Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans

This is the final version. Available on open access from the Federation of American Society of Experimental Biology via the DOI in this recordMitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)-based proteolysis and, consequentially, muscle cell dystrophy. We found that inhibition of the mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, matrix metalloproteinase (MMP), and Furin inhibitors in Antimycin A-treated animal as well as in the C. elegans Duchenne muscular dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A-treated worms, and its down-regulation rescued the muscle damage, suggesting that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage.-Sudevan, S., Takiura, M., Kubota, Y., Higashitani, N., Cooke, M., Ellwood, R. A., Etheridge, T., Szewczyk, N. J., Higashitani, A. Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.Ministry of Education, Culture, Sports, Science, and Technology (MEXT)Cross-Ministerial Strategic Innovation Promotion ProgramAdvanced Research and Development Programs for Medical Innovation (AMED-CRESTBiotechnology and Biological Sciences Research Council (BBSRC)UK Space AgencyScience and Technology Facilities Council (STFC)Otsuka Toshimi FoundationTohoku UniversityJapan Student Services Organizatio

Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response

Clearance of mitochondria following damage is critical for neuronal homeostasis. Here, we investigate the role of Miro proteins in mitochondrial turnover by the PINK1/Parkin mitochondrial quality control system in vitro and in vivo. We find that upon mitochondrial damage, Miro is promiscuously ubiquitinated on multiple lysine residues. Genetic deletion of Miro or block of Miro1 ubiquitination and subsequent degradation lead to delayed translocation of the E3 ubiquitin ligase Parkin onto damaged mitochondria and reduced mitochondrial clearance in both fibroblasts and cultured neurons. Disrupted mitophagy in vivo, upon post-natal knockout of Miro1 in hippocampus and cortex, leads to a dramatic increase in mitofusin levels, the appearance of enlarged and hyperfused mitochondria and hyperactivation of the integrated stress response (ISR). Altogether, our results provide new insights into the central role of Miro1 in the regulation of mitochondrial homeostasis and further implicate Miro1 dysfunction in the pathogenesis of human neurodegenerative disease

The many faces of nitric oxide: cytotoxic, cytoprotective or both

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74882/1/j.1365-2982.2007.00958.x.pd

A cost-effectiveness analysis of shortened direct-acting antiviral treatment in genotype 1 noncirrhotic treatment-naive patients with chronic hepatitis C virus

BACKGROUND:Direct-acting antivirals are successful in curing hepatitis C virus infection in more than 95% of patients treated for 12 weeks, but they are expensive. Shortened treatment durations, which may have lower cure rates, have been proposed to reduce costs. OBJECTIVES:To evaluate the lifetime cost-effectiveness of different shortened treatment durations for genotype 1 noncirrhotic treatment-naive patients. METHODS:Assuming a UK National Health Service perspective, we used a probabilistic decision tree and Markov model to compare 3 unstratified shortened treatment durations (8, 6, and 4 weeks) against a standard 12-week treatment duration. Patients failing shortened first-line treatment were re-treated with a 12-week treatment regimen. Parameter inputs were taken from published studies. RESULTS:The 8-week treatment duration had an expected incremental net monetary benefit of £7737 (95% confidence interval £3242-£11 819) versus the standard 12-week treatment, per 1000 patients. The 6-week treatment had a positive incremental net monetary benefit, although some uncertainty was observed. The probability that the 8- and 6-week treatments were the most cost-effective was 56% and 25%, respectively, whereas that for the 4-week treatment was 17%. Results were generally robust to sensitivity analyses, including a threshold analysis that showed that the 8-week treatment was the most cost-effective at all drug prices lower than £40 000 per 12-week course. CONCLUSIONS:Shortening treatments licensed for 12 weeks to 8 weeks is cost-effective in genotype 1 noncirrhotic treatment-naive patients. There was considerable uncertainty in the estimates for 6- and 4-week treatments, with some indication that the 6-week treatment may be cost-effective

An ACACB Variant Implicated in Diabetic Nephropathy Associates with Body Mass Index and Gene Expression in Obese Subjects

published_or_final_versio

Statin prescription initiation and lifestyle behaviour: A primary care cohort study

BACKGROUND: Statin prescribing and healthy lifestyles contribute to declining cardiovascular disease mortality. Recent guidelines emphasise the importance of giving lifestyle advice in association with prescribing statins but adherence to healthy lifestyle recommendations is sub-optimal. However, little is known about any change in patients’ lifestyle behaviours when starting statins or of their recall of receiving advice. This study aimed to examine patients’ diet and physical activity (PA) behaviours and their recall of lifestyle advice following initiation of statin prescribing in primary care. METHOD: In 12 general practices, patients with a recent initial prescription of statin therapy, were invited to participate. Those who agreed received a food diary by post, to record food consumed over 4 consecutive days and return to the researcher. We also telephoned participants to administer brief validated questionnaires to assess typical daily diet (DINE) and PA level (Godin). Using the same methods, food diaries and questionnaires were repeated 3 months later. At both times participants were asked if they had changed their behaviour or received advice about their diet or PA. RESULTS: Of 384 invited, 122 (32 %) participated; 109 (89.3 %) completed paired datasets; 50 (45.9 %) were male; their mean age was 64 years. 53.2 % (58/109) recalled receiving lifestyle advice. Of those who did, 69.0 % (40/58) reported having changed their diet or PA, compared to 31.4 % (16/51) of those who did not recall receiving advice. Initial mean daily saturated fat intake (12.9 % (SD3.5) of total energy) was higher than recommended; mean fibre intake (13.8 g/day (SD5.5)), fruit/vegetable consumption (2.7 portions/day (SD1.3)) and PA levels (Godin score 7.1 (SD13.9)) were low. Overall, although some individuals showed evidence of behaviour change, there were no significant changes in the proportions who reported high or medium fat intake (42.2 % v 49.5 %), low fibre (51.4 % v 55.0 %), or insufficient PA (80.7 % v 83.5 %) at 3-month follow-up. CONCLUSION: Whilst approximately half of our cohort recalled receiving lifestyle advice associated with statin prescribing this did not translate into significant changes in diet or PA. Further research is needed to explore gaps between people’s knowledge and behaviours and determine how best to provide advice that supports behaviour change. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12875-016-0471-6) contains supplementary material, which is available to authorized users

A Synthesis of Tagging Studies Examining the Behaviour and Survival of Anadromous Salmonids in Marine Environments

This paper synthesizes tagging studies to highlight the current state of knowledge concerning the behaviour and survival of anadromous salmonids in the marine environment. Scientific literature was reviewed to quantify the number and type of studies that have investigated behaviour and survival of anadromous forms of Pacific salmon (Oncorhynchus spp.), Atlantic salmon (Salmo salar), brown trout (Salmo trutta), steelhead (Oncorhynchus mykiss), and cutthroat trout (Oncorhynchus clarkii). We examined three categories of tags including electronic (e.g. acoustic, radio, archival), passive (e.g. external marks, Carlin, coded wire, passive integrated transponder [PIT]), and biological (e.g. otolith, genetic, scale, parasites). Based on 207 papers, survival rates and behaviour in marine environments were found to be extremely variable spatially and temporally, with some of the most influential factors being temperature, population, physiological state, and fish size. Salmonids at all life stages were consistently found to swim at an average speed of approximately one body length per second, which likely corresponds with the speed at which transport costs are minimal. We found that there is relatively little research conducted on open-ocean migrating salmonids, and some species (e.g. masu [O. masou] and amago [O. rhodurus]) are underrepresented in the literature. The most common forms of tagging used across life stages were various forms of external tags, coded wire tags, and acoustic tags, however, the majority of studies did not measure tagging/handling effects on the fish, tag loss/failure, or tag detection probabilities when estimating survival. Through the interdisciplinary application of existing and novel technologies, future research examining the behaviour and survival of anadromous salmonids could incorporate important drivers such as oceanography, tagging/handling effects, predation, and physiology