A34 Mitochondrial respiration is limited by atp-production in the skeletal muscle of the R6/2 hd mouse model

Background Previous work has shown that mitochondrial respiration is not severely affected in the skeletal muscle of pre-symptomatic mHTT-mutation carriers.1 In contrast, patients with manifest HD exhibit a low anaerobic threshold and an increased skeletal muscle lactate production.2 This could result not only from a decreased capacity of the mitochondrial respiratory chain but also from a compromised ATP production process, which depends from the activity of the ATP-synthase and of the adenine nucleotide translocator. Aim The scope of the present study was therefore to compare ex-vivo the maximum respiratory activity in the coupled (OxPhos)-state and in the uncoupled (ETS)-state in skeletal muscle tissue samples from 12 weeks old R6/2 HD model male mice. Methods The mitochondrial respiratory activity in the homogenized tissue samples from 12 R6/2 mice and 11 wildtype controls were quantified according to previously published protocols.1 Results In the skeletal muscle from R6/2 mice we found a lower OxPhos-activity (118±47 [pmol O2/(s x mg tissue)]) compared to control (183±54 [pmol O2/(s x mg tissue)], p=0.006). The activity in the ETS-state did not show a statistically significant difference (148±59 [pmol O2/(s x mg tissue)] vs. 189±80 [pmol O2/(s x mg tissue)], p=0.21). The ratio of both capacities (OxPhos/ETS) was close to unity in the controls, but statistically significantly lower in the R6/2 mice (103±17 [%] vs. 82±6 [%], p=0.005) Conclusions We conclude that in HD, in addition to a possible reduction of the capacity of the mitochondrial respiratory chain, the ATP-production process may also assume a strong limiting role with regard to aerobic metabolism of the skeletal muscle. References . Buck, et al. PLoS One2017. https://doi.org/10.1371/journal.pone.0175248 . Ciammola, et al. Movement Disorders2011;26:130–7.