Understanding the effects of nutrition and post-exercise nutrition on skeletal muscle protein turnover: insights from stable isotope studies

Skeletal muscle is the largest organ of the human body and plays a pivotal role in whole-body homeostasis through the maintenance of physical and metabolic health. Establishing strategies aimed at increasing the amount, and minimising loss, of muscle mass are of upmost importance. Muscle mass is primarily dictated by the meal-to-meal fluctuations in muscle protein synthesis (MPS) and muscle protein breakdown (MPB), each of which can be quantified through the use of stable isotopically labelled tracers. Importantly, both MPS and MPB can be influenced by external factors such as nutritional manipulation, specifically protein ingestion, and changes in loading via exercise. To date, research involving stable isotopic tracers has focused on determining the optimal dose, timing surrounding bouts of exercise, distribution and composition of protein to maximally stimulate MPS and inhibit MPB, both at rest and following exercise. In this review we focus on the use of these stable isotopically-labeled tracers to unravel the intricacies of skeletal muscle protein turnover in response to specific nutritional interventions

Increased protein intake derived from leucine-enriched protein enhances the integrated myofibrillar protein synthetic response to short-term resistance training in untrained men and women: a 4-day randomized controlled trial

Leucine is a critical amino acid stimulating myofibrillar protein synthesis (MyoPS). The consumption of higher leucine-containing drinks stimulates MyoPS, but we know less about higher leucine solid foods. Here we examined the effect of short-term resistance exercise training (STRT) combined with supplementation of a protein and leucine-enriched bar, compared with STRT alone, on integrated (%/d) rates of MyoPS and anabolic protein signaling. In a non-blinded, randomized crossover trial, eight young adults performed four sessions of STRT without or while consuming the study bar (STRT+Leu, 16g of protein containing ∼3g of leucine) for two 4d phases, separated by 2d non-exercise (Rest) washout. In combination with serial muscle biopsies, deuterated water permitted the measurement of myofibrillar protein synthesis and protein signaling phosphorylation. MyoPS during STRT (1.43 ± 0.06 %/d) and STRT+Leu (1.53 ± 0.06 %/d) were greater than Rest (1.31 ± 0.05 %/d), and MyoPS during STRT+Leu (1.53 ± 0.06 %/d) was greater than STRT alone (1.43 ± 0.06 %/d). STRT+Leu increased the ratio of phosphorylated to total mTOR and 4EBP1 compared to Rest. Engaging in STRT increased integrated MyoPS and protein signaling in young adults and was enhanced with increased protein intake derived from a leucine-enriched protein bar. This study was registered at clinicaltrials.gov as NCT03796897

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Consumo de ácidos graxos n-3 e função renal: indicativos de efeitos protetores em situações patológicas

Com o aumento do consumo de ácidos graxos poli-insaturados (AGPI) n-6 em detrimento dos n-3, há maior produção de metabólitos que apresentam potentes características pró-inflamatórias, trombóticas e agregadoras. Tais efeitos são distintos das ações dos derivados dos AGPI n-3. Atualmente, estudos em modelos animais e humanos portadores de doença investigam o uso dos AGPI n-3 como potenciais modulares da função renal, que pode estar frequentemente alterada em doenças com cunho inflamatório. Em animais, a suplementação com AGPI n-3 foi capaz de prevenir o desenvolvimento de doença renal em ratos diabéticos do tipo I, melhorar o quadro de caquexia e parâmetros renais em ratos portadores de tumor, melhorar o perfil lipídico em ratos hipertensos espontâneos e também em ratos diabéticos do tipo II. Já em humanos, mesmo que a suplementação com óleo de peixe não seja completamente encorajada, existem evidências de que pacientes em diálise apresentam melhora da dislipidemia que os acomete, o que pode potencialmente prevenir alterações cardiovasculares. Tendo em vista que pesquisas utilizando AGPI  n-3 mostram modificações positivas, podendo levar a uma melhora no quadro de doenças renais já instaladas, estudos com esse foco devem ser encorajados a fim de esclarecer mecanismos de ação e revelar conclusões sobre suas aplicabilidades em diversas doenças. Nesta revisão, potenciais evidências e mecanismos envolvidos no uso do AGPI n-3 para modular a função renal modificada por doença são discutidos

Consumo de ácidos graxos n-3 e função renal: indicativos de efeitos protetores em situações patológicas

Com o aumento do consumo de ácidos graxos poli-insaturados (AGPI) n-6 em detrimento dos n-3, há maior produção de metabólitos que apresentam potentes características pró-inflamatórias, trombóticas e agregadoras. Tais efeitos são distintos das ações dos derivados dos AGPI n-3. Atualmente, estudos em modelos animais e humanos portadores de doença investigam o uso dos AGPI n-3 como potenciais modulares da função renal, que pode estar frequentemente alterada em doenças com cunho inflamatório. Em animais, a suplementação com AGPI n-3 foi capaz de prevenir o desenvolvimento de doença renal em ratos diabéticos do tipo I, melhorar o quadro de caquexia e parâmetros renais em ratos portadores de tumor, melhorar o perfil lipídico em ratos hipertensos espontâneos e também em ratos diabéticos do tipo II. Já em humanos, mesmo que a suplementação com óleo de peixe não seja completamente encorajada, existem evidências de que pacientes em diálise apresentam melhora da dislipidemia que os acomete, o que pode potencialmente prevenir alterações cardiovasculares. Tendo em vista que pesquisas utilizando AGPI  n-3 mostram modificações positivas, podendo levar a uma melhora no quadro de doenças renais já instaladas, estudos com esse foco devem ser encorajados a fim de esclarecer mecanismos de ação e revelar conclusões sobre suas aplicabilidades em diversas doenças. Nesta revisão, potenciais evidências e mecanismos envolvidos no uso do AGPI n-3 para modular a função renal modificada por doença são discutidos

The influence of omega-3 fatty acids on skeletal muscle protein turnover in health, disuse, and disease

Ingestion of omega-3 fatty acids is known to exert favorable health effects on a number of biological processes such as improved immune profile, enhanced cognition, and optimized neuromuscular function. Recently, data have emerged demonstrating a positive influence of omega-3 fatty acid intake on skeletal muscle. For instance, there are reports of clinically-relevant gains in muscle size and strength in healthy older persons with omega-3 fatty acid intake as well as evidence that omega-3 fatty acid ingestion alleviates the loss of muscle mass and prevents decrements in mitochondrial respiration during periods of muscle-disuse. Cancer cachexia that is characterized by a rapid involuntary loss of lean mass may also be attenuated by omega-3 fatty acid provision. The primary means by which omega-3 fatty acids positively impact skeletal muscle mass is via incorporation of eicosapentaenoic acid (EPA; 20:5n−3) and docosahexaenoic acid (DHA; 22:6n−3) into membrane phospholipids of the sarcolemma and intracellular organelles. Enrichment of EPA and DHA in these membrane phospholipids is linked to enhanced rates of muscle protein synthesis, decreased expression of factors that regulate muscle protein breakdown, and improved mitochondrial respiration kinetics. However, exactly how incorporation of EPA and DHA into phospholipid membranes alters these processes remains unknown. In this review, we discuss the interaction between omega-3 fatty acid ingestion and skeletal muscle protein turnover in response to nutrient provision in younger and older adults. Additionally, we examine the role of omega-3 fatty acid supplementation in protecting muscle loss during muscle-disuse and in cancer cachexia, and critically evaluate the molecular mechanisms that underpin the phenotypic changes observed in skeletal muscle with omega-3 fatty acid intake

ASSESSING THE MECHANISTIC TARGET OF RAPAMYCIN COMPLEX-1 PATHWAY IN RESPONSE TO RESISTANCE EXERCISE AND FEEDING IN HUMAN SKELETAL MUSCLE by MULTIPLEX ASSAY

ABSTRACT Background: The mechanistic target of rapamycin complex-1 (mTORC-1) is a key nutrient and contraction-sensitive protein that regulates a pathway leading to skeletal muscle growth. Utilizing a multiplex assay, we aimed to examine the phosphorylation status of key mTORC-1-related signalling molecules in response to protein feeding and resistance exercise. Methods: Eight healthy men (22.5 ± 3.1 yr, 80 ± 9 kg, 1-repetition maximum [1RM] leg extension: 87 ± 5 kg) performed 4 sets of unilateral leg extensions until volitional failure. Immediately following the final set, all participants consumed a protein-enriched beverage. A single skeletal muscle biopsy was obtained from the vastus lateralis before (Pre) with further bilateral biopsies at 1 h (1 h FEDEX and 1 h FED) and 3 h (3 h FEDEX and 3 h FED) post drink ingestion Results: Phosphorylated Akt Ser473 was significantly elevated from Pre at 1 h FEDEX. Phosphorylated p70S6K1 Thr412 was significantly increased above Pre at 1 h FEDEX and 1 h FED and was still significantly elevated at 3 h FEDEX but not 3 h FED. Phosphorylated rpS6 Ser235/236 was also significantly increased above Pre at 1 h FEDEX and 1 h FED with 1 h FEDEX greater than 1 h FED. Conclusion: Our data highlight the utility of a multiplex assay to assess anabolic signaling molecules in response to protein feeding and resistance exercise in humans. Importantly, these changes are comparable to those as previously reported using standard immunoblotting and protein activity assays.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author