Objective The aim of our study was to determine the steady state and dynamic in mitochondrial fission and fusion balance, in quadriceps muscle tissue of the zQ175 HD mouse model and human HTT gene expansion carriers.
Background Mitochondrial fission and fusion processes are important for maintaining proper mitochondrial and cellular functions. In post-mortem brain tissue from HD patients as well as in human HD fibroblasts, mHTT interferes with Drp1, the major fission enzyme, leading to an increased fragmented mitochondrial network. In neurons, mHTT-mediated mitochondrial fragmentation and defects in mitochondrial transport can be rescued by reducing the Drp1 activity (Shirendeb et al. HMG 2012, Song et al. Nature Medicine 2011).
Material and methods mRNA expression and protein analyses of fission and fusion enzymes in quadriceps tissue of zQ175 mice (6 months and 9 months) and in near to motor onset pre-manifest HD (n = 20), early motor onset HD patients (n = 20), and sex and age matched healthy controls (n = 20), as part of the Multiple-Tissue Molecular Signatures in HD project (MTM-HD). In addition, we analysed the mitochondrial network in human HD fibroblasts and myoblasts.
Results Steady state tissue Drp1 mRNA levels were decreased in early HD patients and zQ175 mice. In addition protein levels were lower in early HD patients compared to controls. However the mitochondrial morphology was unchanged in zQ175 mice and HD patients as well as the Drp1 activity, which was not altered in zQ175mice. Furthermore, in human primary HD fibroblasts and myoblasts the mitochondrial network was similar to control cells.
Conclusions mHTT is expressed in HD skeletal muscle. However, we found no evidence for a disruption of the steady-state fission-fusion balance in skeletal muscle of zQ175 mice or human HD gene carriers. The presence of mHTT does not compromise the steady-state fission and fusion balance.
Shirendeb et al. Hum Mol Genet 2012 Jan 15;21(2):406–420
Song et al. Nat Med 2011 Mar;17(3):377–382