LAUSR

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by hyperkinesia with choreatic movements, cachexia, and impaired cognitive function. HD is caused by the expansion of a CAG repeat in the gene encoding the protein huntingtin, which is also present in peripheral tissues including skeletal muscle. Despite considerable progress in the comprehension of the pathophysiology of HD, the role of huntingtin and according pathomechanisms in peripheral tissues still remain elusive. A possible cause for muscular dysfunction might be metabolic alterations. In particular, impaired mitochondrial function has been proposed to be a major pathogenic factor. Many HD patients suffer from cachexia, which has been related to alterations in energy metabolism and mitochondrial impairment. However, the underlying mechanisms for the muscle atrophy and mitochondrial disturbances are not known, whether they are primary or secondary to the disease. Unraveling these mechanisms may add to a better understanding of the HD pathogenesis and offer new potential therapeutic approaches. We investigated skeletal muscle morphology and mitochondrial function of 10 patients with genetically verified HD (6 men and 4 women, 54 6 7 years), and 11 ageand gender-matched healthy controls (7 men and 4 women, 56 6 14 years). Patients and healthy controls underwent a skeletal muscle biopsy obtained from the vastus lateralis muscle and mitochondrial respirometric measurements. The main finding was a difference in skeletal muscle fiber phenotype in HD patients when compared with healthy controls. Namely, HD patients had a significantly higher proportion of type I fibers than controls (67.1 6 9.2 vs 39.2 6 22.8%; P < .05). In contrast, there was no difference in cross-sectional area of any fiber type between patients and controls. In addition, mitochondrial respiratory capacity specific to complex I (63.9 6 13.1 vs 80.6 6 18.2 pmol O2 mg 21 s) and maximal oxidative phosphorylation capacity (88.9 6 18.7 vs 106.1 6 18.4 pmol O2 mg 21 s) were slightly lower in HD patients when compared with healthy controls (P < .05; Fig. 1A). However, when respiratory capacity was normalized to respiratory capacity of complex IV activity, no difference was observed, although respiratory capacity of complex IV FIG. 1. (A) Mass-specific mitochondrial respiratory capacity and (B) mitochondrial-specific respiratory capacity (normalized to COX) in patients with Huntington’s disease (white bars) and healthy controls (black bars). LN, leak respiration without adenylates; PETF, fatty acid oxidative capacity; PCI, respiratory capacity of complex I; P, oxidative phosphorylation capacity; LOmy, oligomycin-induced leak respiration; E, electron transport system capacity; PCII, respiratory capacity of complex II; ROX, residual oxygen consumption; COX, respiratory capacity of complex IV. Values are mean 6 standard deviation. *P < .050; nPatients 5 10, nControls 5 11.