Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle
Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle
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DOI：
10.1093/hmg/dds048
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发表时间：
2012-05-15
影响因子：
3.5
通讯作者：
Shore, Gordon C.
中科院分区：
文献类型：
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作者：
Chang, Natasha C.;Mai Nguyen;Shore, Gordon C.
营养剥夺自噬因子-1(NAF-1)是一种与内质网(ER)bcl2相互作用的蛋白，其功能是介导ER bcl2拮抗Beclin 1依赖的自噬和抑制ER钙储存。在人类中，Naf-1(同义词：Cisd2，Eris，Miner1和Noxp70)的点突变是导致神经退行性疾病Wolfram综合征2的原因。在这里，我们描述了Naf-1基因缺失在小鼠中的产生和特征。NAF-1基因缺失的小鼠在23个月大时表现出明显的临床退化迹象，早期证据表明骨骼肌的结构和性能存在显著缺陷。NAF-1基因敲除小鼠的骨骼肌显示出向慢抽动(I型)纤维的显著转变，并对肌肉疲劳有更强的抵抗力。NAF-1(/)肌肉的力量生成能力显著降低。与其在ER、bcl2介导的自噬和钙流量调节中的作用一致，这些生理缺陷伴随着自噬的增强和钙稳态的失调。相反，这也包括线粒体的适应性放大，具有广泛的脊结构。因此，NAF-1，一种与bcl2相关的自噬调节因子，是维持骨骼肌内环境平衡所必需的。我们的发现揭示了一种正常肌肉维持所需的新途径，这最终可能为治疗某些肌肉病理提供新的治疗靶点。
Nutrient-deprivation autophagy factor-1 (NAF-1) was identified as an endoplasmic reticulum (ER) BCL-2-interacting protein, which functions to mediate the ability of ER BCL-2 to antagonize Beclin 1-dependent autophagy and depress ER calcium stores. In humans, a point mutation in Naf-1 (synonyms: Cisd2, Eris, Miner1 and Noxp70) is responsible for the neurodegenerative disorder Wolfram Syndrome 2. Here, we describe the generation and characterization of the Naf-1 gene deletion in mice. Naf-1 null mice display discernable clinical signs of degeneration at 23 months of age, with early evidence of significant defects in the structure and performance of skeletal muscle. Skeletal muscles from Naf-1 knockout mice demonstrate a significant shift towards slow-twitch (type I) fibers and greater resistance to muscle fatigue. Force-generating capacity is dramatically reduced in Naf-1(/) muscle. Consistent with its role in ER BCL-2-mediated regulation of autophagy and calcium flux, these physiological deficiencies were accompanied by augmented autophagy and dysregulated calcium homeostasis. In contrast, this also included adaptive enlargement of mitochondria with extensive cristae structures. Thus, NAF-1, a BCL-2-associated autophagy regulator, is required for homeostatic maintenance of skeletal muscle. Our findings uncover a novel pathway that is required for normal muscle maintenance, which may ultimately provide a novel therapeutic target for treating certain muscle pathologies.