Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR8195, Orsay F-91405, France.
Hum Mol Genet. 2012 May 15;21(10):2263-76. doi: 10.1093/hmg/dds047. Epub 2012 Feb 15.
Dystrophin, the protein responsible for X-linked Duchenne muscular dystrophy (DMD), is normally expressed in both muscle and brain, which explains that its loss also leads to cognitive deficits. The utrophin protein, an autosomal homolog, is a natural candidate for dystrophin replacement in patients. Pharmacological upregulation of endogenous utrophin improves muscle physiology in dystrophin-deficient mdx mice, and represents a potential therapeutic tool that has the advantage of allowing delivery to various organs following peripheral injections. Whether this could alleviate cognitive deficits, however, has not been explored. Here, we first investigated basal expression of all utrophins and dystrophins in the brain of mdx mice and found no evidence for spontaneous compensation by utrophins. Then, we show that systemic chronic, spaced injections of arginine butyrate (AB) alleviate muscle alterations and upregulate utrophin expression in the adult brain of mdx mice. AB selectively upregulated brain utrophin Up395, while reducing expression of Up113 and Up71. This, however, was not associated with a significant improvement of behavioral functions typically affected in mdx mice, which include exploration, emotional reactivity, spatial and fear memories. We suggest that AB did not overcome behavioral and cognitive dysfunctions because the regional and cellular expression of utrophins did not coincide with dystrophin expression in untreated mice, nor did it in AB-treated mice. While treatments based on the modulation of utrophin may alleviate DMD phenotypes in certain organs and tissues that coexpress dystrophins and utrophins in the same cells, improvement of cognitive functions would likely require acting on specific dystrophin-dependent mechanisms.
肌营养不良蛋白（dystrophin）是导致 X 连锁型杜氏肌营养不良症（Duchenne muscular dystrophy，DMD）的蛋白，正常情况下在肌肉和大脑中均有表达，这也解释了其缺失会导致认知缺陷。肌联蛋白（utrophin）是一种常染色体同源蛋白，是 DMD 患者肌营养不良蛋白替代治疗的天然候选蛋白。内源性肌联蛋白的药理学上调可改善肌营养不良蛋白缺陷型 mdx 小鼠的肌肉生理学，这代表一种有潜力的治疗工具，其优势在于外周注射后可递送至多种器官。然而，这种方法是否能缓解认知缺陷尚未得到探索。在此，我们首先研究了 mdx 小鼠大脑中所有肌联蛋白和肌营养不良蛋白的基础表达情况，未发现肌联蛋白自发代偿的证据。然后，我们发现系统慢性、间隔注射丁酸钠（arginine butyrate，AB）可改善 mdx 小鼠的肌肉改变并上调成年大脑中的肌联蛋白表达。AB 选择性地上调大脑肌联蛋白 Up395，同时降低 Up113 和 Up71 的表达。但这与 mdx 小鼠的行为功能（包括探索、情绪反应、空间和恐惧记忆）的显著改善无关。我们认为 AB 没有克服行为和认知功能障碍，因为在未经处理的小鼠中，肌联蛋白的区域和细胞表达与未处理小鼠中肌营养不良蛋白的表达不一致，在 AB 处理的小鼠中也不一致。虽然基于肌联蛋白调节的治疗可能会缓解在某些同时表达肌营养不良蛋白和肌联蛋白的器官和组织中的 DMD 表型，但认知功能的改善可能需要针对特定的依赖于肌营养不良蛋白的机制。
