the 3′ untranslated region of the DMPK gene. The CUG repeats transcribed from the expanded CTG repeats sequestrate a splicing factor, MBNL1, causing the clinical symptoms in DM1. Nowadays, only symptomatic treatments are available for DM1, and no rational therapy is available. Recently, upregulation of MBNL1 expression has been found to be one of the promising therapies for DM1. Methods All experiments were conducted in the C2C12 myoblasts and HSALR mice, a DM1 mouse model. Real-time PCR and western blot were used to detect the mRNA and protein level, respectively. The rotarod exercise, grip strength and hanging time were used to evaluate the muscle strength of mice. Results In this study, we demonstrated that calcitriol, an active form of vitamin D3, increased MBNL1 in C2C12 mouse myoblasts as well as in HSALR mice model for DM1. In HSALR mice model, calcitriol improved muscle strength, and corrected aberrant splicing in skeletal muscle. Besides, calcitriol reduced the number of central nuclei, and improved muscle histopathology in HSALR mice. In addition, we identified that calcitriol upregulated MBNL1 expression via activating the promoter of Mbnl1 in C2C12 myogenic cells. Conclusion Our study suggests that calcitriol is a potential pharmacological strategy for DM1 that enhances MBNL1 expression.

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“…The disruption of this careful balance can lead to aberrant gene expression, which in turn can contribute to prominent complex diseases such as cancer [6][7][8][9]. Mutations in RBPs have also been directly linked to a variety of inherited human diseases, which includes orphan diseases [6], such as mutations in fragile X mental retardation protein (FMRP) leading to fragile X-associated tremor/ataxia syndrome (FXTAS) [10], and muscleblind-like 1 (MBNL1) in myotonic dystrophy type 1 [11]. Interestingly, the top Mendelian disorders affected by RBP mutations tend to be diseases of the nervous system, pathologies of the metabolism, and cell proliferation disorders including certain cancers [6].…”

Section: Introductionmentioning

confidence: 99%

RNA-binding proteins modulate drug sensitivity of cancer cells

Rogoyski

Gerber

2021

Emerging Topics in Life Sciences

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As our understanding of the complex network of regulatory pathways for gene expression continues to grow, avenues of investigation for how these new findings can be utilised in therapeutics are emerging. The recent growth of interest in the RNA binding protein (RBP) interactome has revealed it to be rich in targets linked to, and causative of diseases. While this is, in and of itself, very interesting, evidence is also beginning to arise for how the RBP interactome can act to modulate the response of diseases to existing therapeutic treatments, especially in cancers. Here we highlight this topic, providing examples of work that exemplifies such modulation of chemotherapeutic sensitivity.

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hnRNP L is essential for myogenic differentiation and modulates myotonic dystrophy pathologies

Cited by 10 publications

References 74 publications

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Calcitriol increases MBNL1 expression and alleviates myotonic dystrophy phenotypes in HSALR mouse models

RNA-binding proteins modulate drug sensitivity of cancer cells

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