PTEN Contributes to Profound PI3K/Akt Signaling Pathway Deregulation in Dystrophin-Deficient Dog Muscle

Féron, Marie; Guével, Laëtitia; Rouger, Karl; Dubreil, Laurence; Arnaud, Marie-Claire; Ledevin, Mireille; Megeney, Lynn A.; Chérel, Yan; Sakanyan, Vehary

doi:10.2353/ajpath.2009.080460

Cited by 39 publications

(47 citation statements)

References 54 publications

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“…1B). Protein analysis of Pitpna in muscle tissue confirmed the mRNA findings and showed increased PTEN and decreased pAkt in severely affected GRMD muscle, which has been shown previously (26). Escaper dogs showed the opposite expression pattern (Fig.…”

Section: Grmd Escaper Dogssupporting

confidence: 62%

“…In addition, induction of pAkt is known to play a significant role in muscle growth and metabolism, impacting several downstream target genes that promote muscle hypertrophy (35,36), vascularization (37), and inhibit apoptosis (38). Conversely, aberrant PTEN signaling has been attributed to PI3K/Akt signaling dysregulation in severely affected GRMD dogs, which exhibit depressed Akt activation (26).…”

Section: Pitpna Knockdown In Human Dmd Myoblasts Increases Pakt Andmentioning

confidence: 99%

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Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy

Vieira

Spinazzola

Alexander

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN (DMD) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these "escaper" dogs revealed reduced expression of phosphatidylinositol transfer protein-α (PITPNA) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophindeficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases.Duchenne muscular dystrophy | genetic modifier | phosphatidylinositol transfer protein-α | skeletal muscle D uchenne muscular dystrophy (DMD) is a progressive, X-linked muscle wasting disease caused by mutations in the DYSTROPHIN gene (1, 2). Absence of dystrophin protein from the muscle sarcolemma disrupts the link between the cytoskeleton and extracellular matrix, causing a multitude of pathological effects on muscle mechanics, signaling, and metabolic pathways. These consequences render myofibers susceptible to contractioninduced injury and cause severe muscle degeneration, fibrosis, and inflammation. Patients with DMD typically lose ambulation by age 12, and cardiorespiratory failure leads to premature death by the third decade of life (3). Despite advances in palliative support and ongoing efforts to restore dystrophin expression, there is no cure for DMD. Therefore, identification of potential genetic modifiers, which could be targets for disease therapy and discovery, are of significant interest.Identification of genetic modifiers that reduce the pathogenic features of DMD is an emerging gateway to new therapeutic targets. Modifiers identified include osteopontin, encoded by the SPP1 gene, which ...

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Section: Grmd Escaper Dogssupporting

confidence: 62%

Section: Pitpna Knockdown In Human Dmd Myoblasts Increases Pakt Andmentioning

confidence: 99%

Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy

Vieira

Spinazzola

Alexander

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, prolonged stimulation of schwannoma cells with recombinant IGFBP-1 increases AKT activity ( Figure 6). As PTEN is an important AKT antagonist regulating cell growth (Blanco-Aparicio et al, 2007;Liu et al, 2008;Feron et al, 2009) (Perks et al, 2007), IGFBP-1 also contributes to the downregulation of PTEN (Figure 6). Thus, based on our data we here demonstrate a novel mechanism involved in schwannoma development via autocrine release of IGFBP-1, which downregulates PTEN leading to increased AKT activity and survival of schwannoma cells ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

et al. 2011

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Merlin is a tumour suppressor involved in the development of a variety of tumours including mesotheliomas. Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, is also caused by loss of merlin. NF2 patients suffer from multiple genetically well-defined tumours, schwannomas are most frequent among those. Using our in vitro model for human schwannoma, we found that schwannoma cells display enhanced proliferation because of the overexpression/activation of platelet-derived growth factor receptor and ErbB2/3, increased cell-matrix adhesion because of the overexpression of integrins, and decreased apoptosis. Mechanisms underlying schwannomas basal proliferation and cell-matrix adhesion are not understood. Here, we investigated insulin-like growth factor-binding protein-1 (IGFBP-1), which is expressed and released from central nervous system tumours and strongly overexpressed in schwannoma at the mRNA level. IGFBP-1 acts via b1-integrin and focal-adhesion-kinase (FAK), which are strongly overexpressed and basally activated in schwannoma. Using short hairpin RNA knockdown, small inhibitors and recombinant IGFBP-1, we demonstrate that schwannoma cells, in contrast to Schwann cells, release IGFBP-1 that activates the Src/FAK pathway, via integrin b1, potentiating schwannoma's proliferation and cell-matrix adhesion. We show that FAK localizes to the nucleus and Src triggers IGFBP-1 production. Further, we observed downregulation of the tumour-suppressor phosphatase and tensin homolog in schwannoma cells leading to increased activity of antiapoptotic AKT. Thus, IGFBP-1/integrin b1/Src/FAK pathway has a crucial role in merlin-related tumourigenesis and therefore represents an important therapeutic target in the treatment of merlin-deficient tumours.

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“…One strategy that has shown beneficial effects in dystrophindeficient animal models is the modulation of components of the PTEN/AKT signaling pathway (9)(10)(11). PTEN, a tumor suppressor gene with diverse functions in multiple tissues, is induced in dystrophin-deficient muscle (12)(13)(14). This increase in Pten expression levels is accompanied by a subsequent reduction in phosphorylated Akt, both of which have been shown to regulate glucose and insulin signaling pathways in skeletal muscle (15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Alexander¹,

Casar²,

Matsuki³

et al. 2014

J. Clin. Invest.

126

122

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Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which resultsin dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmd mdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmd mdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle-specific miR-486 overexpression in Dmd mdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle.

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PTEN Contributes to Profound PI3K/Akt Signaling Pathway Deregulation in Dystrophin-Deficient Dog Muscle

Cited by 39 publications

References 54 publications

Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy

Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

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