A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle.
A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle.
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DOI：
10.1126/science.aad4076
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发表时间：
2016-01-15
期刊：
影响因子：
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通讯作者：
Olson EN
中科院分区：
文献类型：
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作者：
Nelson BR;Makarewich CA;Anderson DM;Winders BR;Troupes CD;Wu F;Reese AL;McAnally JR;Chen X;Kavalali ET;Cannon SC;Houser SR;Bassel-Duby R;Olson EN
肌肉收缩依赖于肌浆网（SR）释放的Ca 2+和Ca 2+三磷酸腺苷酶SERCA的再摄取。我们发现了一个假定的肌肉特异性长非编码RNA，编码一个34个氨基酸的肽，我们命名为侏儒开放阅读框架（DWORF）。DWORF定位于SR膜，在那里它通过置换SERCA抑制剂受磷蛋白、肌磷脂和肌调节蛋白来增强SERCA活性。在小鼠中，心肌细胞中DWORF的过表达增加了峰值Ca 2+瞬时振幅和SR Ca 2+负荷，同时降低了每个收缩-舒张周期中细胞溶质Ca 2+衰减的时间常数。相反，缺乏DWORF的慢骨骼肌表现出延迟的Ca 2+清除和松弛以及降低的SERCA活性。DWORF是已知通过物理相互作用激活SERCA泵的唯一内源性肽，并提供了增强肌肉收缩性的手段。
Muscle contraction depends on release of Ca2+ from the sarcoplasmic reticulum (SR) and reuptake by the Ca2+adenosine triphosphatase SERCA. We discovered a putative muscle-specific long noncoding RNA that encodes a peptide of 34 amino acids and that we named dwarf open reading frame (DWORF). DWORF localizes to the SR membrane, where it enhances SERCA activity by displacing the SERCA inhibitors, phospholamban, sarcolipin, and myoregulin. In mice, overexpression of DWORF in cardiomyocytes increases peak Ca2+ transient amplitude and SR Ca2+ load while reducing the time constant of cytosolic Ca2+ decay during each cycle of contraction-relaxation. Conversely, slow skeletal muscle lacking DWORF exhibits delayed Ca2+ clearance and relaxation and reduced SERCA activity. DWORF is the only endogenous peptide known to activate the SERCA pump by physical interaction and provides a means for enhancing muscle contractility.