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

Abstract

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 Nterminal 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.

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

“…For instance, aggregated forms of mHtt may account for the mitochondrial dysfunction, because truncated models generate larger and more numerous mHtt aggregates than do full-length. Consistent with this explanation, mitochondria are not dysfunctional in heart tissue from R6/2 mice, in which mHtt is expressed but does not aggregate, whereas in quadriceps muscle in R6/2 mice, aggregates are present and respiratory chain complex activities are decreased [211]. Interestingly, aggregates and mitochondria are frequently closely apposed [212].…”

Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies

“…It has been noted that the skeletal muscles of HD patients are characterized by dysfunction of oxidative metabolism [ 77 ]. Studies in experimental mouse models have also shown that mitochondria isolated from the quadriceps muscle of the R6/2 mice model were characterized by reduced activity of the respiratory chain complexes [ 78 ]. Increased production of energy substrates such as lactate and acetate were also shown which confirms the presence of oxidative metabolism disorders [ 79 ].…”

“…Furthermore, in vitro myocyte cultures revealed disturbances of the mitochondrial membrane potential and cytochrome c release [ 80 ]. Moreover, increased levels of the mitochondrial pro-fission factor DRP1 and its phosphorylated active form, and decreased levels of the pro-fusion factor MFN2 in quadriceps of the R6/2 mice model were detected [ 78 ]. Interestingly, experimental studies have also shown a reduction in the level of PGC-1α, one of the proteins activated by peroxisomal proliferator gamma (PPAR γ) in skeletal muscles of HD mice models as well as HD patients [ 50 ].…”

“…The studies performed on this model have also shown that the hearts of these mice are characterized by decreased activity of the mammalian target of rapamycin kinase complex 1 (mTORC1) that could be the cause of the reduced heart weight which is observed in this strain as well as the lack of resistance to severe and chronic stress [ 98 ]. Nevertheless, Kojer et al highlighted no changes in mitochondrial oxidative chain complexes in R6/2 mice hearts [ 78 ]. Mechanistically, pathological huntingtin was found to be responsible for cellular death via inhibition of the proteasome in the cytosol and the nucleus of cardiomyocytes of R6/2 mice [ 97 ].…”

“…Mechanistically, pathological huntingtin was found to be responsible for cellular death via inhibition of the proteasome in the cytosol and the nucleus of cardiomyocytes of R6/2 mice [ 97 ]. On the other hand, some studies indicated the mHTT absence may be the underlying mechanism, as observed in HD mouse hearts [ 78 , 90 ]. Taken together, cardiac dysfunction in HD might derive not only from autonomic nervous system dysfunction but also from several cellular and tissue defects, such as energy metabolism impairment, associated with dysfunctional cardiac purine metabolism and signaling [ 99 ].…”