Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Hum Mol Genet. 2012 Oct 15;21(20):4448-59. doi: 10.1093/hmg/dds286. Epub 2012 Jul 13.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by mutations in the survival of motor neuron 1 (SMN1) gene and deficient expression of the ubiquitously expressed SMN protein. Pathologically, SMA is characterized by motor neuron loss and severe muscle atrophy. During muscle atrophy, the E3 ligase atrogenes, atrogin-1 and muscle ring finger 1 (MuRF1), mediate muscle protein breakdown through the ubiquitin proteasome system. Atrogene expression can be induced by various upstream regulators. During acute denervation, they are activated by myogenin, which is in turn regulated by histone deacetylases 4 and 5. Here we show that atrogenes are induced in SMA model mice and in SMA patient muscle in association with increased myogenin and histone deacetylase-4 (HDAC4) expression. This activation during both acute denervation and SMA disease progression is suppressed by treatment with a histone deacetylase inhibitor; however, this treatment has no effect when atrogene induction occurs independently of myogenin. These results indicate that myogenin-dependent atrogene induction is amenable to pharmacological intervention with histone deacetylase inhibitors and help to explain the beneficial effects of these agents on SMA and other denervating diseases.
脊髓性肌萎缩症（SMA）是一种常染色体隐性神经肌肉疾病，由运动神经元生存 1 基因（SMN1）突变和广泛表达的 SMN 蛋白表达不足引起。从病理学角度来看，SMA 的特征是运动神经元丧失和严重的肌肉萎缩。在肌肉萎缩过程中，E3 连接酶肌萎缩基因（atrogin-1 和肌肉环指 1（MuRF1））通过泛素蛋白酶体系统介导肌肉蛋白降解。肌萎缩基因的表达可以被各种上游调节剂诱导。在急性去神经支配时，它们被肌生成素激活，而肌生成素又受到组蛋白去乙酰化酶 4 和 5 的调节。在这里，我们发现，在 SMA 模型小鼠和 SMA 患者的肌肉中，与肌生成素和组蛋白去乙酰化酶 4（HDAC4）表达增加相关，肌萎缩基因被诱导。这种在急性去神经支配和 SMA 疾病进展过程中的激活被组蛋白去乙酰化酶抑制剂的治疗所抑制；然而，当肌萎缩基因的诱导独立于肌生成素发生时，这种治疗没有效果。这些结果表明，肌生成素依赖性肌萎缩基因诱导可通过组蛋白去乙酰化酶抑制剂进行药物干预，并有助于解释这些药物对 SMA 和其他去神经支配疾病的有益作用。
