Huntingtin Aggregates and Mitochondrial Pathology in Skeletal Muscle but not Heart of Late-Stage R6/2 Mice

J Huntingtons Dis. 2019;8(2):145-159. doi: 10.3233/JHD-180324.


Background: Cell or tissue specific background may influence the consequences of expressing the Huntington's disease (HD) mutation. Aggregate formation is known to occur in skeletal muscle, but not heart of the R6/2 fragment HD model.

Objective: We asked whether aggregate formation and the expression and subcellular localization of huntingtin species was associated with mitochondrial dysfunction.

Methods: We analyzed levels of soluble HTT and HTT aggregates, as well as important fission and fusion proteins and mitochondrial respiratory chain activities, in quadriceps and heart of the R6/2 N-terminal fragment mouse model (12 weeks, 160±10 CAG repeats).

Results: Soluble mutant HTT was present in both tissues with expression higher in cytoplasmic/mitochondrial than nuclear fractions. HTT aggregates were only detectable in R6/2 quadriceps, in association with increased levels of the pro-fission factor DRP1 and its phosphorylated active form, and decreased levels of the pro-fusion factor MFN2. In addition, respiratory chain complex activities were decreased. In heart that was without detectable HTT aggregates, we found no evidence for mitochondrial dysfunction.

Conclusion: Tissue specific factors may exist that protect the R6/2 heart from HTT aggregate formation and mitochondrial pathology.

Keywords: Huntingtin; fission and fusion; mitochondria; respiratory chain; skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Huntingtin Protein*
  • Huntington Disease / pathology
  • Mice
  • Mitochondria / pathology*
  • Muscle, Skeletal / pathology*
  • Myocardium / pathology*


  • Huntingtin Protein