High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington's disease expansion mutation carriers shows normal mitochondrial respiratory function
High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington's disease expansion mutation carriers shows normal mitochondrial respiratory function
复制标题
DOI：
10.1371/journal.pone.0175248
复制
发表时间：
2017-04-13
期刊：
影响因子：
3.7
通讯作者：
Lindenberg, Katrin S.
中科院分区：
文献类型：
--
作者：
Buck, Eva;Zuegel, Martina;Lindenberg, Katrin S.
线粒体呼吸的改变是亨廷顿氏病（HD）的一个重要标志，亨廷顿氏病是神经变性最常见的单基因原因之一。引起突变亨廷顿蛋白基因的疾病的普遍表达提出了在骨骼肌中检测线粒体呼吸缺陷的前景。虽然这种组织在人类身上很容易获得，但转基因动物模型提供了交叉验证发现的机会，并允许跨器官（包括大脑）进行比较。采用高分辨率呼吸仪（HRR）对7例HD扩增突变前携带者和9例对照者进行细针活检，测量了人股外侧肌的综合呼吸链功能。呼吸参数未受影响。为了进行比较，从HD敲入小鼠（Hdh(Q111)）分离的骨骼肌以及包括皮质、肝脏和心肌在内的更广泛的组织被HRR检查。HdhQ敲入小鼠模型中线粒体呼吸的显著变化仅限于肝脏和皮层。以线粒体DNA拷贝数和柠檬酸合成酶活性量化的线粒体质量在小鼠hd模型组织中与对照组相比是稳定的。测定HdhQ小鼠线粒体代谢途径的关键酶mRNA水平。我们证明了通过小型人类HD肌肉活检进行高分辨率呼吸测量的可行性。此外，我们得出结论，预先表现的人类肌肉活检的呼吸参数的改变是相当有限的，并反映在HdhQ骨骼肌中类似的没有明显的改变。相比之下，Hdh Q111小鼠皮层和肝脏确实显示出呼吸改变，这突出了突变亨廷顿蛋白对呼吸作用的组织特异性。
Alterations in mitochondrial respiration are an important hallmark of Huntington's disease (HD), one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain. The integrated respiratory chain function of the human vastus lateralis muscle was measured by high-resolution respirometry (HRR) in freshly taken fine-needle biopsies from seven pre-manifest HD expansion mutation carriers and nine controls. The respiratory parameters were unaffected. For comparison skeletal muscle isolated from HD knock-in mice (Hdh(Q111)) as well as a broader spectrum of tissues including cortex, liver and heart muscle were examined by HRR. Significant changes of mitochondrial respiration in the HdhQ knock-in mouse model were restricted to the liver and the cortex. Mitochondrial mass as quantified by mitochondrial DNA copy number and citrate synthase activity was stable in murine HD-model tissue compared to control. mRNA levels of key enzymes were determined to characterize mitochondrial metabolic pathways in HdhQ mice. We demonstrated the feasibility to perform high-resolution respirometry measurements from small human HD muscle biopsies. Furthermore, we conclude that alterations in respiratory parameters of pre-manifest human muscle biopsies are rather limited and mirrored by a similar absence of marked alterations in HdhQ skeletal muscle. In contrast, the Hdh Q111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration.