The Childhood Resilience Study: Resilience and emotional and behavioural wellbeing experienced by Australian Aboriginal and Torres Strait Islander boys and girls aged 5-9 years.

BACKGROUND: Resilience is a process of drawing on internal or external strengths to regain, sustain or improve adaptive outcomes despite adversity. Using a child resilience measure co-designed with Aboriginal and Torres Strait Islander communities, we investigate: 1) children's personal, family, school and community strengths; 2) gender differences; and 3) associations between resilience and wellbeing. METHODS: 1132 parent/caregivers of children aged 5-12 years were recruited to the Childhood Resilience Study, including through the Aboriginal Families Study. The Aboriginal Families Study is a population-based cohort of 344 mothers of an Aboriginal and/or Torres Strait Islander child. This paper focuses on the wave 2 survey data on child resilience at age 5-9 years (n = 231). Resilience was assessed with the Child Resilience Questionnaire-parent/caregiver report (CRQ-P/C), categorised into tertiles of low, moderate and high scores. Child emotional/behavioural wellbeing and mental health competence was assessed with the parent-report Strengths and Difficulties Questionnaire. All Tobit regression models adjusted for child age. OUTCOMES: Aboriginal and Torres Strait Islander girls had higher resilience scores compared to boys (Adj.ß = 0·9, 95%CI 0·9-1·4), with higher School Engagement, Friends and Connectedness to language scale scores. Resilience scores were strongly associated with wellbeing and high mental health competence. A higher proportion of girls with low resilience scores had positive wellbeing than did boys (73.3% versus 49.0%). High resilience scores were associated with lower SDQ total difficulties score after adjusting for child age, gender, maternal age and education and family location (major city, regional, remote) (Adj.ß = -3.4, 95%CI -5.1, -1.7). Compared to the Childhood Resilience Study sample, Aboriginal Families Study children had higher mean CRQ-P/C scores in the personal and family domains. INTERPRETATION: High family strengths can support Aboriginal and Torres Strait Islander children at both an individual and cultural level. Boys may benefit from added scaffolding by schools, family and communities to support their social and academic connectedness.

Fate and behaviour of Microplastics (> 25µm) within the water distribution network, from water treatment works to service reservoirs and customer taps.

Water treatment works have previously shown high efficiency in removing microplastics > 25 µm from raw source water. However, what is less well known is the extent to which microplastics of this size class are generated or lost within the water distribution network, particularly whether there is a greater presence in the customer tap than in the water treatment works outlet. This study focused on the presence of 21 different types of synthetic polymer particles with sizes larger than 25 µm examined through multiple rounds of sampling at outlets of water treatment works (WTW), service reservoirs (SR), and customer taps (CT) managed by seven different water companies in Britain. Nineteen different types of polymers were detected; their signature and concentration varied based on the round of sampling, the location within the water supply network, and the water company responsible for managing the supply. Among the polymers examined, polyamide (PA), polyethene terephthalate (PET), polypropylene (PP), and polystyrene (PS) were the most commonly found. Apart from PET having its highest concentration of 0.0189 microplastic per litre (MP/L) in the SR, the concentrations of the other three most frequent polymers (PS = 0.017 MP/L, PA = 0.0752 MP/L, PP= 0.1513 MP/L) were highest in the CT. The overall prevalence of this size of microplastics in the network is low, but there was a high variability of polymer types and occurrences. These spatial and temporal variations suggested that the MP in the distribution network may exist as a series of pulses. Given the presence and polymer types, the potential for some of the microplastics to originate from materials used in the water network and domestic plumbing systems cannot be ruled out. As found before, the absolute number of microplastics in the water distribution network remained extremely low.

Significant Turning Point: Common Buzzard (Buteo buteo) Exposure to Second-Generation Anticoagulant Rodenticides in the United Kingdom.

Second-generation anticoagulant rodenticides (SGARs) are widely used to control rodent populations, resulting in the serious secondary exposure of predators to these contaminants. In the United Kingdom (UK), professional use and purchase of SGARs were revised in the 2010s. Certain highly toxic SGARs have been authorized since then to be used outdoors around buildings as resistance-breaking chemicals under risk mitigation procedures. However, it is still uncertain whether and how these regulatory changes have influenced the secondary exposure of birds of prey to SGARs. Based on biomonitoring of the UK Common Buzzard (Buteo buteo) collected from 2001 to 2019, we assessed the temporal trend of exposure to SGARs and statistically determined potential turning points. The magnitude of difenacoum decreased over time with a seasonal fluctuation, while the magnitude and prevalence of more toxic brodifacoum, authorized to be used outdoors around buildings after the regulatory changes, increased. The summer of 2016 was statistically identified as a turning point for exposure to brodifacoum and summed SGARs that increased after this point. This time point coincided with the aforementioned regulatory changes. Our findings suggest a possible shift in SGAR use to brodifacoum from difenacoum over the decades, which may pose higher risks of impacts on wildlife.

Co-occurrence of macroplastics, microplastics, and legacy and emerging plasticisers in UK soils.

Despite a theoretical link between plastic and plasticiser occurrence in the terrestrial environment, there are few empirical studies of the relationship between these contaminants in soils. We carried out a field study to assess the co-occurrence of plastic waste, and legacy and emerging plasticisers in UK soils (n = 19) from various land uses (woodlands, urban roadsides, urban parklands, landfill-associated). Surface plastics and soil microplastics were quantified and characterised using ATR-FTIR and µ-FTIR. Eight legacy (phthalate) and three emerging (adipate, citrate, trimellitate) plasticisers were quantified using GC-MS. Surface plastics were found at higher prevalence at landfill-associated and urban roadside sites, with levels significantly (2 orders of magnitude) greater than in woodlands. Microplastics were detected in landfill-associated (mean 12.3 particles g-1 dw), urban roadside (17.3 particles g-1 dw) and urban parkland (15.7 particles g-1 dw) soils, but not in woodland soils. The most commonly detected polymers were polyethene, polypropene and polystyrene. Mean ∑plasticiser concentration in urban roadside soils (3111 ng g-1 dw) was significantly higher than in woodlands (134 ng g-1 dw). No significant difference was found between landfill-associated (318 ng g-1 dw) and urban parkland (193 ng g-1 dw) soils and woodlands. Di-n-butyl phthalate (94.7% detection frequency) and the emerging plasticiser trioctyl trimellitate (89.5%) were the most commonly detected plasticisers, with diethylhexyl phthalate (493 ng g-1 dw) and di-iso-decyl phthalate (96.7 ng g-1 dw) present at the highest concentrations. ∑plasticiser concentrations were significantly correlated with surface plastic (R2 = 0.23), but not with soil microplastic concentrations. Whilst plastic litter seems a fundamental source of plasticisers in soils, mechanisms such as airborne transport from source areas may be as important. Based on the data from this study, phthalates remain the dominant plasticisers in soils, but emerging plasticisers are already widespread, as reflected by their presence in all land uses studied.

A Study of Arizona Physician Relocation Patterns by Rurality and Primary Care Status.

BACKGROUND AND OBJECTIVES: Physician location is an important element of health care access. However, physician shortages and disparities in geographic distribution exist. This study examines physician locations, relocation patterns, and factors associated with relocating. METHODS: We used Arizona licensure data and rural-urban commuting area (RUCA) codes to identify Arizona physicians and their office or mailing address locations. Our sample included Arizona physicians estimated to be younger than 70 years of age who had an active license between in 2014 and 2019. We used multivariable logistic regression to assess physicians' adjusted odds of relocating in Arizona by RUCA code, primary care status, age, gender, and medical education location. RESULTS: We identified 11,202 Arizona physicians in our sample, 33% of whom changed practice addresses within Arizona between 2014 and 2019. Primary care physicians (PCPs) in large rural areas had lower odds of relocating in Arizona (0.62, 95% CI 0.43-0.90) than PCPs in urban areas. Compared to 64-69-year-old physicians, those less than 34 and 34-43 years old had statistically higher odds of relocating within Arizona. CONCLUSIONS: Primary care status and rurality are important factors consider to understand physician relocation patterns. We found that a substantial number of Arizona physicians relocated within Arizona between 2014 and 2019, and few of those who relocated (2%) moved to a more rural area.

Feeling WELL: COVID-19 and the Adoption of Wellness Themes in Interior Design Curricula.

Interior design (ID) pedagogy should include theories and applications, which advance human health and wellness in the built environment. Design for wellness and well-being is referenced in 5 of the 13 Council for Interior Design Accreditation (CIDA) knowledge application standards. This focus on wellness was amplified during the coronavirus disease 2019 (COVID-19) pandemic experience, which elevated our collective understanding of contagions, disease transmission, sanitation practices, vaccination efficacy, and immunity, as well as the devastating turmoil-social, economic, and psychological-of the pandemic's tragic spread. Thus, the purpose of this study was to examine ID educators' attitudes, intentions, and behaviors related to teaching wellness and to determine if the pandemic impacted wellness pedagogy. For this mixed methods study, we employed an online survey (n = 86) followed by participant interviews (n = 11). Data from the questionnaire and interviews suggested that peer attitudes toward wellness were a significant factor that influenced teaching behavior. Teaching intentions were predicted by prior teaching, attitudes, and perceived behavioral control (ability to teach wellness). Although experience with the pandemic was not a predictor of teaching behavior, it did surface as a strong motivator for future teaching adjustments. Findings also showed wide-ranging understandings and definitions of wellness-related themes. Implications for design programs seeking to equip faculty with the tools needed to integrate wellness more deeply into ID curricula are discussed.

Long-term trends of second generation anticoagulant rodenticides (SGARs) show widespread contamination of a bird-eating predator, the Eurasian Sparrowhawk (Accipiter nisus) in Britain.

Second generation anticoagulant rodenticides (SGARs) are widely used to control rodents around the world. However, contamination by SGARs is detectable in many non-target species, particularly carnivorous mammals or birds-of-prey that hunt or scavenge on poisoned rodents. The SGAR trophic transfer pathway via rodents and their predators/scavengers appears widespread, but little is known of other pathways of SGAR contamination in non-target wildlife. This is despite the detection of SGARs in predators that do not eat rodents, such as specialist bird-eating hawks. We used a Bayesian modelling framework to examine the extent and spatio-temporal trends of SGAR contamination in the livers of 259 Eurasian Sparrowhawks, a specialist bird-eating raptor, in regions of Britain during 1995-2015. SGARs, predominantly difenacoum, were detected in 81% of birds, with highest concentrations in males and adults. SGAR concentrations in birds were lowest in Scotland and higher or increasing in other regions of Britain, which had a greater arable or urban land cover where SGARs may be widely deployed for rodent control. However, there was no overall trend for Britain, and 97% of SGAR residues in Eurasian Sparrowhawks were below 100 ng/g (wet weight), which is a potential threshold for lethal effects. The results have potential implications for the population decline of Eurasian Sparrowhawks in Britain. Fundamentally, the results indicate an extensive and persistent contamination of the avian trophic transfer pathway on a national scale, where bird-eating raptors and, by extension, their prey appear to be widely exposed to SGARs. Consequently, these findings have implications for wildlife contamination worldwide, wherever these common rodenticides are deployed, as widespread exposure of non-target species can apparently occur via multiple trophic transfer pathways involving birds as well as rodents.

Ensuring Access to Albuterol in Schools: From Policy to Implementation. An Official ATS/AANMA/ALA/NASN Policy Statement.

Rationale: For children with asthma, access to quick-relief medications is critical to minimizing morbidity and mortality. An innovative and practical approach to ensure access at school is to maintain a supply of stock albuterol that can be used by any student who experiences respiratory distress. To make this possible, state laws allowing for stock albuterol are needed to improve medication access.Objectives: To provide policy recommendations and outline steps for passing and implementing stock albuterol laws.Methods: We assembled a diverse stakeholder group and reviewed guidelines, literature, statutes, regulations, and implementation documents related to school-based medication access. Stakeholders were divided into two groups-legislation and implementation-on the basis of expertise. Each group met virtually to review documents and draft recommendations. Recommendations were compiled and revised in iterative remote meetings with all stakeholders.Main Results: We offer several recommendations for crafting state legislation and facilitating program implementation. 1) Create a coalition of stakeholders to champion legislation and implement stock albuterol programs. The coalition should include school administrators, school nurses and health personnel, parents, or caregivers of children with asthma, pediatric primary care and subspecialty providers (e.g., pulmonologists/allergists), pharmacists, health department staff, and local/regional/national advocacy organizations. 2) Legislative components critical for effective implementation of stock albuterol programs include specifying that medication can be administered in good faith to any child in respiratory distress, establishing training requirements for school staff, providing immunity from civil liability for staff and prescribers, ensuring pharmacy laws allow prescriptions to be dispensed to schools, and suggesting inhalers with valved holding chambers/spacers for administration. 3) Select an experienced and committed legislator to sponsor legislation and guide revisions as needed during passage and implementation. This person should be from the majority party and serve on the legislature's health or education committee. 4) Develop plans to disseminate legislation and regulations/policies to affected groups, including school administrators, school nurses, pharmacists, emergency responders, and primary/subspecialty clinicians. Periodically evaluate implementation effectiveness and need for adjustments.Conclusions: Stock albuterol in schools is a safe, practical, and potentially life-saving option for children with asthma, whether asthma is diagnosed or undiagnosed, who lack access to their personal quick-relief medication. Legislation is imperative for aiding in the adoption and implementation of school stock albuterol policies, and key policy inclusions can lay the groundwork for success. Future work should focus on passing legislation in all states, implementing policy in schools, and evaluating the impact of such programs on academic and health outcomes.

Organizational Readiness for Community Health Worker Workforce Integration Among Medicaid Contracted Health Plans and Provider Networks: An Arizona Case Study.

Understanding and building organizational capacity for system change and the integration of the Community Health Worker (CHW) workforce within the health scare sector requires a supportive organizational culture among sector leaders and providers. The aim of this mixed-methods study was to assess organizational readiness for CHW workforce integration into Arizona Medicaid health systems and care teams. This collaborative effort was in direct response to emergent state and national CHW workforce policy opportunities, and the shifting health care landscape in Arizona - which merged behavior and physical health. Specifically, and in collaboration with a broad-based, statewide CHW workforce coalition, led by the CHW professional association, we assessed 245 licensed health care professionals with experience working with CHWs and 16 Medicaid-contracted health plan leadership. Our goal was to generate a baseline understanding of the knowledge, attitudes and beliefs these stakeholders held about the integration of CHWs into systems and teams. Our findings demonstrate a high level of organizational readiness and action toward integration of CHWs within the Arizona health care system and care teams. CHWs have emerged as a health care workforce able to enhance the patient experience of care, improve population health, reduce cost of care, and improve the experience of providing care among clinicians and staff.

Chemicals with increasingly complex modes of action result in greater variation in sensitivity between earthworm species.

The scale of variation in species sensitivity to toxicants has been theoretically linked to mode of action. Specifically, it has been proposed there will be greater variations for chemicals with a putative specific biological target than for toxicants with a non-specific narcotic mechanism. Here we test the hypothesis that mode of action is related to variation in sensitivity in a specifically designed experiment for species from a single ecologically important terrestrial taxa, namely earthworms. Earthworm toxicity tests were conducted with five species for four chemicals, providing a series of increasingly complex modes of action: a putative narcotic polycyclic aromatic hydrocarbon (fluoranthene), and three insecticides (chlorpyrifos, cypermethrin, imidacloprid) with known neuronal receptor targets. Across all the chemicals, the standard epigeic test species Eisenia fetida and Lumbricus rubellus, were generally among the two least sensitive, while the endogenic Aporrectodea caliginosa and Megascolecidae Amynthas gracilis were generally more sensitive (never being among the two least sensitive species). This indicates a potential for bias in the earthworm ecotoxicology literature, which is dominated by studies in epigeic Lumbricidae, but contains few endogeic or Megascolecidae data. Results confirmed the lowest range of variation in sensitivities for effects on reproduction was for fluoranthene (2.5 fold). All insecticides showed greater variation for species sensitivity (cypermethrin: 7.5 fold, chlorpyrifos: 10.3 fold, imidacloprid: 31.5 fold) consistent with the specific mechanisms of the pesticides. Difference in toxicodynamics, based on mode of action specificity and receptor complexity was reflected in the magnitude of sensitivity variation. However, measurements of tissue concentrations also indicated the potential importance of toxicokinetics in explaining species sensitivity variations for chlorpyrifos and cypermethrin.

Making the Case for Centralized Dementia Care Through Adaptive Reuse in the Time of COVID-19.

It is estimated that 5.4 million Americans have some form of dementia and these numbers are expected to rise in the coming decades, leading to an unprecedented demand for memory care housing and services. At the same time, infectious disease outbreaks like the COVID-19 pandemic have raised great concerns for the future of care settings for people living with dementia. In searching for innovative options to create more autonomy and better quality of life in dementia care settings, while at the same time improving infectious disease control, repurposing existing structures, in particular vacant urban malls, may be one option for the large sites needed for the European model of dementia villages. This editorial paper makes the case for the Dementia Friendly City Center model for centralized dementia programs, medical services and housing. By working across multiple disciplines, this research team has simultaneously addressed numerous issues, including community revitalization, building sustainability, and the strengthening of infectious disease control in care sites which are inclusive, progressive and convergent with the needs of an aging population.

Establishing voluntary certification of community health workers in Arizona: a policy case study of building a unified workforce.

BACKGROUND: Community health workers (CHWs) are widely recognized as essential to addressing disparities in health care delivery and outcomes in US vulnerable populations. In the state of Arizona, the sustainability of the workforce is threatened by low wages, poor job security, and limited opportunities for training and advancement within the profession. CHW voluntary certification offers an avenue to increase the recognition, compensation, training, and standardization of the workforce. However, passing voluntary certification legislation in an anti-regulatory state such as Arizona posed a major challenge that required a robust advocacy effort. CASE PRESENTATION: In this article, we describe the process of unifying the two major CHW workforces in Arizona, promotoras de salud in US-Mexico border communities and community health representatives (CHRs) serving American Indian communities. Differences in the origins, financing, and even language of the population-served contributed to historically divergent interests between CHRs and promotoras. In order to move forward as a collective workforce, it was imperative to integrate the perspectives of CHRs, who have a regular funding stream and work closely through the Indian Health Services, with those of promotoras, who are more likely to be grant-funded in community-based efforts. As a unified workforce, CHWs were better positioned to gain advocacy support from key health care providers and health insurance companies with policy influence. We seek to elucidate the lessons learned in our process that may be relevant to CHWs representing diverse communities across the US and internationally. CONCLUSIONS: Legislated voluntary certification provides a pathway for further professionalization of the CHW workforce by establishing a standard definition and set of core competencies. Voluntary certification also provides guidance to organizations in developing appropriate training and job activities, as well as ongoing professional development opportunities. In developing certification with CHWs representing different populations, and in particular Tribal Nations, it is essential to assure that the CHW definition is in alignment with all groups and that the scope of practice reflects CHW roles in both clinic and community-based settings. The Arizona experience underscores the benefits of a flexible approach that leverages existing strengths in organizations and the population served.

Accumulation of polybrominated diphenyl ethers and microbiome response in the great pond snail Lymnaea stagnalis with exposure to nylon (polyamide) microplastics.

Microplastics attract widespread attention, including for their potential to transport toxic chemicals in the form of plasticisers and associated hydrophobic organic chemicals, such as polybrominated diphenyl ethers (PBDEs). The aims of this study were to investigate how nylon (polyamide) microplastics may affect PBDE accumulation in snails, and the acute effects of nylon particles and PBDEs on survival, weight change and inherent microbiome diversity and community composition of the pond snail Lymnaea stagnalis. Snails were exposed for 96 h to BDEs-47, 99, 100 and 153 in the presence and absence of 1% w/w nylon microplastics in quartz sand sediment. No mortality was observed over the exposure period. Snails not exposed to microplastics lost significantly more weight compared to those exposed to microplastics. Increasing PBDE concentration in the sediment resulted in an increased PBDE body burden in the snails, however microplastics did not significantly influence total PBDE uptake. Based on individual congeners, uptake of BDE 47 by snails was significantly reduced in the presence of microplastics. The diversity and composition of the snail microbiome was not significantly altered by the presence of PBDEs nor by the microplastics, singly or combined. Significant effects on a few individual operational taxonomic units (OTUs) occurred when comparing the highest PBDE concentration with the control treatment, but in the absence of microplastics only. Overall within these acute experiments, only subtle effects on weight loss and slight microbiome alterations occurred. These results therefore highlight that L. stagnalis are resilient to acute exposures to microplastics and PBDEs, and that microplastics are unlikely to influence HOC accumulation or the microbiome of this species over short timescales.

Effects of brownification and warming on algal blooms, metabolism and higher trophic levels in productive shallow lake mesocosms.

An increase of dissolved organic carbon (DOC) in inland waters has been reported across the northern temperate region but the effects of this on whole lake ecosystems, often combined with other anthropogenic stressors like nutrient inputs and warming, are poorly known. The effects of these changes on different component of the ecosystem were assessed in an experiment using twenty-four large (3000L) outdoor mesocosms simulating shallow lakes. Two different temperature regimes (ambient and ambient +4 °C) combined with three levels of organic matter (OM, added as filtered peaty water), simulating the DOC increase that is predicted to take place over the next 4 to 21 years were used. Neither temperature nor OM had significant effects on net ecosystem production, respiration or gross primary production. Phytoplankton chlorophyll a concentration was not significantly affected by warming, however in summer, autumn and winter it was significantly higher in mesocosms receiving intermediate OM levels (July-Feb DOC concentrations 2-6 mg L-1). Summer cyanobacterial blooms were highest in intermediate, and lowest in the highest OM treatments. OM concentration also influenced total macroinvertebrate abundance which was greater in spring and summer in mesocosms with intermediate and high OM. Fish abundance was not significantly affected by OM concentration, but abundance was greater in ambient (55 fish subsample-1) compared to heated mesocosms (17 fish subsample-1) and maximum abundance occurred two weeks later compared to heated mesocosms. The results suggest that changes in OM may have a greater effect on shallow lakes than temperature and that phytoplankton, especially cyanobacteria, benefit from intermediate OM concentrations, therefore, nuisance algal blooms might increase in relatively clear shallow eutrophic lakes where DOC concentrations increase.

Contractile activity attenuates autophagy suppression and reverses mitochondrial defects in skeletal muscle cells.

Macroautophagy/autophagy is a survival mechanism that facilitates protein turnover in post-mitotic cells in a lysosomal-dependent process. Mitophagy is a selective form of autophagy, which arbitrates the selective recognition and targeting of aberrant mitochondria for degradation. Mitochondrial content in cells is the net balance of mitochondrial catabolism via mitophagy, and organelle biogenesis. Although the latter process has been well described, mitophagy in skeletal muscle is less understood, and it is currently unknown how these two opposing mechanisms converge during contractile activity. Here we show that chronic contractile activity (CCA) in muscle cells induced mitochondrial biogenesis and coordinately enhanced the expression of TFEB (transcription factor EB) and PPARGC1A/PGC-1α, master regulators of lysosome and mitochondrial biogenesis, respectively. CCA also enhanced the expression of PINK1 and the lysosomal protease CTSD (cathepsin D). Autophagy blockade with bafilomycin A1 (BafA) reduced mitochondrial state 3 and 4 respiration, increased ROS production and enhanced the accumulation of MAP1LC3B-II/LC3-II and SQSTM1/p62. CCA ameliorated this mitochondrial dysfunction during defective autophagy, increased PPARGC1A, normalized LC3-II levels and reversed mitochondrially-localized SQSTM1 toward control levels. NAC emulated the LC3-II reductions induced by contractile activity, signifying that a decrease in oxidative stress could represent a mechanism of autophagy normalization brought about by CCA. CCA enhances mitochondrial biogenesis and lysosomal activity, and normalizes autophagy flux during autophagy suppression, partly via ROS-dependent mechanisms. Thus, contractile activity represents a potential therapeutic intervention for diseases in which autophagy is inhibited, such as vacuolar myopathies in skeletal muscle, by establishing a healthy equilibrium of anabolic and catabolic pathways. ABBREVIATIONS: AMPK: AMP-activated protein kinase; BafA: bafilomycin A1; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCA: chronic contractile activity; COX4I1: cytochrome c oxidase subunit 4I1; DMEM: Dulbecco's modified Eagle's medium; GFP: green fluorescent protein; LSD: lysosomal storage diseases; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SOD2: superoxide dismutase 2, mitochondrial; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.

Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity.

KEY POINTS: A healthy mitochondrial pool is dependent on the removal of dysfunctional organelles via mitophagy, but little is known about how mitophagy is altered with ageing and chronic exercise. Chronic contractile activity (CCA) is a standardized exercise model that can elicit mitochondrial adaptations in both young and aged muscle, albeit to a lesser degree in the aged group. Assessment of mitophagy flux revealed enhanced targeting of mitochondria for degradation in aged muscle, in contrast to previous theories. Mitophagy flux was significantly reduced as an adaptation to CCA suggesting that an improvement in organelle quality reduces the need for mitochondrial turnover. CCA enhances lysosomal capacity and may ameliorate lysosomal dysfunction in aged muscle. ABSTRACT: Skeletal muscle exhibits deficits in mitochondrial quality with age. Central to the maintenance of a healthy mitochondrial pool is the removal of dysfunctional organelles via mitophagy. Little is known on how mitophagy is altered with ageing and chronic exercise. We assessed mitophagy flux using colchicine treatment in vivo following chronic contractile activity (CCA) of muscle in young and aged rats. CCA evoked mitochondrial biogenesis in young muscle, with an attenuated response in aged muscle. Mitophagy flux was higher in aged muscle and was correlated with the enhanced expression of mitophagy receptors and upstream transcriptional regulators. CCA decreased mitophagy flux in both age groups, suggesting an improvement in organelle quality. CCA also reduced the exaggerated expression of TFEB evident in aged muscle, which may be promoting the age-induced increase in lysosomal markers. Thus, aged muscle possesses an elevated drive for autophagy and mitophagy which may contribute to the decline in organelle content observed with age, but which may serve to maintain mitochondrial quality. CCA improves organelle integrity and reduces mitophagy, illustrating that chronic exercise is a modality to improve muscle quality in aged populations.

Effect of contractile activity on PGC-1α transcription in young and aged skeletal muscle.

Mitochondrial impairments are often noted in aged skeletal muscle. The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is integral to maintaining mitochondria, and its expression declines in aged muscle. It remains unknown whether this is due to a transcriptional deficit during aging. Our study examined PGC-1α transcription in muscle from young and old F344BN rats. Using a rat PGC-1α promoter-reporter construct, we found that PGC-1α transcription was reduced by ∼65% in aged TA muscle, accompanied by decreases in PGC-1α mRNA and transcript stability. Altered expression patterns in PGC-1α transcription regulatory factors, including nuclear respiratory factor 2, upstream transcription factor 1, activating transcription factor 2, and yin yang 1, were noted in aged muscle. Acute contractile activity (CA) followed by recovery was employed to examine whether PGC-1α transcription could be activated in aged muscle similar to that observed in young muscle. AMPK and p38 signaling was attenuated in aged muscle. CA evoked an upregulation of PGC-1α transcription in both young and aged groups, whereas mRNAs encoding PGC-1α and cytochrome oxidase subunit IV were induced during the recovery period. Global DNA methylation, an inhibitory event for transcription, was enhanced in aged muscle, likely a result of elevated methyltransferase enzyme Dnmt3b in aged muscle. Successive bouts of CA for 7 days to evaluate longer-term consequences resulted in a rescue of PGC-1α and downstream mRNAs in aged muscle. Our data indicate that diminished mitochondria in aged muscle is due partly to a deficit in PGC-1α transcription, a result of attenuated upstream signaling. Contractile activity is an appropriate countermeasure to restore PGC-1α expression and mitochondrial content in aged muscle. NEW & NOTEWORTHY PGC-1α is a regulator of mitochondrial biogenesis in muscle. We demonstrate that PGC-1α expression is reduced in aging muscle due to decreases in transcriptional and posttranscriptional mechanisms. The transcriptional deficit is due to alterations in transcription factor expression, reduced signaling, and DNA methylation. Acute exercise can initiate signaling to reverse the transcriptional defect, restoring PGC-1α expression toward young values, suggesting a mechanism whereby aged muscle can respond to exercise for the promotion of mitochondrial biogenesis.

Unravelling the mechanisms regulating muscle mitochondrial biogenesis.

Skeletal muscle is a tissue with a low mitochondrial content under basal conditions, but it is responsive to acute increases in contractile activity patterns (i.e. exercise) which initiate the signalling of a compensatory response, leading to the biogenesis of mitochondria and improved organelle function. Exercise also promotes the degradation of poorly functioning mitochondria (i.e. mitophagy), thereby accelerating mitochondrial turnover, and preserving a pool of healthy organelles. In contrast, muscle disuse, as well as the aging process, are associated with reduced mitochondrial quality and quantity in muscle. This has strong negative implications for whole-body metabolic health and the preservation of muscle mass. A number of traditional, as well as novel regulatory pathways exist in muscle that control both biogenesis and mitophagy. Interestingly, although the ablation of single regulatory transcription factors within these pathways often leads to a reduction in the basal mitochondrial content of muscle, this can invariably be overcome with exercise, signifying that exercise activates a multitude of pathways which can respond to restore mitochondrial health. This knowledge, along with growing realization that pharmacological agents can also promote mitochondrial health independently of exercise, leads to an optimistic outlook in which the maintenance of mitochondrial and whole-body metabolic health can be achieved by taking advantage of the broad benefits of exercise, along with the potential specificity of drug action.

Spatial patterns and environmental constraints on ecosystem services at a catchment scale.

Improved understanding and prediction of the fundamental environmental controls on ecosystem service supply across the landscape will help to inform decisions made by policy makers and land-water managers. To evaluate this issue for a local catchment case study, we explored metrics and spatial patterns of service supply for water quality regulation, agriculture production, carbon storage, and biodiversity for the Macronutrient Conwy catchment. Methods included using ecosystem models such as LUCI and JULES, integration of national scale field survey datasets, earth observation products and plant trait databases, to produce finely resolved maps of species richness and primary production. Analyses were done with both 1×1km gridded and subcatchment data. A common single gradient characterised catchment scale ecosystem services supply with agricultural production and carbon storage at opposing ends of the gradient as reported for a national-scale assessment. Species diversity was positively related to production due to the below national average productivity levels in the Conwy combined with the unimodal relationship between biodiversity and productivity at the national scale. In contrast to the national scale assessment, a strong reduction in water quality as production increased was observed in these low productive systems. Various soil variables were tested for their predictive power of ecosystem service supply. Soil carbon, nitrogen, their ratio and soil pH all had double the power of rainfall and altitude, each explaining around 45% of variation but soil pH is proposed as a potential metric for ecosystem service supply potential as it is a simple and practical metric which can be carried out in the field with crowd-sourcing technologies now available. The study emphasises the importance of considering multiple ecosystem services together due to the complexity of covariation at local and national scales, and the benefits of exploiting a wide range of metrics for each service to enhance data robustness.