Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin.
Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin.
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DOI：
10.1186/2044-5040-4-2
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发表时间：
2014-01-22
期刊：
影响因子：
4.9
通讯作者：
Arany Z
中科院分区：
文献类型：
--
作者：
Chan MC;Rowe GC;Raghuram S;Patten IS;Farrell C;Arany Z
杜兴氏肌营养不良症(DMD)在美国困扰着100万男孩，几乎没有有效的治疗方法。在DMD的小鼠“mdx”模型中，转录共激活物过氧化物酶体增殖物激活受体γ共激活物-1α的组成性转基因表达改善了骨骼肌功能，但这是如何发生的，或者它是否会在出生后发生，尚不清楚。关于pGC-1α益处的主要机制假说包括诱导滋养蛋白、抗肌营养不良蛋白同系物和/或诱导和稳定神经肌肉接头。通过不同的骨骼肌结构和功能分析，观察pGC-1β基因在mdx小鼠体内的转基因过表达对mdx小鼠骨骼肌结构和功能的影响。为了正式验证pGC-1α通过诱导滋养素和稳定神经肌肉接头而对mdx小鼠有益的假设，将pgc-1α转基因动物与更严重的营养不良模型dstrophin utroin双敲除(mdx/ucn-/-)小鼠杂交。最后，我们还检测了出生后诱导骨骼肌特异性pGC-1α过表达对mdx小鼠肌肉结构和功能的影响。我们在这里表明，当pGC-1β在小鼠骨骼肌中转基因表达时，不会诱导utroin或其他神经肌肉基因的表达。然而，令人惊讶的是，转基因pGC-1β可以和pGC-1α一样有效地保护营养不良症小鼠的肌肉退化，这表明存在替代的保护机制。当pGC-1α在mdx/UTUN-/-小鼠中过表达时，我们发现pGC-1α即使在没有中营养素的情况下也能显著改善肌肉损伤。最后，我们还使用了可诱导的骨骼肌特异性PGC-1α的过度表达来表明PGC-1α即使在出生后被激活也可以预防营养不良，这是一种更合理的治疗选择。这些数据表明，pGC-1α可以改善出生后肌肉营养不良，突出其治疗潜力。数据还显示，pGC-1α在受影响更严重的mdx/UTUN-/-小鼠中同样具有保护作用，这更接近地概括了DMD患者肌肉损伤的侵袭性进展。这些数据还表明，pGC-1β是一种新的潜在靶点，在预防肌肉营养不良方面同样有效。最后，数据还表明，pGC-1α和pGC-1β对营养不良的保护作用不依赖于营养素或神经肌肉连接的诱导，这表明存在其他机制。
Duchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α improves skeletal muscle function in the murine “mdx” model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1α include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction. The effects of transgenic overexpression of PGC-1β, a homolog of PGC-1α in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1α confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1α transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1α overexpression on muscle structure and function in mdx mice. We show here that PGC-1β does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1β transgenesis protects as efficaciously as PGC-1α against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1α is overexpressed in mdx/utrn-/- mice, we find that PGC-1α dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1α overexpression to show that PGC-1α can protect against dystrophy even if activated post-natally, a more plausible therapeutic option. These data demonstrate that PGC-1α can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1α is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1β as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1α and PGC-1β protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.
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