Metabolic Dysfunction and Altered Mitochondrial Dynamics in the Utrophin-Dystrophin Deficient Mouse Model of Duchenne Muscular Dystrophy
Metabolic Dysfunction and Altered Mitochondrial Dynamics in the Utrophin-Dystrophin Deficient Mouse Model of Duchenne Muscular Dystrophy
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DOI：
10.1371/journal.pone.0123875
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发表时间：
2015-04-10
期刊：
影响因子：
3.7
通讯作者：
Periasamy, Muthu
中科院分区：
文献类型：
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作者：
Pant, Meghna;Sopariwala, Danesh H.;Periasamy, Muthu
DKO小鼠模型已被广泛用于了解Duchenne肌营养不良症(DMD)的进展。然而，目前还不清楚肌肉病理对新陈代谢的影响程度。因此，本研究旨在了解整个动物和离体趾长伸肌(EDL)的能量消耗，并测定代谢酶的变化。我们的结果表明，8周龄的DKO小鼠相对于活动水平消耗更高的氧气。有趣的是，DKO小鼠的EDL肌肉单位整合力消耗的氧气更高，产生的力更少，在丙酮酸存在的情况下表现更好，从而模仿缓慢的抽动肌肉。我们还发现己糖激酶1和丙酮酸激酶M2的表达上调了几倍，这表明糖酵解通量增加。此外，动力蛋白相关蛋白1(DRP 1)和丝裂蛋白2蛋白水平显著增加，表明线粒体分裂和融合增加，这一特征与能量需求增加和线粒体动力学改变有关。总而言之，我们的研究指出，营养不良疾病导致了肌肉代谢的显着变化。为了满足增加的能量需求，在营养不良的肌肉中观察到代谢酶和线粒体融合和分裂的调节器的上调。更好地了解营养不良肌肉的代谢需求和伴随的变化有助于我们在现有药物治疗的基础上为DMD患者设计改进的干预疗法。
The utrophin-dystrophin deficient (DKO) mouse model has been widely used to understand the progression of Duchenne muscular dystrophy (DMD). However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was focused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL) muscle and to determine changes in metabolic enzymes. Our results show that the 8 week-old DKO mice consume higher oxygen relative to activity levels. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Additionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1) and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our studies point out that the dystrophic disease has caused significant changes in muscle metabolism. To meet the increased energetic demand, upregulation of metabolic enzymes and regulators of mitochondrial fusion and fission is observed in the dystrophic muscle. A better understanding of the metabolic demands and the accompanied alterations in the dystrophic muscle can help us design improved intervention therapies along with existing drug treatments for the DMD patients.