Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy
Autor: | Genri Kawahara, Matthew S. Alexander, Mayana Zatz, Lillian Mead, Yuri B Moreira, Sergio Verjovski-Almeida, Natássia M. Vieira, Janelle M. Spinazzola, Louis M. Kunkel, Devin E. Gibbs |
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Rok vydání: | 2017 |
Předmět: |
musculoskeletal diseases
0301 basic medicine congenital hereditary and neonatal diseases and abnormalities Pathology medicine.medical_specialty Duchenne muscular dystrophy Muscle Fibers Skeletal MÚSCULO ESQUELÉTICO macromolecular substances Biology Cell Line Dystrophin 03 medical and health sciences Myoblast fusion Dogs 0302 clinical medicine medicine Animals Humans PTEN Phospholipid Transfer Proteins Phosphorylation Muscle Skeletal Zebrafish Muscle Cells Gene knockdown Multidisciplinary Sarcolemma Myogenesis Skeletal muscle Biological Sciences Muscular Dystrophy Animal medicine.disease Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology medicine.anatomical_structure Mutation biology.protein Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery |
Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
ISSN: | 1091-6490 0027-8424 |
Popis: | 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, dystrophin-deficient 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. |
Databáze: | OpenAIRE |
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