論文 - 詳細
| RRC ID | 15540 |
|---|---|
| 著者 | Melkani GC, Bodmer R, Ocorr K, Bernstein SI. |
| タイトル | The UNC-45 chaperone is critical for establishing myosin-based myofibrillar organization and cardiac contractility in the Drosophila heart model. |
| ジャーナル | PLoS One |
| Abstract |
UNC-45 is a UCS (UNC-45/CRO1/She4P) class chaperone necessary for myosin folding and/or accumulation, but its requirement for maintaining cardiac contractility has not been explored. Given the prevalence of myosin mutations in eliciting cardiomyopathy, chaperones like UNC-45 are likely to be equally critical in provoking or modulating myosin-associated cardiomyopathy. Here, we used the Drosophila heart model to examine its role in cardiac physiology, in conjunction with RNAi-mediated gene silencing specifically in the heart in vivo. Analysis of cardiac physiology was carried out using high-speed video recording in conjunction with movement analysis algorithms. unc-45 knockdown resulted in severely compromised cardiac function in adults as evidenced by prolonged diastolic and systolic intervals, and increased incidence of arrhythmias and extreme dilation; the latter was accompanied by a significant reduction in muscle contractility. Structural analysis showed reduced myofibrils, myofibrillar disarray, and greatly decreased cardiac myosin accumulation. Cardiac unc-45 silencing also dramatically reduced life-span. In contrast, third instar larval and young pupal hearts showed mild cardiac abnormalities, as severe cardiac defects only developed during metamorphosis. Furthermore, cardiac unc-45 silencing in the adult heart (after metamorphosis) led to less severe phenotypes. This suggests that UNC-45 is mostly required for myosin accumulation/folding during remodeling of the forming adult heart. The cardiac defects, myosin deficit and decreased life-span in flies upon heart-specific unc-45 knockdown were significantly rescued by UNC-45 over-expression. Our results are the first to demonstrate a cardiac-specific requirement of a chaperone in Drosophila, suggestive of a critical role of UNC-45 in cardiomyopathies, including those associated with unfolded proteins in the failing human heart. The dilated cardiomyopathy phenotype associated with UNC-45 deficiency is mimicked by myosin knockdown suggesting that UNC-45 plays a crucial role in stabilizing myosin and possibly preventing human cardiomyopathies associated with functional deficiencies of myosin. |
| 巻・号 | 6(7) |
| ページ | e22579 |
| 公開日 | 2011-7-25 |
| DOI | 10.1371/journal.pone.0022579 |
| PII | PONE-D-11-07011 |
| PMID | 21799905 |
| PMC | PMC3143160 |
| MeSH | Animals Animals, Genetically Modified Drosophila Proteins / deficiency Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / cytology* Drosophila melanogaster / metabolism* Drosophila melanogaster / physiology Female Gene Knockdown Techniques Gene Silencing Heart / physiology* Larva / cytology Larva / metabolism Larva / physiology Male Models, Animal Molecular Chaperones / genetics Molecular Chaperones / metabolism* Muscle Contraction* / genetics Myocardium / metabolism Myofibrils / metabolism* Myosin Heavy Chains / deficiency Myosin Heavy Chains / genetics Myosin Heavy Chains / metabolism Myosins / deficiency Myosins / genetics Myosins / metabolism* Sarcomeres / metabolism Sarcomeres / physiology |
| IF | 2.74 |
| 引用数 | 26 |
| WOS 分野 | CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ショウジョウバエ | 2708R-1 2708R-2 17927R-1 |