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

PLoS One. 2017 Apr 13;12(4):e0175248. doi: 10.1371/journal.pone.0175248. eCollection 2017.


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.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Biopsy, Fine-Needle
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Female
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease* / genetics
  • Huntington Disease* / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Mitochondria, Muscle* / genetics
  • Mitochondria, Muscle* / metabolism
  • Muscle, Skeletal / metabolism*
  • Mutation*
  • Oxygen Consumption*


  • DNA, Mitochondrial
  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein

Grant support

This work was supported by the Virtual Helmholtz Institute “RNA dysmetabolism in Amyotrophic lateral sclerosis and frontotemporal dementia” (AW), the seed fund grant of the EINSTEIN study from the European Huntington's disease network (no 584/14, https://www.euro-hd.net/, MZ KL EC) and the Deutsche Forschungsgemeinschaft (GRK1789 Cellular and molecular mechanisms of aging, AW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.