Dystrophin Dp71 Subisoforms Localize to the Mitochondria of Human Cells

Niba, Emma Tabe Eko; Awano, Hiroyuki; Lee, Tomoko; Takeshima, Yasuhiro; Shinohara, Masakazu; Nishio, Hisahide; Matsuo, Masafumi

doi:10.3390/life11090978

Cited by 3 publications

(3 citation statements)

References 70 publications

(95 reference statements)

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“…The Dp71 protein was found in the skeletal muscles of DMDdel8-50 mice, but not DMDdel8-34 mice, similar to previously obtained in-frame models [38,49]. Dp71 upregulation was also found in DMD patients' muscle samples [50]. Dp71 is known to be widespread, with a high prevalence in nervous tissue.…”

Section: Discussionsupporting

confidence: 87%

In-Frame Deletion of Dystrophin Exons 8–50 Results in DMD Phenotype

Егорова

Galkin

Velyaev

et al. 2023

IJMS

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Mutations that prevent the production of proteins in the DMD gene cause Duchenne muscular dystrophy. Most frequently, these are deletions leading to reading-frame shift. The “reading-frame rule” states that deletions that preserve ORF result in a milder Becker muscular dystrophy. By removing several exons, new genome editing tools enable reading-frame restoration in DMD with the production of BMD-like dystrophins. However, not every truncated dystrophin with a significant internal loss functions properly. To determine the effectiveness of potential genome editing, each variant should be carefully studied in vitro or in vivo. In this study, we focused on the deletion of exons 8–50 as a potential reading-frame restoration option. Using the CRISPR-Cas9 tool, we created the novel mouse model DMDdel8-50, which has an in-frame deletion in the DMD gene. We compared DMDdel8-50 mice to C57Bl6/CBA background control mice and previously generated DMDdel8-34 KO mice. We discovered that the shortened protein was expressed and correctly localized on the sarcolemma. The truncated protein, on the other hand, was unable to function like a full-length dystrophin and prevent disease progression. On the basis of protein expression, histological examination, and physical assessment of the mice, we concluded that the deletion of exons 8–50 is an exception to the reading-frame rule.

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Section: Discussionsupporting

confidence: 87%

In-Frame Deletion of Dystrophin Exons 8–50 Results in DMD Phenotype

Егорова

Galkin

Velyaev

et al. 2023

IJMS

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“…These functions include transmitting forces during contraction by connecting the internal cytoskeleton with the extracellular matrix (muscle cells), establishing cell polarity (satellite cells), maturation of neurotransmitter receptor complexes and their release regulation at the neuro-muscular junctions (NMJs) and central synapses (nervous system), and binding several regulatory proteins important in signal transduction inside the cell and between different cell types. Some dystrophins were also found in non-subplasmalemmal localizations, including the nucleus, mitochondria, and cytoplasm [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Dystrophin- and Utrophin-Based Therapeutic Approaches for Treatment of Duchenne Muscular Dystrophy: A Comparative Review

Szwec,

Kapłucha,

Chamberlain

et al. 2023

BioDrugs

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Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.

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“…The carboxy-terminal isoform Dp71, which is expressed ubiquitously, has been linked to myoblast proliferation [ 13 ] and neural stem/progenitor cell proliferation and differentiation [ 14 ]. This isoform has been shown to localize within and closely around the nucleus of PC12, HeLa, C2C12 and HEK293 cells and human myoblasts [ 13 , 15 , 16 , 17 , 18 , 19 ], but also to mitochondria [ 20 ]. Depletion of Dp71 alters the distribution of aquaporin-4 channels in brain macroglial cells, but the question of which function Dp71 fulfils in the nucleus and how stable it appears there remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Small Dystrophin Isoforms during Muscle Differentiation

Donandt

Todorow

Hintze

et al. 2023

Life

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Mutations in the DMD gene can cause Duchenne or Becker muscular dystrophy (DMD/BMD) by affecting the giant isoform of dystrophin, a protein encoded by the DMD gene. The role of small dystrophin isoforms is not well investigated yet, and they may play a role in muscle development and molecular pathology. Here, we investigated the nuclear localization of short carboxy-terminal dystrophin isoforms during the in vitro differentiation of human, porcine, and murine myoblast cultures. We could not only confirm the presence of Dp71 in the nucleoplasm and at the nuclear envelope, but we could also identify the Dp40 isoform in muscle nuclei. The localization of both isoforms over the first six days of differentiation was similar between human and porcine myoblasts, but murine myoblasts behaved differently. This highlights the importance of the porcine model in investigating DMD. We could also detect a wave-like pattern of nuclear presence of both Dp71 and Dp40, indicating a direct or indirect involvement in gene expression control during muscle differentiation.

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Dystrophin Dp71 Subisoforms Localize to the Mitochondria of Human Cells

Cited by 3 publications

References 70 publications

In-Frame Deletion of Dystrophin Exons 8–50 Results in DMD Phenotype

In-Frame Deletion of Dystrophin Exons 8–50 Results in DMD Phenotype

Dystrophin- and Utrophin-Based Therapeutic Approaches for Treatment of Duchenne Muscular Dystrophy: A Comparative Review

Nuclear Small Dystrophin Isoforms during Muscle Differentiation

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