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Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness.
Rademaker, G, Hennequière, V, Brohée, L, Nokin, MJ, Lovinfosse, P, Durieux, F, Gofflot, S, Bellier, J, Costanza, B, Herfs, M, et al
Oncogene. 2018;(32):4398-4412
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.
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Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients.
Fichna, JP, Macias, A, Piechota, M, Korostyński, M, Potulska-Chromik, A, Redowicz, MJ, Zekanowski, C
Human genomics. 2018;(1):34
Abstract
BACKGROUND Limb girdle muscular dystrophies (LGMD) are a group of heterogeneous hereditary myopathies with similar clinical symptoms. Disease onset and progression are highly variable, with an elusive genetic background, and around 50% cases lacking molecular diagnosis. METHODS Whole exome sequencing (WES) was performed in 73 patients with clinically diagnosed LGMD. A filtering strategy aimed at identification of variants related to the disease included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of genes expressed in muscle, analysis of the disease-associated interactome and copy number variants analysis. RESULTS Genetic diagnosis was possible in 68.5% of cases. On average, 36.3 rare variants in genes associated with various muscle diseases per patient were found that could relate to the clinical phenotype. The putative causative mutations were mostly in LGMD-associated genes, but also in genes not included in the current LGMD classification (DMD, COL6A2, and COL6A3). In three patients, mutations in two genes were suggested as the joint cause of the disease (CAPN3+MYH7, COL6A3+CACNA1S, DYSF+MYH7). Moreover, a variety of phenotype-influencing variants were postulated, including in patients with an identified already known primary pathogenic mutation. CONCLUSIONS We hypothesize that LGMD could be better described as oligogenic disorders in which dominant clinical presentation can result from the combined effect of mutations in a set of genes. In this view, the inter- and intrafamilial variability could reflect a specific genetic background and the presence of sets of phenotype-influencing or co-causative mutations in genes that either interact with the known LGMD-associated genes or are a part of the same pathways or structures.
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Presleep dietary protein-derived amino acids are incorporated in myofibrillar protein during postexercise overnight recovery.
Trommelen, J, Kouw, IWK, Holwerda, AM, Snijders, T, Halson, SL, Rollo, I, Verdijk, LB, van Loon, LJC
American journal of physiology. Endocrinology and metabolism. 2018;(5):E457-E467
Abstract
The purpose of this study was to determine the impact of ingesting 30 g casein protein with and without 2 g free leucine before sleep on myofibrillar protein synthesis rates during postexercise overnight recovery. Thirty-six healthy young men performed a single bout of resistance-type exercise in the evening (1945) after a full day of dietary standardization. Thirty minutes before sleep (2330), subjects ingested 30 g intrinsically l-[1-13C]phenylalanine-labeled protein with (PRO+leu, n = 12) or without (PRO, n = 12) 2 g free leucine, or a noncaloric placebo (PLA, n = 12). Continuous intravenous l-[ ring-2H5]phenylalanine, l-[1-13C]leucine, and l-[ ring-2H2]tyrosine infusions were applied. Blood and muscle tissue samples were collected to assess whole body protein net balance, myofibrillar protein synthesis rates, and overnight incorporation of dietary protein-derived amino acids into myofibrillar protein. Protein ingestion before sleep improved overnight whole body protein net balance ( P < 0.001). Myofibrillar protein synthesis rates did not differ significantly between treatments as assessed by l-[ ring-2H5]phenylalanine (0.057 ± 0.002, 0.055 ± 0.002, and 0.055 ± 0.004%/h for PLA, PRO, and PRO+leu, respectively; means ± SE; P = 0.850) or l-[1-13C]leucine (0.080 ± 0.004, 0.073 ± 0.004, and 0.083 ± 0.006%/h, respectively; P = 0.328). Myofibrillar l-[1-13C]phenylalanine enrichments increased following protein ingestion but did not differ between the PRO and PRO+leu treatments. In conclusion, protein ingestion before sleep improves whole body protein net balance and provides amino acids that are incorporated into myofibrillar protein during sleep. However, the ingestion of 30 g casein protein with or without additional free leucine before sleep does not increase muscle protein synthesis rates during postexercise overnight recovery.
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Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.
Vanninen, SUM, Leivo, K, Seppälä, EH, Aalto-Setälä, K, Pitkänen, O, Suursalmi, P, Annala, AP, Anttila, I, Alastalo, TP, Myllykangas, S, et al
PloS one. 2018;(9):e0203422
Abstract
During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.
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Effect of dietary arachidonic acid supplementation on acute muscle adaptive responses to resistance exercise in trained men: a randomized controlled trial.
Mitchell, CJ, D'Souza, RF, Figueiredo, VC, Chan, A, Aasen, K, Durainayagam, B, Mitchell, S, Sinclair, AJ, Egner, IM, Raastad, T, et al
Journal of applied physiology (Bethesda, Md. : 1985). 2018;(4):1080-1091
Abstract
Arachidonic acid (ARA), a polyunsaturated ω-6 fatty acid, acts as precursor to a number of prostaglandins with potential roles in muscle anabolism. It was hypothesized that ARA supplementation might enhance the early anabolic response to resistance exercise (RE) by increasing muscle protein synthesis (MPS) via mammalian target of rapamycin (mTOR) pathway activation and/or the late anabolic response by modulating ribosome biogenesis and satellite cell expansion. Nineteen men with ≥1 yr of resistance-training experience were randomized to consume either 1.5 g daily ARA or a corn-soy-oil placebo in a double-blind manner for 4 wk. Participants then undertook fasted RE (8 sets each of leg press and extension at 80% 1-repetition maximum), with vastus lateralis biopsies obtained before exercise, immediately postexercise, and at 2, 4, and 48 h of recovery. MPS (measured via stable isotope infusion) was not different between groups ( P = 0.212) over the 4-h recovery period. mTOR pathway members p70 S6 kinase and S6 ribosomal protein were phosphorylated postexercise ( P < 0.05), with no difference between groups. 45S preribosomal RNA increased 48 h after exercise only in ARA ( P = 0.012). Neural cell adhesion molecule-positive satellite cells per fiber increased 48 h after exercise ( P = 0.013), with no difference between groups ( P = 0.331). Prior ARA supplementation did not alter the acute anabolic response to RE in previously resistance-trained men; however, at 48 h of recovery, ribosome biogenesis was stimulated only in the ARA group. The findings do not support a mechanistic link between ARA and short-term anabolism, but ARA supplementation in conjunction with resistance training may stimulate increases in translational capacity. NEW & NOTEWORTHY Four weeks of daily arachidonic acid supplementation in trained men did not alter their acute muscle protein synthetic or anabolic signaling response to resistance exercise. However, 48 h after exercise, men supplemented with arachidonic acid showed greater ribosome biogenesis and a trend toward greater change in satellite cell content. Chronic arachidonic acid supplementation does not appear to regulate the acute anabolic response to resistance exercise but may augment muscle adaptation in the following days of recovery.
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Nutritional Considerations in Preventing Muscle Atrophy.
Cretoiu, SM, Zugravu, CA
Advances in experimental medicine and biology. 2018;:497-528
Abstract
Muscle atrophy may occur under different circumstances throughout a person's life. These conditions include periods of immobilization of a limb or of the whole body and aging accompanied by the onset of sarcopenia. Muscle mass is reduced as a result of decreased protein synthesis or increased protein degradation. Most studies aim to prevent the degradation of muscle proteins, but the way in which protein synthesis can be stimulated is often neglected. This study will provide an up-to-date review regarding nutritional considerations and resistance exercise countermeasures in the prevention of muscle mass loss and recovery of muscle mass in muscle atrophy secondary to immobilization or in sarcopenic obesity. We do not address muscle atrophy in disease states associated with inflammation (rheumatoid arthritis, COPD, cancer cachexia, AIDS, burns, sepsis, and uremia) which are governed by particular mechanisms of muscle loss.
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[Amino Acid Nutrition in the Prevention and Treatment of Sarcopenia].
Kobayashi, H
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2018;(10):1277-1283
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Abstract
Sarcopenia is the decrease in skeletal muscle mass and muscular function that occurs with aging. The underlying mechanisms of sarcopenia include anabolic resistance, which is defined as a poor muscle protein synthetic response to previously effective stimuli such as nutrients and exercise. Among the nutrients that humans ingest, amino acids directly trigger the synthesis of muscle proteins. The essential amino acid leucine, in particular, functions as a stimulatory signal. Leucine-enriched essential amino acids help overcome anabolic resistance in elderly individuals to effectively stimulate muscle protein synthesis. Long-term intake of leucine-enriched essential amino acids has a synergistic effect with exercise to increase skeletal muscle mass, strength, and walking speed in elderly individuals, and can be an effective countermeasure to sarcopenia.
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Achieving Optimal Post-Exercise Muscle Protein Remodeling in Physically Active Adults through Whole Food Consumption.
Vliet, SV, Beals, JW, Martinez, IG, Skinner, SK, Burd, NA
Nutrients. 2018;(2)
Abstract
Dietary protein ingestion is critical to maintaining the quality and quantity of skeletal muscle mass throughout adult life. The performance of acute exercise enhances muscle protein remodeling by stimulating protein synthesis rates for several hours after each bout, which can be optimized by consuming protein during the post-exercise recovery period. To date, the majority of the evidence regarding protein intake to optimize post-exercise muscle protein synthesis rates is limited to isolated protein sources. However, it is more common to ingest whole food sources of protein within a normal eating pattern. Emerging evidence demonstrates a promising role for the ingestion of whole foods as an effective nutritional strategy to support muscle protein remodeling and recovery after exercise. This review aims to evaluate the efficacy of the ingestion of nutrient-rich and protein-dense whole foods to support post-exercise muscle protein remodeling and recovery with pertinence towards physically active people.
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Is There a Postworkout Anabolic Window of Opportunity for Nutrient Consumption? Clearing up Controversies.
Schoenfeld, BJ, Aragon, AA
The Journal of orthopaedic and sports physical therapy. 2018;(12):911-914
Abstract
Nutrient timing is a popular strategy for enhancing muscular adaptations and athletic performance. From the standpoint of muscle hypertrophy, the concept of a "postworkout anabolic window of opportunity" has been proposed, whereby a limited time exists after training to optimize accretion of muscle proteins. Some researchers have gone so far as to claim that the timing of nutritional consumption is even more critical to muscle development than the absolute daily consumption of nutrients. Thus, the purpose of this paper is to review the current literature as to the relevance of the anabolic window of opportunity, and draw evidence-based conclusions for application into practice. J Orthop Sports Phys Ther 2018;48(12):911-914. doi:10.2519/jospt.2018.0615.
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A randomized controlled trial of the impact of protein supplementation on leg lean mass and integrated muscle protein synthesis during inactivity and energy restriction in older persons.
Oikawa, SY, McGlory, C, D'Souza, LK, Morgan, AK, Saddler, NI, Baker, SK, Parise, G, Phillips, SM
The American journal of clinical nutrition. 2018;(5):1060-1068
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Abstract
BACKGROUND In older persons, muscle loss is accelerated during physical inactivity and hypoenergetic states, both of which are features of hospitalization. Protein supplementation may represent a strategy to offset the loss of muscle during inactivity, and enhance recovery on resumption of activity. OBJECTIVE We aimed to determine if protein supplementation, with proteins of substantially different quality, would alleviate the loss of lean mass by augmenting muscle protein synthesis (MPS) while inactive during a hypoenergetic state. DESIGN Participants (16 men, mean ± SD age: 69 ± 3 y; 15 women, mean ± SD age: 68 ± 4 y) consumed a diet containing 1.6 g protein · kg-1 · d-1, with 55% ± 9% of protein from foods and 45% ± 9% from supplements, namely, whey protein (WP) or collagen peptides (CP): 30 g each, consumed 2 times/d. Participants were in energy balance (EB) for 1 wk, then began a period of energy restriction (ER; -500 kcal/d) for 1 wk, followed by ER with step reduction (ER + SR; <750 steps/d) for 2 wk, before a return to habitual activity in recovery (RC) for 1 wk. RESULTS There were significant reductions in leg lean mass (LLM) from EB to ER, and from ER to ER + SR in both groups (P < 0.001) with no differences between WP and CP or when comparing the change from phase to phase. During RC, LLM increased from ER + SR, but in the WP group only. Rates of integrated muscle protein synthesis decreased during ER and ER + SR in both groups (P < 0.01), but increased during RC only in the WP group (P = 0.05). CONCLUSIONS Protein supplementation did not confer a benefit in protecting LLM, but only supplemental WP augmented LLM and muscle protein synthesis during recovery from inactivity and a hypoenergetic state. This trial was registered at http://www.clinicaltrials.gov as NCT03285737.