BACKGROUND Wolfram syndrome (WS), caused by mutations in WFS1 gene, is a multi-targeting disease affecting multiple organ systems. Wolframin is localized in the membrane of the endoplasmic reticulum (ER), influencing Ca2+ metabolism and ER interaction with mitochondria, but the exact role of the protein remains unclear. In this study we aimed to characterize alterations in energy metabolism in the cardiac and in the oxidative and glycolytic skeletal muscles in Wfs1-deficiency. METHODS Alterations in the bioenergetic profiles in the cardiac and skeletal muscles of Wfs1-knock-out (KO) male mice and their wild type male littermates were determined using high resolution respirometry, quantitative RT-PCR, NMR spectroscopy, and immunofluorescence confocal microscopy. RESULTS Oxygen consumption without ATP synthase activation (leak) was significantly higher in the glycolytic muscles of Wfs1 KO mice compared to wild types. ADP-stimulated respiration with glutamate and malate was reduced in the Wfs1-deficient cardiac as well as oxidative and glycolytic skeletal muscles. CONCLUSIONS Wfs1-deficiency in both cardiac and skeletal muscles results in functional alterations of energy transport from mitochondria to ATP-ases. There was a substrate-dependent decrease in the maximal Complex I -linked respiratory capacity of the electron transport system in muscles of Wfs1 KO mice. Moreover, in cardiac and gastrocnemius white muscles a decrease in the function of one pathway were balanced by the increase in the activity of the parallel pathway. GENERAL SIGNIFICANCE This work provides new insights to the muscle involvement at early stages of metabolic syndrome like WS as well as developing glucose intolerance.

中文翻译：

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横纹肌适应小鼠Wolframin缺乏症：细胞生物能学的改变。

背景技术由WFS1基因突变引起的Wolfram综合征（WS）是一种影响多个器官系统的多目标疾病。Wolframin位于内质网（ER）的膜中，影响Ca2 +代谢和ER与线粒体的相互作用，但该蛋白的确切作用仍不清楚。在这项研究中，我们旨在表征Wfs1缺乏症的心肌以及氧化和糖酵解骨骼肌能量代谢的变化。方法使用高分辨率呼​​吸测定法，定量RT-PCR，NMR光谱和免疫荧光共聚焦显微镜测定Wfs1基因敲除（KO）雄性小鼠及其野生型雄性同窝仔小鼠的心肌和骨骼肌生物能谱的变化。结果与野生型相比，Wfs1 KO小鼠的糖酵解肌肉中没有ATP合酶激活（泄漏）的耗氧量显着更高。在缺乏Wfs1的心肌以及氧化性和糖酵解性骨骼肌中，谷氨酸和苹果酸引起的ADP刺激的呼吸作用减少。结论心肌和骨骼肌中的Wfs1缺乏导致从线粒体到ATP酶的能量转运功能改变。在Wfs1 KO小鼠的肌肉中，电子传输系统的最大复合物I关联最大呼吸能力存在底物依赖性降低。此外，在心脏和腓肠肌的白肌肉中，一种途径功能的降低可通过平行途径活性的增加来平衡。