High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington’s disease expansion mutation carriers shows normal mitochondrial respiratory function

• Published in: PloS one Vol. 12; no. 4; p. e0175248
• Main Authors: Buck, Eva, Zügel, Martina, Schumann, Uwe, Merz, Tamara, Gumpp, Anja M., Witting, Anke, Steinacker, Jürgen M., Landwehrmeyer, G. Bernhard, Weydt, Patrick, Calzia, Enrico, Lindenberg, Katrin S.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.04.2017; Public Library of Science (PLoS)
• Subjects: Abdomen; Accessibility; Adenocarcinoma; Adult; Aged; Aging; Aging (artificial); Animal models; Animals; Atrophy; Biochemical markers; Biochemistry; Bioenergetics; Biology and Life Sciences; Biomarkers; Biopsy; Biopsy, Fine-Needle; Brain; Calcium; Calcium permeability; Cardiac muscle; Care and treatment; Carriers; Cell death; Central nervous system; Chorea; Citrate synthase; Control theory; Cortex; Cytochrome; Defects; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Enzymatic activity; Excitotoxicity; Expansion; Female; Food intake; Gene expression; Genetic aspects; Heart; Heart diseases; High resolution; Histopathology; Human subjects; Humans; Huntingtin Protein - genetics; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington's disease; Huntingtons disease; Identification methods; Inhibition; Liver; Male; Medical research; Medicine; Medicine and Health Sciences; Metabolism; Mice; Mice, Transgenic; Middle Aged; Mitochondria; Mitochondria, Muscle - genetics; Mitochondria, Muscle - metabolism; Mitochondrial DNA; Mortality; Movement disorders; Muscle, Skeletal - metabolism; Musculoskeletal system; Mutation; Neostriatum; Nervous system; Neurodegenerative diseases; Neurology; Organs; Oxidative phosphorylation; Oxygen Consumption; Permeability; Physiological aspects; Platelets; Proteins; Rehabilitation; Research and Analysis Methods; Respiration; Respiratory function; Risk factors; Rodents; Skeletal muscle; Studies; Tissues; Translocation; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0175248

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 (HdhQ111) 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 HdhQ111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration.