Muscle-specific SIRT1 gain-of-function increases slow-twitch fibers and ameliorates pathophysiology in a mouse model of duchenne muscular dystrophy.
Muscle-specific SIRT1 gain-of-function increases slow-twitch fibers and ameliorates pathophysiology in a mouse model of duchenne muscular dystrophy.
复制标题
DOI：
10.1371/journal.pgen.1004490
复制
发表时间：
2014-07
期刊：
影响因子：
4.5
通讯作者：
Guarente L
中科院分区：
文献类型：
--
作者：
Chalkiadaki A;Igarashi M;Nasamu AS;Knezevic J;Guarente L
SIRT 1是多种哺乳动物组织中的代谢传感器和调节器，其功能是抵抗代谢和年龄相关疾病。在这里，我们生成并分析了在骨骼肌中特异性高水平表达SIRT 1的小鼠。我们发现，SIRT 1转基因肌肉表现出从快到慢的纤维转变，PGC-1α水平的增加，氧化代谢和线粒体生物发生的标志物，以及萎缩基因程序的表达减少。为了检查SIRT 1活性的增加是否可以防止肌肉萎缩症（一种肌肉退行性疾病），我们将SIRT 1肌肉转基因小鼠与mdx小鼠杂交，mdx小鼠是杜氏肌营养不良症的遗传模型。肌肉中SIRT 1的过度表达逆转了mdx小鼠的表型，如通过组织学、肌酸激酶释放到血液中以及跑步机运动中的耐力所确定的。此外，SIRT 1过表达还导致utrophin（肌营养不良蛋白的功能类似物）水平升高，以及PGC-1α靶基因和神经肌肉接头基因表达升高。基于这些发现，我们认为激活骨骼肌中SIRT 1的药物干预可能为治疗肌肉疾病提供一种新的方法。骨骼肌在身体姿势、移动性和全身代谢中起着核心作用。SIRT 1是一种在骨骼肌和大多数哺乳动物组织中表达的酶，已被证明可以感知来自环境的代谢线索，并介导这些组织的变化，从而抵消年龄和代谢疾病。在这里，我们产生并研究了在骨骼肌中表达高水平SIRT 1的小鼠。我们发现，骨骼肌中SIRT 1水平的增加导致基因表达的变化与耐力运动中通常发生的变化相似。我们还观察到，SIRT 1过表达抵消肌肉萎缩，肌肉老化的标志，和肌肉退行性疾病杜氏肌营养不良症（DMD）。DMD是一种由结构蛋白肌营养不良蛋白突变引起的衰弱性疾病。SIRT 1过表达改善了小鼠模型中DMD疾病的病理生理学。我们的研究结果提供了组成性激活SIRT 1酶活性的药物可能用于治疗肌肉退行性疾病的希望。
SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1α, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1α targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases. Skeletal muscle has a central role in body posture, mobility and whole-body metabolism. SIRT1 is an enzyme expressed in skeletal muscle, as well as in most mammalian tissues, and has been shown to sense metabolic cues from the environment and mediate changes in these tissues, counteracting age and metabolic diseases. Here we generated and studied mice that express high levels of SIRT1 in skeletal muscle. We found that increased levels of SIRT1 in skeletal muscle led to gene expression changes similar to those that normally occur with endurance exercise. We also observed that SIRT1 overexpression counteracts muscle atrophy, a hallmark of aging muscle, and the muscle degenerative disease Duchenne muscular dystrophy (DMD). DMD is a debilitating disease caused by a mutation in the structural protein dystrophin. SIRT1 overexpression ameliorated the pathophysiology of DMD disease in a mouse model. Our results offer the hope that drugs that constitutively activate the enzymatic activity of SIRT1 might be used to cure muscle degenerative diseases.
登录
查看更多内容
影响因子：
15.8
作者：
Civitarese AE;Carling S;Heilbronn LK;Hulver MH;Ukropcova B;Deutsch WA;Smith SR;Ravussin E;CALERIE Pennington Team
通讯作者：
CALERIE Pennington Team
影响因子：
29
作者：
Chalkiadaki A;Guarente L
通讯作者：
Guarente L
影响因子：
10.5
作者：
Chen, Danica;Bruno, Joanne;Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
16
作者：
Bruning, JC;Michael, MD;Kahn, CR
通讯作者：
Kahn, CR
抗肌萎缩蛋白在小鼠骨骼、心脏和平滑肌中的亚细胞分布。
DOI：
10.1083/jcb.115.2.411
发表时间：
1991-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Byers TJ;Kunkel LM;Watkins SC
通讯作者：
Watkins SC