Ageing has no effect on the regulation of the ubiquitin proteasome-related genes and proteins following resistance exercise

Skeletal muscle atrophy is a critical component of the ageing process. Age-related muscle wasting is due to disrupted muscle protein turnover, a process mediated in part by the ubiquitin proteasome pathway (UPP). Additionally, older subjects have been observed to have an attenuated anabolic response, at both the molecular and physiological levels, following a single-bout of resistance exercise (RE). We investigated the expression levels of the UPP-related genes and proteins involved in muscle protein degradation in 10 older (60-75 years) versus 10 younger (18-30 years) healthy male subjects at basal as well as 2 hours after a single-bout of RE. MURF1, atrogin-1 and FBXO40, their substrate targets PKM2, myogenin, MYOD, MHC and EIF3F as well as MURF1 and atrogin-1 transcriptional regulators FOXO1 and FOXO3 gene and/or protein expression levels were measured via real time PCR and western blotting, respectively. At basal, no age-related difference was observed in the gene/protein levels of atrogin-1, MURF1, myogenin, MYOD and FOXO1/3. However, a decrease in FBXO40 mRNA and protein levels was observed in older subjects, while PKM2 protein was increased in older subjects. In response to RE, MURF1, atrogin-1 and FBXO40 mRNA were upregulated in both the younger and older subjects, with changes observed in protein levels. In conclusion, UPP-related gene/protein expression is comparably regulated in healthy young and old male subjects at basal and following RE. These findings suggest that UPP signalling plays a limited role in the process of age-related muscle wasting. Future studies are required to investigate additional proteolytic mechanisms in conjunction with skeletal muscle protein breakdown measurements following RE in older versus younger subjects

Effect of ageing and exercise training on myokine expression responses to acute exercise

Age-related muscle loss is a major contributor to falls, fraility and mortality. It has been widely suggested that chronic, age-related inflammation contributes to the gradual loss of skeletal muscle mass that occurs with ageing. Indeed, ageing is associated with elevations in a number of circulating inflammatory proteins, many of which have detrimental effects on skeletal muscle growth and protein balance. Exercise training has been shown to reduce chronic inflammation and, therefore, may represent an appropriate means to reduce age-related inflammation and counteract sarcopenia. Yet few studies have evaluated the effect of aging on skeletal muscle expression of inflammatory proteins and the effect of acute and repeated exercise on these factors. The aim of the current study was to determine the effect of 12 weeks of resistance exercise training on the levels of myokines within skeletal muscle, both at rest and following an acute bout of exercise and to examine how these responses may vary in young and older subjects, thus evaluating the potential for exercise to reduce age-related muscle inflammation. Six healthy young (aged 18-25 years) and 8 healthy older men (aged 60-75 years) completed 12 weeks of resistance exercise training. Muscle biopsies were collected before and 2 h after an acute exercise bout at the beginning and the end of the 12 week training period. Muscle tissue was analyzed for the expression of key inflammatory (MCP-1, IL-8, IL-6 and TNF-α) and anti-inflammatory cytokines (IL-10, IL-13 and IL-4) via bead-based multiplex analysis. Acute exercise increased the expression of inflammatory myokines, while anti-inflammatory myokines remained unchanged. In contrast to the hypothesis for this study, neither age nor training had a significant effect on the expression of myokines within skeletal muscle either in the resting state or 2 hours following exercise. However, older individuals displayed an increased inflammatory response to exercise prior to training when compared to younger individuals. Twelve weeks of resistance exercise training appeared to normalize this difference. Given the variability in myokine levels between individuals and the small subject number in the current study, further research is required to confirm this findin

Identification of MicroRNAs Linked to Regulators of Muscle Protein Synthesis and Regeneration in Young and Old Skeletal Muscle

Over the course of ageing there is a natural and progressive loss of skeletal muscle mass. The onset and progression of age-related muscle wasting is associated with an attenuated activation of Akt-mTOR signalling and muscle protein synthesis in response to anabolic stimuli such as resistance exercise. MicroRNAs (miRNAs) are novel and important post-transcriptional regulators of numerous cellular processes. The role of miRNAs in the regulation of muscle protein synthesis following resistance exercise is poorly understood. This study investigated the changes in skeletal muscle miRNA expression following an acute bout of resistance exercise in young and old subjects with a focus on the miRNA species predicted to target Akt-mTOR signalling

Enhanced skeletal muscle ribosome biogenesis, yet attenuated mTORC1 and ribosome biogenesis-related signalling, following short-term concurrent versus single-mode resistance training

Combining endurance training with resistance training (RT) may attenuate skeletal muscle hypertrophic adaptation versus RT alone; however, the underlying mechanisms are unclear. We investigated changes in markers of ribosome biogenesis, a process linked with skeletal muscle hypertrophy, following concurrent training versus RT alone. Twenty-three males underwent eight weeks of RT, either performed alone (RT group, n = 8), or combined with either high-intensity interval training (HIT+RT group, n = 8), or moderate-intensity continuous training (MICT+RT group, n = 7). Muscle samples (vastus lateralis) were obtained before training, and immediately before, 1 h and 3 h after the final training session. Training-induced changes in basal expression of the 45S ribosomal RNA (rRNA) precursor (45S pre-rRNA), and 5.8S and 28S mature rRNAs, were greater with concurrent training versus RT. However, during the final training session, RT further increased both mTORC1 (p70S6K1 and rps6 phosphorylation) and 45S pre-rRNA transcription-related signalling (TIF-1A and UBF phosphorylation) versus concurrent training. These data suggest that when performed in a training-accustomed state, RT induces further increases mTORC1 and ribosome biogenesis-related signalling in human skeletal muscle versus concurrent training; however, changes in ribosome biogenesis markers were more favourable following a period of short-term concurrent training versus RT performed alon

Erythropoietin Does Not Enhance Skeletal Muscle Protein Synthesis Following Exercise in Young and Older Adults

PURPOSE: Erythropoietin (EPO) is a renal cytokine that is primarily involved in hematopoiesis while also playing a role in non-hematopoietic tissues expressing the EPO-receptor (EPOR). The EPOR is present in human skeletal muscle. In mouse skeletal muscle, EPO stimulation can activate the AKT serine/threonine kinase 1 (AKT) signaling pathway, the main positive regulator of muscle protein synthesis. We hypothesized that a single intravenous EPO injection combined with acute resistance exercise would have a synergistic effect on skeletal muscle protein synthesis via activation of the AKT pathway. METHODS: Ten young (24.2 ± 0.9 years) and 10 older (66.6 ± 1.1 years) healthy subjects received a primed, constant infusion of [ring-13C(6)] L-phenylalanine and a single injection of 10,000 IU epoetin-beta or placebo in a double-blind randomized, cross-over design. 2 h after the injection, the subjects completed an acute bout of leg extension resistance exercise to stimulate skeletal muscle protein synthesis. RESULTS: Significant interaction effects in the phosphorylation levels of the members of the AKT signaling pathway indicated a differential activation of protein synthesis signaling in older subjects when compared to young subjects. However, EPO offered no synergistic effect on vastus lateralis mixed muscle protein synthesis rate in young or older subjects. CONCLUSIONS: Despite its ability to activate the AKT pathway in skeletal muscle, an acute EPO injection had no additive or synergistic effect on the exercise-induced activation of muscle protein synthesis or muscle protein synthesis signaling pathways

Appetite-regulatory hormone responses on the day following a prolonged bout of moderate-intensity exercise

This article was accepted for publication in the journal Physiology and Behavior [© Elsevier] and the definitive version is available at: http://dx.doi.org/10.1016/j.physbeh.2014.12.050Exercise increases energy expenditure however acutely this does not cause compensatory changes in appetite or food intake. This unresponsiveness contrasts the rapid counter-regulatory changes seen after food restriction. The present investigation examined whether corrective changes in appetite-regulatory parameters occur after a time delay, namely, on the day after a single bout of exercise. Nine healthy males completed two, two-day trials (exercise & control) in a random order. On the exercise trial participants completed 90 min of moderate-intensity treadmill running on day one (10:30–12:00 h). On day two appetite-regulatory hormones and subjective appetite perceptions were assessed frequently in response to two test meals provided at 08:00 and 12:00 h. Identical procedures occurred in the control trial except no exercise was performed on day one. Circulating levels of leptin were reduced on the day after exercise (AUC 5841 ± 3335 vs. 7266 ± 3949 ng− 1·mL− 1 · 7 h, P = 0.012). Conversely, no compensatory changes were seen for circulating acylated ghrelin, total PYY, insulin or appetite perceptions. Unexpectedly, levels of acylated ghrelin were reduced on the exercise trial following the second test meal on day two (AUC 279 ± 136 vs. 326 ± 136 pg− 1·mL− 1 · 3 h, P = 0.021). These findings indicate that short-term energy deficits induced by exercise initially prompt a compensatory response by chronic but not acute hormonal regulators of appetite and energy balance. Within this 24 h time-frame however there is no conscious recognition of the perturbation to energy balance

Surveillance of malaria vector population density and biting behaviour in western Kenya

BACKGROUND: Malaria is a great public health burden and Africa suffers the largest share of malaria-attributed deaths. Despite control efforts targeting indoor malaria transmission, such as insecticide-treated bed nets (ITNs) and deployment of indoor residual spraying, transmission of the parasite in western Kenya is still maintained. This study was carried out to determine the impact of ITNs on indoor vector densities and biting behaviour in western Kenya. METHODS: Indoor collection of adult mosquitoes was done monthly in six study sites in western Kenya using pyrethrum spray collections from 2012 to 2014. The rotator trap collections were done in July–August in 2013 and May–June in 2014. Mosquitoes were collected every 2 h between 18.00 and 08.00 h. Human behaviour study was conducted via questionnaire surveys. Species within Anopheles gambiae complex was differentiated by PCR and sporozoite infectivity was determined by ELISA. Species distribution was determined and bed net coverage in the study sites was recorded. RESULTS: During the study a total of 5,469 mosquito vectors were collected from both PSC and Rotator traps comprising 3,181 (58.2%) Anopheles gambiae and 2,288 (41.8%) Anopheles funestus. Compared to all the study sites, Rae had the highest density of An. gambiae with a mean of 1.2 (P < 0.001) while Kombewa had the highest density of An. funestus with a mean of 1.08 (P < 0.001). Marani had the lowest density of vectors with 0.06 An. gambiae and 0.17 An. funestus (P < 0.001). Among the 700 PCR confirmed An. gambiaes.l. individuals, An. gambiaes.s. accounted for 49% and An. arabiensis 51%. Over 50% of the study population stayed outdoors between 18.00 and 20.00 and 06.00 and 08.00 which was the time when highest densities of blood fed vectors were collected. Anopheles gambies.s. was the main malaria parasite vector in the highland sites and An. arabiensis in the lowland sites. Bed net ownership in 2012 averaged 87% across the study sites. CONCLUSIONS: This study suggests that mass distribution of ITNs has had a significant impact on vector densities, species distribution and sporozoite rate. However, shift of biting time poses significant threats to the current malaria vector control strategies which heavily rely on indoor controls

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P &lt; 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P &lt; 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Molecular epidemiology of drug-resistant malaria in western Kenya highlands

<p>Abstract</p> <p>Background</p> <p>Since the late 1980s a series of malaria epidemics has occurred in western Kenya highlands. Among the possible factors that may contribute to the highland malaria epidemics, parasite resistance to antimalarials has not been well investigated.</p> <p>Methods</p> <p>Using parasites from highland and lowland areas of western Kenya, we examined key mutations associated with <it>Plasmodium falciparum </it>resistance to sulfadoxine – pyrimethamine and chloroquine, including dihydrofolate reductase (<it>pfdhfr</it>) and dihydropteroate synthetase (<it>pfdhps</it>), chloroquine resistance transporter gene (<it>pfcrt</it>), and multi-drug resistance gene 1 (<it>pfmdr1</it>).</p> <p>Results</p> <p>We found that >70% of samples harbored 76T <it>pfcrt </it>mutations and over 80% of samples harbored quintuple mutations (51I/59R/108N <it>pfdhfr </it>and 437G/540E <it>pfdhps</it>) in both highland and lowland samples. Further, we did not detect significant difference in the frequencies of these mutations between symptomatic and asymptomatic malaria volunteers, and between highland and lowland samples.</p> <p>Conclusion</p> <p>These findings suggest that drug resistance of malaria parasites in the highlands could be contributed by the mutations and their high frequencies as found in the lowland. The results are discussed in terms of the role of drug resistance as a driving force for malaria outbreaks in the highlands.</p

The International Limits and Population at Risk of Plasmodium vivax Transmission in 2009

Growing evidence shows that Plasmodium vivax malaria is clinically less benign than has been commonly believed. In addition, it is the most widely distributed species of human malaria and is likely to cause more illness in certain regions than the more extensively studied P. falciparum malaria. Understanding where P. vivax transmission exists and measuring the number of people who live at risk of infection is a fundamental first step to estimating the global disease toll. The aim of this paper is to generate a reliable map of the worldwide distribution of this parasite and to provide an estimate of how many people are exposed to probable infection. A geographical information system was used to map data on the presence of P. vivax infection and spatial information on climatic conditions that impede transmission (low ambient temperature and extremely arid environments) in order to delineate areas where transmission was unlikely to take place. This map was combined with population distribution data to estimate how many people live in these areas and are, therefore, exposed to risk of infection by P. vivax malaria. The results show that 2.85 billion people were exposed to some level of risk of transmission in 2009