Disease risk estimates in V30M variant transthyretin amyloidosis (A-ATTRv) from Mallorca.

BACKGROUND: Variant transthyretin amyloidosis (A-ATTRv) is an autosomal dominant disease caused by a range of TTR gene variants which entail great phenotypical heterogeneity and penetrance. In Majorca, the A-ATTRv caused by the V30M gene variant (A-ATTRV30M) is the most common. Since asymptomatic carriers are at risk of developing the disease, estimating age of onset is vital for proper management and follow-up. Thus, the aim of this study was to estimate age-related penetrance in ATTRV30M variant carriers from Majorca. METHODS: The disease risk among carriers from ATTRV30M families from Majorca was estimated by Non-parametric survival estimation. Factors potentially involved in the disease expression, namely gender and parent of origin were also analysed. RESULTS: A total of 48 heterozygous ATTRV30M families (147 affected patients and 123 were asymptomatic carriers) were included in the analysis. Penetrance progressively increased from 6% at 30 years to 75% at 90 years of age. In contrast to other European populations, we observe a similar risk for both males and females, and no difference of risk according to the parent of origin. CONCLUSIONS: In this first study assessing the age-related penetrance of ATTRV30M variant in Majorcan families, no effect of gender or parent of origin was observed. These findings will be helpful for improving management and follow-up of TTR variant carrier individuals.

High-fat diet feeding induces a depot-dependent response on the pro-inflammatory state and mitochondrial function of gonadal white adipose tissue.

Obesity has been related to a chronic pro-inflammatory state affecting white adipose tissue (WAT), which has a great impact on carbohydrate, lipid and energy metabolism. In turn, the dysregulation of adipokine secretion derived from the accumulation of excess lipids in adipocytes further contributes to the development of insulin resistance and can be associated with mitochondrial dysfunction. The aim of the present study was to determine whether sexual dimorphism found in the systemic insulin sensitivity profile is related to sex differences in a high-fat diet (HFD) response of gonadal WAT at mitochondrial function and inflammatory profile levels. Wistar rats (10 weeks old) of both sexes were fed a control pelleted diet (3 % (w/w) fat; n 8 for each sex) or a HFD (24 % (w/w) fat; n 8 for each sex). Serum insulin sensitivity markers, mRNA expression levels of inflammatory factors and the protein content of insulin and adiponectin signalling pathways were analysed, as well as the levels of the main markers of mitochondrial biogenesis, antioxidant defence and oxidative damage. In the present study, the periovarian depot exhibits a greater expandability capacity, along with a lower hypoxic and pro-inflammatory state, without signs of mitochondrial dysfunction or changes in its dynamics. In contrast, epididymal fat has a much more pronounced pro-inflammatory, hypoxic and insulin-resistant profile accompanied by changes in mitochondrial dynamics, probably associated with HFD-induced mitochondrial dysfunction. Thus, this explains the worse serum insulin sensitivity profile of male rats.

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice.

AIMS/HYPOTHESIS: High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function. METHODS: The Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ), a mitochondria-specific antioxidant, was used to target ROS production in C2C12 muscle cells as well as in HF-fed (16 weeks old) male C57Bl/6 mice, compared with mice on low-fat chow diet (LF) or HF alone. Oxidative stress was measured as protein carbonylation levels. Glucose tolerance tests, glucose uptake assays and insulin-stimulated signalling were determined to assess muscle insulin sensitivity. Mitochondrial function was determined by high-resolution respirometry. RESULTS: SkQ treatment reduced oxidative stress in muscle cells (-23% p < 0.05), but did not improve insulin sensitivity and glucose uptake under insulin-resistant conditions. In HF mice, oxidative stress was elevated (56% vs LF p < 0.05), an effect completely blunted by SkQ. However, HF and HF+SkQ mice displayed impaired glucose tolerance (AUC HF up 33%, p < 0.001; HF+SkQ up 22%; p < 0.01 vs LF) and disrupted skeletal muscle insulin signalling. ROS sequestering did not improve mitochondrial function. CONCLUSIONS/INTERPRETATION: SkQ treatment reduced muscle mitochondrial ROS production and prevented HF-induced oxidative stress. Nonetheless, whole-body glucose tolerance, insulin-stimulated glucose uptake, muscle insulin signalling and mitochondrial function were not improved. These results suggest that HF-induced oxidative stress is not a prerequisite for the development of muscle insulin resistance.

Rat visceral yolk sac (VYS) and placenta mitochondrial features during the placentation period.

The transference of the nutritional function from the VYS to the chorioallantoic placenta during middle pregnancy is a key event for the activation of embryo oxidative metabolism. However, the metabolic adaptations occurring in these tissues during this critical period have not been studied to date. Herein, we investigate the VYS and placenta mitochondrial adaptations throughout gestational days 11, 12 and 13. The results reflect that, during the placentation period, mitochondrial proliferation predominates over differentiation in placenta. Besides, VYS development and mitochondriogenesis show a slowdown despite maintaining the mitochondrial OXPHOS capacities, hence becoming a supporting tissue until the placenta functions are completely available.