Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy
Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy
复制标题
DOI：
10.1152/ajpendo.00472.2014
复制
发表时间：
2015-01-15
影响因子：
5.1
通讯作者：
Adams, Christopher M.
中科院分区：
文献类型：
--
作者：
Bongers, Kale S.;Fox, Daniel K.;Adams, Christopher M.
骨骼肌萎缩是一种常见的使人衰弱的疾病，在分子水平上仍然知之甚少。为了更好地理解肌肉萎缩的机制，我们使用小鼠模型来寻找一种有助于维持肌肉质量的骨骼肌蛋白，这种蛋白在肌肉萎缩期间特别丢失。我们发现肌肉萎缩的多种原因（肢体固定、禁食、肌肉去神经支配和衰老）强烈地降低了精胺氧化酶的表达。重要的是，精胺氧化酶的减少足以诱导肌纤维萎缩。相反，在多种肌肉萎缩模型（固定、禁食和去神经支配）中，精胺氧化酶的强制表达增加了肌纤维的大小。有趣的是，肌肉萎缩过程中精胺氧化酶的减少是由p21介导的，p21是一种在肌肉萎缩过程中高度诱导并积极促进肌肉萎缩的蛋白质。此外，我们发现精胺氧化酶减少了促进肌肉萎缩的骨骼肌mrna（如肌原素），增加了有助于维持肌肉质量的mrna（如丝裂酶-2）。因此，在健康的骨骼肌中，相对低水平的p21允许精胺氧化酶的表达，这有助于维持基础肌基因表达和纤维大小；相反，在引起肌肉萎缩的情况下，p21表达升高，导致精胺氧化酶表达减少，基底肌基因表达中断，肌纤维萎缩。总之，这些结果确定精胺氧化酶是肌肉基因表达和纤维大小的重要正调节因子，并阐明p21介导的精胺氧化酶抑制是骨骼肌萎缩发病机制的关键步骤。
Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy.