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OBJECTIVE: This study aimed to assess the impact of time-restricted eating (TRE) on integrated skeletal muscle myofibrillar protein synthesis (MyoPS) rates in males with overweight/obesity.METHODS: A total of 18 healthy males (age 46 ± 5 years; BMI: 30 ± 2 kg/m2 ) completed this exploratory, parallel, randomized dietary intervention after a 3-day lead-in diet. Participants then consumed an isoenergetic diet (protein: ~1.0 g/kg body mass per day) following either TRE (10:00 a.m. to 6:00 p.m.) or an extended eating control (CON; 8:00 a.m. to 8:00 p.m.) protocol for 10 days. Integrated MyoPS rates were measured using deuterated water administration with repeated saliva, blood, and muscle sampling. Secondary measures included continuous glucose monitoring and body composition (dual-energy x-ray absorptiometry).RESULTS: There were no differences in daily integrated MyoPS rates (TRE: 1.28% ± 0.18% per day, CON: 1.26% ± 0.22% per day; p = 0.82) between groups. From continuous glucose monitoring, 24-hour total area under the curve was reduced following TRE (-578 ± 271 vs. CON: 12 ± 272 mmol/L × 24 hours; p = 0.001). Total body mass declined (TRE: -1.6 ± 0.9 and CON: -1.1 ± 0.7 kg; p CONCLUSION: Consuming food within an 8-hour time-restricted period does not lower daily MyoPS rates when compared with an isoenergetic diet consumed over 12 hours. Future research should investigate whether these results translate to free-living TRE.

Rationale: Dietary protein may attenuate the muscle atrophy experienced by patients in the ICU, yet protein handling is poorly understood. Objectives: To quantify protein digestion and amino acid absorption and fasting and postprandial myofibrillar protein synthesis during critical illness. Methods: Fifteen mechanically ventilated adults (12 male; aged 50 ± 17 yr; body mass index, 27 ± 5 kg⋅m-2) and 10 healthy control subjects (6 male; 54 ± 23 yr; body mass index, 27 ± 4 kg⋅m-2) received a primed intravenous L-[ring-2H5]-phenylalanine, L-[3,5-2H2]-tyrosine, and L-[1-13C]-leucine infusion over 9.5 hours and a duodenal bolus of intrinsically labeled (L-[1-13C]-phenylalanine and L-[1-13C]-leucine) intact milk protein (20 g protein) over 60 minutes. Arterial blood and muscle samples were taken at baseline (fasting) and for 6 hours following duodenal protein administration. Data are mean ± SD, analyzed with two-way repeated measures ANOVA and independent samples t test. Measurements and Main Results: Fasting myofibrillar protein synthesis rates did not differ between ICU patients and healthy control subjects (0.023 ± 0.013% h-1 vs. 0.034 ± 0.016% h-1; P = 0.077). After protein administration, plasma amino acid availability did not differ between groups (ICU patients, 54.2 ± 9.1%, vs. healthy control subjects, 61.8 ± 13.1%; P = 0.12), and myofibrillar protein synthesis rates increased in both groups (0.028 ± 0.010% h-1 vs. 0.043 ± 0.018% h-1; main time effect P = 0.046; P-interaction = 0.584) with lower rates in ICU patients than in healthy control subjects (main group effect P = 0.001). Incorporation of protein-derived phenylalanine into myofibrillar protein was ∼60% lower in ICU patients (0.007 ± 0.007 mol percent excess vs. 0.017 ± 0.009 mol percent excess; P = 0.007). Conclusions: The capacity for critically ill patients to use ingested protein for muscle protein synthesis is markedly blunted despite relatively normal protein digestion and amino acid absorption.

Plant-derived proteins have been suggested to have less anabolic properties when compared with animal-derived proteins. Whether blends of plant- and animal-derived proteins can compensate for their lesser anabolic potential has not been assessed. The present study compares post-prandial muscle protein synthesis rates following the ingestion of milk protein with wheat protein or a blend of wheat plus milk protein in healthy, young males. In a randomised, double-blind, parallel-group design, 36 males (23 (sd 3) years) received a primed continuous L-[ring-13C6]-phenylalanine infusion after which they ingested 30 g milk protein (MILK), 30 g wheat protein (WHEAT) or a 30 g blend combining 15 g wheat plus 15 g milk protein (WHEAT+MILK). Blood and muscle biopsies were collected frequently for 5 h to assess post-prandial plasma amino acid profiles and subsequent myofibrillar protein synthesis rates. Ingestion of protein increased myofibrillar protein synthesis rates in all treatments (P < 0·001). Post-prandial myofibrillar protein synthesis rates did not differ between MILK v. WHEAT (0·053 (sd 0·013) v. 0·056 (sd 0·012) %·h−1, respectively; t test P = 0·56) or between MILK v. WHEAT+MILK (0·053 (sd 0·013) v. 0·059 (sd 0·025) %·h−1, respectively; t test P = 0·46). In conclusion, ingestion of 30 g milk protein, 30 g wheat protein or a blend of 15 g wheat plus 15 g milk protein increases muscle protein synthesis rates in young males. Furthermore, muscle protein synthesis rates following the ingestion of 30 g milk protein do not differ from rates observed after ingesting 30 g wheat protein or a blend with 15 g milk plus 15 g wheat protein in healthy, young males.

Addressing skeletal muscle mass loss is an important focus in oncology research to improve clinical outcomes, including cancer treatment tolerability and survival. Exercise is likely a necessary component of muscle-mass-preserving interventions for people with cancer. However, randomized controlled trials with exercise that include people with cancer with increased susceptibility to more rapid and severe muscle mass loss are limited. The aim of the current review is to highlight features of cancer-related skeletal muscle mass loss, discuss the impact in patients most at risk, and describe the possible role of exercise as a management strategy. We present current gaps within the exercise oncology literature and offer several recommendations for future studies to support research translation, including (1) utilizing accurate and reliable body composition techniques to assess changes in skeletal muscle mass, (2) incorporating comprehensive assessments of patient health status to allow personalized exercise prescription, (3) coupling exercise with robust nutritional recommendations to maximize the impact on skeletal muscle outcomes, and (4) considering key exercise intervention features that may improve exercise efficacy and adherence. Ultimately, the driving forces behind skeletal muscle mass loss are complex and may impede exercise tolerability and efficacy. Our recommendations are intended to foster the design of high-quality patient-centred research studies to determine whether exercise can counteract muscle mass loss in people with cancer and, as such, improve knowledge on this topic.

Addressing skeletal muscle mass loss is an important focus in oncology research to improve clinical outcomes, including cancer treatment tolerability and survival. Exercise is likely a necessary component of muscle-mass-preserving interventions for people with cancer. However, randomized controlled trials with exercise that include people with cancer with increased susceptibility to more rapid and severe muscle mass loss are limited. The aim of the current review is to highlight features of cancer-related skeletal muscle mass loss, discuss the impact in patients most at risk, and describe the possible role of exercise as a management strategy. We present current gaps within the exercise oncology literature and offer several recommendations for future studies to support research translation, including (1) utilizing accurate and reliable body composition techniques to assess changes in skeletal muscle mass, (2) incorporating comprehensive assessments of patient health status to allow personalized exercise prescription, (3) coupling exercise with robust nutritional recommendations to maximize the impact on skeletal muscle outcomes, and (4) considering key exercise intervention features that may improve exercise efficacy and adherence. Ultimately, the driving forces behind skeletal muscle mass loss are complex and may impede exercise tolerability and efficacy. Our recommendations are intended to foster the design of high-quality patient-centred research studies to determine whether exercise can counteract muscle mass loss in people with cancer and, as such, improve knowledge on this topic.

Key points Protein ingestion and cooling are strategies employed by athletes to improve postexercise recovery and, as such, to facilitate muscle conditioning. However, whether cooling affects postprandial protein handling and subsequent muscle protein synthesis rates during recovery from exercise has not been assessed.We investigated the effect of postexercise cooling on the incorporation of dietary protein‐derived amino acids into muscle protein and acute postprandial (hourly) as well as prolonged (daily) myofibrillar protein synthesis rates during recovery from resistance‐type exercise over 2 weeks.Cold‐water immersion during recovery from resistance‐type exercise lowers the capacity of the muscle to take up and/or direct dietary protein‐derived amino acids towards de novo myofibrillar protein accretion. In addition, cold‐water immersion during recovery from resistance‐type exercise lowers myofibrillar protein synthesis rates during prolonged resistance‐type exercise training.Individuals aiming to improve skeletal muscle conditioning should reconsider applying cooling as a part of their postexercise recovery strategy. Abstract We measured the impact of postexercise cooling on acute postprandial (hourly) as well as prolonged (daily) myofibrillar protein synthesis rates during adaptation to resistance‐type exercise over 2 weeks. Twelve healthy males (aged 21 ± 2 years) performed a single resistance‐type exercise session followed by water immersion of both legs for 20 min. One leg was immersed in cold water (8°C: CWI), whereas the other leg was immersed in thermoneutral water (30°C: CON). After water immersion, a beverage was ingested containing 20 g of intrinsically (l‐[1‐13C]‐phenylalanine and l‐[1‐13C]‐leucine) labelled milk protein with 45 g of carbohydrates. In addition, primed continuous l‐[ring‐2H5]‐phenylalanine and l‐[1‐13C]‐leucine infusions were applied, with frequent collection of blood and muscle samples to assess myofibrillar protein synthesis rates in vivo over a 5 h recovery period. In addition, deuterated water (2H2O) was applied with the collection of saliva, blood and muscle biopsies over 2 weeks to assess the effects of postexercise cooling with protein intake on myofibrillar protein synthesis rates during more prolonged resistance‐type exercise training (thereby reflecting short‐term training adaptation). Incorporation of dietary protein‐derived l‐[1‐13C]‐phenylalanine into myofibrillar protein was significantly lower in CWI compared to CON (0.016 ± 0.006 vs. 0.021 ± 0.007 MPE; P = 0.016). Postexercise myofibrillar protein synthesis rates were lower in CWI compared to CON based upon l‐[1‐13C]‐leucine (0.058 ± 0.011 vs. 0.072 ± 0.017% h−1, respectively; P = 0.024) and l‐[ring‐2H5]‐phenylalanine (0.042 ± 0.009 vs. 0.053 ± 0.013% h−1, respectively; P = 0.025). Daily myofibrillar protein synthesis rates assessed over 2 weeks were significantly lower in CWI compared to CON (1.48 ± 0.17 vs. 1.67 ± 0.36% day−1, respectively; P = 0.042). Cold‐water immersion during recovery from resistance‐type exercise reduces myofibrillar protein synthesis rates and, as such, probably impairs muscle conditioning., Key points Protein ingestion and cooling are strategies employed by athletes to improve postexercise recovery and, as such, to facilitate muscle conditioning. However, whether cooling affects postprandial protein handling and subsequent muscle protein synthesis rates during recovery from exercise has not been assessed.We investigated the effect of postexercise cooling on the incorporation of dietary protein‐derived amino acids into muscle protein and acute postprandial (hourly) as well as prolonged (daily) myofibrillar protein synthesis rates during recovery from resistance‐type exercise over 2 weeks.Cold‐water immersion during recovery from resistance‐type exercise lowers the capacity of the muscle to take up and/or direct dietary protein‐derived amino acids towards de novo myofibrillar protein accretion. In addition, cold‐water immersion during recovery from resistance‐type exercise lowers myofibrillar protein synthesis rates during prolonged resistance‐type exercise training.Individuals aiming to improve skeletal muscle conditioning should reconsider applying cooling as a part of their postexercise recovery strategy.

Rationale: Muscle mass maintenance is largely regulated by the postprandial rise in muscle protein synthesis rates. It remains unclear whether postprandial protein handling differs between women and men.Methods: Healthy men (43 +/- 3 years; body mass index, 23.4 +/- 0.4 kg/m(2); n = 12) and women (46 +/- 2 years; body mass index, 21.3 +/- 0.5 kg/m(2); n = 12) received primed continuous infusions of L-[ring-H-2(5)]-phenylalanine and L-[ring-3,5-H-2(2)]-tyrosine and ingested 25 g intrinsically L-[1-C-13]-phenylalanine-labeled whey protein. Blood samples and muscle biopsies were collected to assess dietary protein digestion and amino acid absorption kinetics as well as basal and postprandial myofibrillar protein synthesis rates.Results: Plasma phenylalanine and leucine concentrations rapidly increased after protein ingestion (both P Conclusions: There are no differences in postabsorptive myofibrillar protein synthesis rates between middle-aged women and men. The myofibrillar protein synthetic response to the ingestion of 25 g whey protein is greater in women than in men.

This review provides an update on recent research assessing the effect of pre-sleep protein ingestion on muscle protein synthesis rates during overnight sleep and the skeletal muscle adaptive response to exercise training. Protein ingested prior to sleep is effectively digested and absorbed during overnight sleep, thereby increasing overnight muscle protein synthesis rates. Protein consumption prior to sleep does not appear to reduce appetite during breakfast the following day and does not change resting energy expenditure. When applied over a prolonged period of resistance-type exercise training, pre-sleep protein supplementation has a beneficial effect on the increase in muscle mass and strength. Protein ingestion before sleep is hypothesized to represent an effective nutritional strategy to preserve muscle mass in the elderly, especially when combined with physical activity or muscle contraction by means of neuromuscular electrical stimulation. In conclusion, protein ingestion prior to sleep is an effective interventional strategy to increase muscle protein synthesis rates during overnight sleep and can be applied to support the skeletal muscle adaptive response to resistance-type exercise training.

Objectives: Short successive periods of skeletal muscle disuse have been suggested to substantially contribute to the observed loss of skeletal muscle mass over the life span. Hospitalization of older individuals due to acute illness, injury, or major surgery generally results in a mean hospital stay of 5 to 7 days, during which the level of physical activity is strongly reduced. We hypothesized that hospitalization following elective total hip arthroplasty is accompanied by substantial leg muscle atrophy in older men and women. Design and participants: Twenty-six older patients (75 ± 1 years) undergoing elective total hip arthroplasty participated in this observational study. Measurements: On hospital admission and on the day of discharge, computed tomographic (CT) scans were performed to assess muscle cross-sectional area (CSA) of both legs. During surgery and on the day of hospital discharge, a skeletal muscle biopsy was taken from the m. vastus lateralis of the operated leg to assess muscle fiber type–specific CSA. Results: An average of 5.6 ± 0.3 days of hospitalization resulted in a significant decline in quadriceps (−3.4% ± 1.0%) and thigh muscle CSA (−4.2% ± 1.1%) in the nonoperated leg (P < .05). Edema resulted in a 10.3% ± 1.7% increase in leg CSA in the operated leg (P < .05). At hospital admission, muscle fiber CSA was smaller in the type II vs type I fibers (3326 ± 253 μm2 vs 4075 ± 279 μm2, respectively; P < .05). During hospitalization, type I and II muscle fiber CSA tended to increase, likely due to edema in the operated leg (P = .10). Conclusions: Six days of hospitalization following elective total hip arthroplasty leads to substantial leg muscle atrophy in older patients. Effective intervention strategies are warranted to prevent the loss of muscle mass induced by short periods of muscle disuse during hospitalization.

Objective Hospitalization is generally accompanied by changes in food intake. Patients typically receive hospital meals upon personal preference within the framework of the food administration services of the hospital. In the present study, we assessed food provision and actual food and snack consumption in older patients admitted for elective hip or knee arthroplasty. Design A prospective observational study. Setting Orthopedic nursing ward of the Maastricht University Medical Centre+. Participants In the present study, n=101 patients (age: 67±10 y; hospital stay: 6.1±1.8 d) were monitored during hospitalization following elective hip or knee arthroplasty. Measurements Energy and protein provided by self-selected hospital meals and snacks, and actual energy and protein (amount, distribution, and source) consumed by patients was weighed and recorded throughout 1–6 days. Results Self-selected meals provided 6.5±1.5 MJ·d-1, with 16, 48, and 34 En% provided as protein, carbohydrate, and fat, respectively. Self-selected hospital meals provided 0.75±0.16 and 0.79±0.21 g·kg-1·d-1 protein in males and females, respectively. Actual protein consumption averaged merely 0.59±0.18 and 0.50±0.21 g·kg-1·d-1, respectively. Protein consumption at breakfast, lunch, and dinner averaged 16±8, 18±9, and 20±6 g per meal, respectively. Conclusions Though self-selected hospital meals provide patients with ∼0.8 g·kg-1·d-1 protein during short-term hospitalization, actual protein consumption falls well below 0.6 g·kg-1·d-1 with a large proportion (∼32%) of the provided food being discarded. Alternative strategies are required to ensure maintenance of habitual protein intake in older patients admitted for elective orthopedic surgery. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s12603-019-1157-2 and is accessible for authorized users.

Protein ingestion and exercise stimulate myofibrillar protein synthesis rates. When combined, exercise further increases the postprandial rise in myofibrillar protein synthesis rates. It remains unclear whether protein ingestion with or without exercise also stimulates muscle connective tissue protein synthesis rates. The authors assessed the impact of presleep protein ingestion on overnight muscle connective tissue protein synthesis rates at rest and during recovery from resistance-type exercise in older men. Thirty-six healthy, older men were randomly assigned to ingest 40 g intrinsically L-[1-13C]-phenylalanine and L-[1-13C]-leucine-labeled casein protein (PRO, n = 12) or a nonprotein placebo (PLA, n = 12) before going to sleep. A third group performed a single bout of resistance-type exercise in the evening before ingesting 40 g intrinsically-labeled casein protein prior to sleep (EX+PRO, n = 12). Continuous intravenous infusions of L-[ring-2H5]-phenylalanine and L-[1-13C]-leucine were applied with blood and muscle tissue samples collected throughout overnight sleep. Presleep protein ingestion did not increase muscle connective tissue protein synthesis rates (0.049 ± 0.013 vs. 0.060 ± 0.024%/hr in PLA and PRO, respectively; p = .73). Exercise plus protein ingestion resulted in greater overnight muscle connective tissue protein synthesis rates (0.095 ± 0.022%/hr) when compared with PLA and PRO (p p de novo muscle connective tissue protein synthesis during overnight sleep.

Purpose To compare endocrine responses to intermittent vs continuous enteral nutrition provision during short-term bed rest. Methods Twenty healthy men underwent 7 days of bed rest, during which they were randomized to receive enteral nutrition (47%E as carbohydrate, 34%E as fat, 16%E as protein and 3%E as fibre) in a continuous (CONTINUOUS; n = 10; 24 h day−1 at a constant rate) or intermittent (INTERMITTENT; n = 10; as 4 meals per day separated by 5 h) pattern. Daily plasma samples were taken every morning to assess metabolite/hormone concentrations. Results During bed rest, plasma leptin concentrations were elevated to a lesser extent with INTERMITTENT vs CONTINUOUS (iAUC: 0.42 ± 0.38 vs 0.95 ± 0.48 nmol L−1, respectively; P = 0.014) as were insulin concentrations (interaction effect, P −1 in CONTINUOUS, compared to 94 ± 38 pmol L−1 in INTERMITTENT (P = 0.001). Changes in glucose infusion rate were positively correlated with changes in fasting plasma GLP-1 concentrations (r = 0.44, P = 0.049). Conclusion Intermittent enteral nutrition attenuates the progressive rise in plasma leptin and insulinemia seen with continuous feeding during bed rest, suggesting that continuous feeding increases insulin requirements to maintain euglycemia. This raises the possibility that hepatic insulin sensitivity is impaired to a greater extent with continuous versus intermittent feeding during bed rest. To attenuate endocrine and metabolic changes with enteral feeding, an intermittent feeding strategy may, therefore, be preferable to continuous provision of nutrition. This trial was registered on clinicaltrials.gov as NCT02521025.

Background Malnutrition is prevalent in hospitalized patients. To support muscle maintenance in older and chronically ill patients, a protein intake of 1.2-1.5 g/kg/d has been recommended during hospitalization. We assessed daily protein intake levels and distribution in older patients at risk for malnutrition during hospitalization. Methods In this prospective, observational study, we measured actual food and food supplement consumption in patients (n= 102; age, 68 +/- 14 years; hospital stay, 14 [8-28] days) at risk of malnutrition during hospitalization. Food provided by hospital meals, ONS, and snacks and the actual amount of food (not) consumed were weighed and recorded for all patients. Results Hospital meals provided 1.03 [0.77-1.26] protein, whereas actual protein consumption was only 0.65 [0.37-0.93] g/kg/d. Protein intake at breakfast, lunch, and dinner was 10 [6-15], 9 [5-14], and 13 [9-18] g, respectively. The use of ONS (n= 62) resulted in greater energy (1.26 [0.40-1.79] MJ/d, 300 [100-430] kcal/d) and protein intake levels (11 [4-16] g/d), without changing the macronutrient composition of the diet. Conclusion Despite protein provision of similar to 1.0 g/kg/d, protein intake remains well below these values (similar to 0.65 g/kg/d), as 30%-40% of the provided food and supplements is not consumed. Provision of ONS may increase energy and protein intake but does not change the macronutrient composition of the diet. Current nutrition strategies to achieve the recommended daily protein intake in older patients during their hospitalization are not as effective as generally assumed.

OBJECTIVES: The muscle protein synthetic response to the ingestion of animal based proteins has been reported to be superior to the ingestion of plant based proteins. The lesser anabolic properties of plant based compared with animal based proteins has been attributed to differences in essential amino acid (EAA) contents and amino acid composition. This study compares post-prandial muscle protein synthesis rates following the ingestion of 30 g milk protein with the ingestion of 30 g corn protein or a blend of 30 g corn and milk protein in vivo, in young males. METHODS: In a randomized, double blind, parallel-group design, 36 healthy young males (26 ± 4 y) received a primed continuous infusion of L-[ring-(13)C(6)]-phenylalanine and ingested 30 g milk protein (MILK), 30 g corn protein (CORN), or a blend of 15 g corn protein plus 15 g milk protein (CORN + MILK) (n = 12 per group). Blood and muscle biopsies were collected for 5 h following protein ingestion to assess post-prandial plasma amino acid profiles and myofibrillar protein synthesis rates. Data were analyzed with 2-way repeated measures ANOVA and independent samples t-test. Data are expressed as mean ± SD. RESULTS: MILK increased plasma EAA concentrations more when compared to CORN (incremental area under curve (iAUC): 151 ± 31 vs 77 ± 19 mmol/L/300 min, respectively; P

Background: Dietary protein ingestion stimulates muscle protein synthesis by providing amino acids to the muscle. The magnitude and duration of the postprandial increase in muscle protein synthesis rates are largely determined by dietary protein digestion and amino acid absorption kinetics.Objective: We assessed the impact of protein type, protein dose, and age on dietary protein digestion and amino acid absorption kinetics in vivo in humans.Methods: We included data from 18 randomized controlled trials with a total of 602 participants [age: 53 +/- 23 y; BMI (kg/m(2)): 24.8 +/- 3.3] who consumed various quantities of intrinsically L-[1-C-13]-phenylalanine-labeled whey (n = 137), casein (n = 393), or milk (n = 72) protein and received intravenous infusions of L-[ring-H-2(5)]-phenylalanine, which allowed us to assess protein digestion and phenylalanine absorption kinetics and the postprandial release of dietary protein-derived phenylalanine into the circulation. The effect of aging on these processes was assessed in a subset of 82 young (aged 22 +/- 3 y) and 83 older (aged 71 +/- 5 y) individuals.Results: A total of 50% +/- 14% of dietary protein-derived phenylalanine appeared in the circulation over a 5-h postprandial period. Casein ingestion resulted in a smaller (45% +/- 11%), whey protein ingestion in an intermediate (57% +/- 10%), and milk protein ingestion in a greater (65% +/- 13%) fraction of dietary protein-derived phenylalanine appearing in the circulation (P Conclusions: Protein type, protein dose, and age modulate dietary protein digestion and amino acid absorption kinetics and subsequent postprandial plasma amino acid availability in vivo in humans. These trials were registered at clinicaltrials.gov as NCT00557388, NCT00936039, NCT00991523, NCT01317511, NCT01473576, NCT01576848, NCT01578590, NCT01615276, NCT01680146, NCT01820975, NCT01986842, and NCT02596542, and at http://www.trialregister.nl as NTR3638, NTR3885, NTR4060, NTR4429, and NTR4492.

Short periods of bed rest lead to the loss of muscle mass and quality. It has been speculated that dietary feeding pattern may have an impact upon muscle protein synthesis rates and, therefore, modulate the loss of muscle mass and quality. We subjected 20 healthy men (age: 25 ± 1 yr, body mass index: 23.8 ± 0.8 kg/m2) to 1 wk of strict bed rest with intermittent (4 meals/day) or continuous (24 h/day) enteral tube feeding. Participants consumed deuterium oxide for 7 days before bed rest and throughout the 7-day bed rest period. Prior to and immediately after bed rest, lean body mass (dual energy X-ray absorptiometry), quadriceps cross-sectional area (CSA; CT), maximal oxygen uptake capacity (V̇o2peak), and whole body insulin sensitivity (hyperinsulinemic-euglycemic clamp) were assessed. Muscle biopsies were collected 7 days before, 1 day before, and immediately after bed rest to assess muscle tracer incorporation. Bed rest resulted in 0.3 ± 0.3 vs. 0.7 ± 0.4 kg lean tissue loss and a 1.1 ± 0.6 vs. 0.8 ± 0.5% decline in quadriceps CSA in the intermittent vs. continuous feeding group, respectively (both P < 0.05), with no differences between groups (both P > 0.05). Moreover, feeding pattern did not modulate the bed rest-induced decline in insulin sensitivity (−46 ± 3% vs. 39 ± 3%; P < 0.001) or V̇o2peak(−2.5 ± 2.2 vs. −8.6 ± 2.2%; P < 0.010) (both P > 0.05). Myofibrillar protein synthesis rates during bed rest did not differ between the intermittent and continuous feeding group (1.33 ± 0.07 vs. 1.50 ± 0.13%/day, respectively; P > 0.05). In conclusion, dietary feeding pattern does not modulate the loss of muscle mass or the decline in metabolic health during 1 wk of bed rest in healthy men.

OBJECTIVES: It has been reported that plant-based proteins are not as effective as animal-based proteins in their capacity to stimulate muscle protein synthesis rates. This has been attributed to the lower essential amino acid content and the selective deficiency in specific amino acids. It has been hypothesized that a blend of different plant-based proteins may complement each other and, as such, compensate for such deficits. This study compares post-prandial muscle protein synthesis rates following the ingestion of 30 g milk protein with the ingestion of a 30 g blend of wheat, corn, and pea protein in vivo, in healthy young males. METHODS: In a randomized, double blind, parallel-group design, 24 healthy young males (24 ± 4 y) received a primed continuous infusion of L-[ring-(13)C(6)]-phenylalanine and ingested 30 g milk protein (MILK), or a 30 g protein blend with 15 g wheat, 7.5 g corn, and 7.5 g pea protein (PLANT) in beverage form (n = 12 per group). Both interventional drinks were matched for leucine content. Blood and muscle biopsies were collected for 5 h following protein ingestion to assess post-prandial plasma amino acid profiles and myofibrillar protein synthesis rates. Data are expressed as mean ± SD. RESULTS: MILK increased plasma essential amino acid concentrations ∼2 fold more than PLANT over the 5 h post-prandial period (incremental area under curve (iAUC): 151 ± 31 vs 79 ± 12 mmol∙5 h∙L(−1) respectively; P 0.05). CONCLUSIONS: Ingestion of 30 g of a wheat, corn, and pea protein blend increases muscle protein synthesis rates in healthy, young males. The post-prandial muscle protein synthetic response to the ingestion of 30 g of a wheat, corn and pea protein blend does not differ from the ingestion of an equivalent amount of milk protein in healthy, young males. FUNDING SOURCES: TiFN

Background: The age-related decline in skeletal muscle mass is partly attributed to anabolic resistance to food intake. Dietary protein ingestion before sleep could be used as a nutritional strategy to compensate for anabolic resistance. Objective: The present study assessed whether physical activity performed in the evening can augment the overnight muscle protein synthetic response to presleep protein ingestion in older men. Methods: In a parallel group design, 23 healthy older men (mean SEM age: 71 1 y) were randomly assigned to ingest 40 g protein intrinsically labeled with L[1-C-13]-phenylalanine and L-[1-C-13]-leucine before going to sleep with (PRO+EX) or without (PRO) performing physical activity earlier in the evening. Overnight protein digestion and absorption kinetics and myofibrillar protein synthesis rates were assessed by combining primed, continuous infusions of L-[ring-H-2(5)]-phenylalanine, L-[1-C-13]-leucine, and L-[ring-H-2(2)]-tyrosine with the ingestion of intrinsically labeled casein protein. Muscle and blood samples were collected throughout overnight sleep. Results: Protein ingested before sleep was normally digested and absorbed, with 54% +/- 2% of the protein-derived amino acids appearing in the circulation throughout overnight sleep. Overnight myofibrillar protein synthesis rates were 31 % (0.058% +/- 0.002%/h compared with 0.044% +/- 0.003%/h; P

OBJECTIVES: The rate of protein digestion and amino acid absorption determines the postprandial rise in circulating amino acids and, as such, modulates postprandial muscle protein synthesis rates. This study compares protein digestion and amino acid absorption kinetics and the subsequent muscle protein synthetic response following ingestion of intact protein versus an equivalent amount of free, crystalline amino acids. METHODS: Twenty-four healthy, young subjects (age: 22 ± 3 y, BMI: 23 ± 2 kg·m(−2), sex: 12 M/12F) ingested 30 g intrinsically L-[1–(13)C]-phenylalanine and L-[1–(13)C]-leucine labeled milk protein (PROT; n = 12) or an equivalent amount of free amino acids (AA; n = 12). In addition, subjects received primed continuous L-[ring-(2)H(5)]-phenylalanine, L-[ring-3,5–(2)H(2)]-tyrosine, and L-[1–(13)C]-leucine infusions. Blood samples and muscle biopsies were obtained frequently to assess protein digestion and amino acid absorption kinetics and subsequent muscle protein synthesis rates over a 6 h postprandial period. An unpaired t-test was used to compare overall exogenous phenylalanine release in plasma. For other parameters repeated measures ANOVA were applied to determine differences between groups over time (time as within, and group as between-subjects factor). Data are expressed as mean ± SD. RESULTS: Postprandial plasma amino acid concentrations and exogenous phenylalanine appearance rates increased after ingestion of PROT and AA (both, P

Context: The progressive loss of muscle mass with aging is accelerated in type 2 diabetes patients. It has been suggested that this is attributed to a blunted muscle protein synthetic response to food intake. Objective: The objective of the study was to test the hypothesis that the muscle protein synthetic response to protein ingestion is impaired in older type 2 diabetes patients when compared with healthy, normoglycemic controls. Design: A clinical intervention study with two parallel groups was conducted between August 2011 and July 2012. Setting: The study was conducted at the research unit of Maastricht University, The Netherlands. Intervention, Participants, and Main Outcome Measures: Eleven older type 2 diabetes males [diabetes; age 71 ± 1 y, body mass index (BMI) 26.2 ± 0.5 kg/m2] and 12 age- and BMI-matched normoglycemic controls (control; age 74 ± 1 y, BMI 24.8 ± 1.1 kg/m2) participated in an experiment in which they ingested 20 g intrinsically L-[1-13C]phenylalanine-labeled protein. Continuous iv L-[ring-2H5]phenylalanine infusion was applied, and blood and muscle samples were obtained to assess amino acid kinetics and muscle protein synthesis rates in the postabsorptive and postprandial state. Results: Plasma insulin concentrations increased after protein ingestion in both groups, with a greater rise in the diabetes group. Postabsorptive and postprandial muscle protein synthesis rates did not differ between groups and averaged 0.029 ± 0.003 vs 0.029 ± 0.003%/h1 and 0.031 ± 0.002 vs 0.033 ± 0.002%/h1 in the diabetes versus control group, respectively. Postprandial L-[1-13C]phenylalanine incorporation into muscle protein did not differ between groups (0.018 ± 0.001 vs 0.019 ± 0.002 mole percent excess, respectively). Conclusions: Postabsorptive muscle protein synthesis and postprandial protein handling is not impaired in older individuals with type 2 diabetes when compared with age-matched, normoglycemic controls.

Background: The loss of skeletal muscle mass with aging has been attributed to the blunted anabolic response to protein intake. Presleep protein ingestion has been suggested as an effective strategy to compensate for such anabolic resistance. Objective: We assessed the efficacy of presleep protein ingestion on dietary protein digestion and absorption kinetics and overnight muscle protein synthesis rates in older men. Methods: In a randomized, double-blind, parallel design, 48 older men (mean ± SEM age: 72 ± 1 y) ingested 40 g casein (PRO40), 20 g casein (PRO20), 20 g casein plus 1.5 g leucine (PRO20+LEU), or a placebo before sleep. Ingestion of intrinsically L-[1-13C]-phenylalanine– and L-[1-13C]-leucine–labeled protein was combined with intravenous L-[ring-2H5]-phenylalanine and L-[1-13C]-leucine infusions during sleep. Muscle and blood samples were collected throughout overnight sleep. Results: Exogenous phenylalanine appearance rates increased after protein ingestion, but to a greater extent in PRO40 than in PRO20 and PRO20+LEU (P < 0.05). Overnight myofibrillar protein synthesis rates (based on L-[ring-2H5]-phenylalanine) were 0.033% ± 0.002%/h, 0.037% ± 0.003%/h, 0.039% ± 0.002%/h, and 0.044% ± 0.003%/h in placebo, PRO20, PRO20+LEU, and PRO40, respectively, and were higher in PRO40 than in placebo (P = 0.02). Observations were similar based on L-[1-13C]-leucine tracer (placebo: 0.047% ± 0.004%/h and PRO40: 0.058% ± 0.003%/h, P = 0.08). More protein-derived amino acids (L-[1-13C]-phenylalanine) were incorporated into myofibrillar protein in PRO40 than in PRO20 (0.033 ± 0.002 and 0.019 ± 0.002 MPE, respectively, P < 0.001) and tended to be higher than in PRO20+LEU (0.025 ± 0.002 MPE, P = 0.06). Conclusions: Protein ingested before sleep is properly digested and absorbed throughout the night, providing precursors for myofibrillar protein synthesis during sleep in healthy older men. Ingestion of 40 g protein before sleep increases myofibrillar protein synthesis rates during overnight sleep. These findings provide the scientific basis for a novel nutritional strategy to support muscle mass preservation in aging and disease. This trial was registered at www.trialregister.nl as NTR3885.

Background: Muscle mass maintenance is largely regulated by basal muscle protein synthesis rates and the ability to increase mus-cle protein synthesis after protein ingestion. To our knowledge, no previous studies have evaluated the impact of habituation to either low protein intake (LOW PRO) or high protein intake (HIGH PRO) on the postprandial muscle protein synthetic response. Objective: We assessed the impact of LOW PRO compared with HIGH PRO on basal and postprandial muscle protein synthesis rates after the ingestion of 25 g whey protein. Design: Twenty-four healthy, older men [age: 62 6 1 y; body mass index (in kg/m2): 25.9 6 0.4 (mean 6 SEM)] participated in a parallel-group randomized trial in which they adapted to either aLOWPRO diet(0.7g $ kg–1 $ d21; n = 12) or a HIGH PRO diet (1.5 g $ kg–1 $ d–1; n = 12) for 14 d. On day 15, partici-pants received primed continuous L-[ring-2H5]-phenylalanine and L-[1-13C]-leucine infusions and ingested 25 g intrinsically L-[1-13C]-phenylalanine– and L-[1-13C]-leucine–labeled whey pro-tein. Muscle biopsies and blood samples were collected to assess muscle protein synthesis rates as well as dietary protein digestion and absorption kinetics. Results: Plasma leucine concentrations and exogenous phenylala-nine appearance rates increased after protein ingestion (P , 0.01) with no differences between treatments (P . 0.05). Plasma exoge-nous phenylalanine availability over the 5-h postprandial period was greater after LOW PRO than after HIGH PRO (61% 6 1% com-pared with 56% 6 2%, respectively; P , 0.05). Muscle protein synthesis rates increased from 0.031% 6 0.004% compared with 0.039% 6 0.007%/h in the fasted state to 0.062% 6 0.005% com-pared with 0.057% 6 0.005%/h in the postprandial state after LOW PRO compared with HIGH PRO, respectively (P , 0.01), with no differences between treatments (P = 0.25). Conclusion: Habituation to LOW PRO (0.7 g $ kg–1 $ d–1)compared with HIGH PRO (1.5 g $ kg–1 $ d–1) augments the postprandial avail-ability of dietary protein–derived amino acids in the circulation and does not lower basal muscle protein synthesis rates or increase postprandial muscle protein synthesis rates after ingestion of 25 g protein in older men. This trial was registered at clinicaltrials.gov as NCT01986842. Am J Clin Nutr 2017;105:332–42.

We aimed to determine the impact of precursor pool dilution on the assessment of postprandial myofibrillar protein synthesis rates (MPS). A Holstein dairy cow was infused with large amounts of L-[1-13C]phenylalanine and L-[1-13C]leucine, and the milk was collected and fractionated. The enrichment levels in the casein were 38.7 and 9.3 mole percent excess, respectively. In a subsequent human experiment, 11 older men (age: 71 ± 1 y, body mass index: 26 ± 0.1 kg·m−2) received a primed constant infusion of L-[ring-2H5]phenylalanine and L-[1-13C]leucine. Blood and muscle samples were collected before and after the ingestion of 20-g doubly labeled casein to assess postprandial MPS based on the 1) constant tracer infusion of L-[ ring-2H5]phenylalanine, 2) ingestion of intrinsically L-[1-13C]phenylalanine-labeled casein, and 3) constant infusion of L-[1-13C]leucine in combination with the ingestion of intrinsically L-[1-13C]leucine-labeled casein. Postprandial MPS was increased ( P < 0.05) after protein ingestion (∼70% above postabsorptive values) based on the L-[1-13C]leucine tracer. There was no significant stimulation of postprandial MPS (∼27% above postabsorptive values) when the calculated fractional synthesis rate was based on the L-[ring-2H5]phenylalanine ( P = 0.2). Comparisons of postprandial MPS based on the primed continuous infusion of L-[1-13C]leucine or the ingestion of intrinsically L-[1-13C]phenylalanine-labeled casein protein demonstrated differences compared with the primed continuous infusion of L-[ ring-2H5]phenylalanine ( P > 0.05). Our findings confirm that the postprandial MPS assessed using the primed continuous tracer infusion approach may differ if tracer steady-state conditions in the precursor pools are perturbed. The use of intrinsically doubly labeled protein provides a method to study the metabolic fate of the ingested protein and the subsequent postprandial MPS response.

Nitrate ([Formula: see text]) ingestion has been shown to have vasoactive and ergogenic effects that have been attributed to increased nitric oxide (NO) production. Recent observations in rodents suggest that skeletal muscle tissue serves as an endogenous [Formula: see text] “reservoir.” The present study determined [Formula: see text] contents in human skeletal muscle tissue in a postabsorptive state and following ingestion of a sodium nitrate bolus (NaNO3). Seventeen male, type 2 diabetes patients (age 72 ± 1 yr; body mass index 26.5 ± 0.5 kg/m2; means ± SE) were randomized to ingest a dose of NaNO3 (NIT; 9.3 mg [Formula: see text]/kg body wt) or placebo (PLA; 8.8 mg NaCl/kg body wt). Blood and muscle biopsy samples were taken before and up to 7 h following [Formula: see text] or placebo ingestion to assess [Formula: see text] [and plasma nitrite ([Formula: see text])] concentrations. Additionally, basal plasma and muscle [Formula: see text] concentrations were assessed in 10 healthy young (CON-Y; age 21 ± 1 yr) and 10 healthy older (CON-O; age 75 ± 1 yr) control subjects. In all groups, baseline [Formula: see text] concentrations were higher in muscle (NIT, 57 ± 7; PLA, 61 ± 7; CON-Y, 80 ± 10; CON-O, 54 ± 6 µmol/l) than in plasma (NIT, 35 ± 3; PLA, 32 ± 3; CON-Y, 38 ± 3; CON-O, 33 ± 3 µmol/l; P ≤ 0.011). Ingestion of NaNO3 resulted in a sustained increase in plasma [Formula: see text], plasma [Formula: see text], and muscle [Formula: see text] concentrations (up to 185 ± 25 µmol/l) in the NIT group (time effect P < 0.001) compared with PLA (treatment effect P < 0.05). In conclusion, basal [Formula: see text] concentrations are substantially higher in human skeletal muscle tissue compared with plasma. Ingestion of a bolus of dietary [Formula: see text] increases both plasma and muscle [Formula: see text] contents in humans. NEW & NOTEWORTHY Literature of the pharmacokinetics following dietary nitrate ingestion is usually limited to the changes observed in plasma nitrate and nitrite concentrations. The present investigation assessed the skeletal muscle nitrate content in humans during the postabsorptive state, as well as following dietary nitrate ingestion. We show that basal nitrate content is higher in skeletal muscle tissue than in plasma and that ingestion of a dietary nitrate bolus strongly increases both plasma and muscle nitrate concentrations.

TROMMELEN, J., A. M. HOLWERDA, I. W. K. KOUW, H. LANGER, S. L. HALSON, I. ROLLO, L. B. VERDIJK, and L. J. C. VAN LOON. Resistance Exercise Augments Postprandial Overnight Muscle Protein Synthesis Rates. Med. Sci. Sports Exerc., Vol. 48, No. 12, pp. 2517–2525, 2016. Introduction: We have previously shown that protein ingestion before sleep increases overnight muscle protein synthesis rates. Whether prior exercise further augments the muscle protein synthetic response to presleep protein ingestion remains to be established. Objective: This study aimed to assess whether resistance-type exercise performed in the evening increases the overnight muscle protein synthetic response to presleep protein ingestion. Methods: Twenty-four healthy young men were randomly assigned to ingest 30 g intrinsically L-[1-13C]-phenylalanine and L-[1-13C]-leucine-labeled casein protein before going to sleep with (PRO + EX, n = 12) or without (PRO, n = 12) prior resistance-type exercise performed in the evening. Continuous intravenous L-[ring- 2 H5]-phenylalanine, L-[1-13C]-leucine, and L-[ring- 2 H2]-tyrosine infusions were applied. Blood and muscle tissue samples were collected to assess whole-body protein balance, myofibrillar protein synthesis rates, and overnight incorporation of dietary protein-derived amino acids into de novo myofibrillar protein. Results: A total of 57% T 1% of the ingested protein-derived phenylalanine appeared in the circulation during overnight sleep. Overnight myofibrillar protein synthesis rates were 37% (0.055%Ihj1 T 0.002%Ihj1 vs. 0.040%Ihj1 T 0.003%Ihj1 , P G 0.001, based on L-[ring-2 H5]-phenylalanine) and 31% (0.073%Ihj1 T 0.004%Ihj1 vs. 0.055%Ihj1 T 0.006%Ihj1 , P = 0.024, based on L-[1-13C]-leucine) higher in PRO + EX compared with PRO. Substantially more of the dietary protein-derived amino acids were incorporated into de novo myofibrillar protein during overnight sleep in PRO + EX compared with PRO (0.026 T 0.003 vs. 0.015 T 0.003 molar percent excess, P = 0.012). Conclusions: Resistance-type exercise performed in the evening augments the overnight muscle protein synthetic response to presleep protein ingestion and allows more of the ingested protein-derived amino acids to be used for de novo myofibrillar protein synthesis during overnight sleep. Key Words: SLEEP, RECOVERY, EXERCISE, MUSCLE, STABLE ISOTOPES, CASEIN

The age-related anabolic resistance to protein ingestion is suggested to be associated with impairments in insulin-mediated capillary recruitment and postprandial muscle tissue perfusion. The present study investigated whether dietary nitrate co-ingestion with protein improves muscle protein synthesis in older, type 2 diabetes patients. Twenty-four men with type 2 diabetes (72 ± 1 yr, 26.7 ± 1.4 m/kg2 body mass index, 7.3 ± 0.4% HbA1C) received a primed continuous infusion of l-[ring-2H5]phenylalanine and l-[1-13C]leucine and ingested 20 g of intrinsically l-[1-13C]phenylalanine- and l-[1-13C]leucine-labeled protein with (PRONO3) or without (PRO) sodium nitrate (0.15 mmol/kg). Blood and muscle samples were collected to assess protein digestion and absorption kinetics and postprandial muscle protein synthesis rates. Upon protein ingestion, exogenous phenylalanine appearance rates increased in both groups ( P < 0.001), resulting in 55 ± 2% and 53 ± 2% of dietary protein-derived amino acids becoming available in the circulation over the 5h postprandial period in the PRO and PRONO3 groups, respectively. Postprandial myofibrillar protein synthesis rates based on l-[ring-2H5]phenylalanine did not differ between groups (0.025 ± 0.004 and 0.021 ± 0.007%/h over 0–2 h and 0.032 ± 0.004 and 0.030 ± 0.003%/h over 2–5 h in PRO and PRONO3, respectively, P = 0.7). No differences in incorporation of dietary protein-derived l-[1-13C]phenylalanine into de novo myofibrillar protein were observed at 5 h (0.016 ± 0.002 and 0.014 ± 0.002 mole percent excess in PRO and PRONO3, respectively, P = 0.8). Dietary nitrate co-ingestion with protein does not modulate protein digestion and absorption kinetics, nor does it further increase postprandial muscle protein synthesis rates or the incorporation of dietary protein-derived amino acids into de novo myofibrillar protein in older, type 2 diabetes patients.

BACKGROUND Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point. The aim of this study was to challenge this diagnostic concept. METHODS Study 1 examined the presence of a diurnal hs-cTn rhythm by hourly blood sampling, day and night, in 24 individuals without a recent history of AMI. Study 2 assessed morning vs evening diagnostic accuracy of hs-cTnT and hs-cTnI in a prospective multicenter diagnostic study of 2782 unselected patients, presenting to the emergency department with acute chest pain. RESULTS In study 1, hs-cTnT, but not hs-cTnI, exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime, to peak concentrations in the morning (mean 16.2 ng/L at 8:30 AM and 12.1 ng/L at 7:30 PM). In study 2, the hs-cTnT rhythm was confirmed by higher hs-cTnT concentrations in early-morning presenters compared to evening presenters with an adjudicated diagnosis of noncardiac disease. The diagnostic accuracy [area under the receiver-operation characteristics curve (AUC)] of hs-cTnT at presentation, 1 h, and for the combination of absolute changes with presenting concentration, were very high and comparable among patients presenting early morning as compared to evening (all AUC >0.93). hs-cTnI exhibited no diurnal rhythm with no differences in AUC among early-morning and evening presenters. CONCLUSIONS Rhythmic diurnal variation of hs-cTnT is a general phenomenon that is not seen with hs-cTnI. While the diurnal hs-cTnT rhythm does not seem to affect the diagnostic accuracy of hs-cTnT for AMI, it should be considered when using hs-cTnT for screening purposes. Clinical Trial Registration 1. Circadian Variation of Cardiac Troponin, NCT02091427, www.clinicaltrials.gov/ct2/show/NCT02091427. 2. Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) Study, NCT00470587, www.clinicaltrials.gov/ct2/show/NCT00470587.

Background: Studying the muscle protein synthetic response to food intake in elderly is important, as it aids the development of interventions to combat sarcopenia. Although sarcopenic elderly are the target group for many of these nutritional interventions, no studies have assessed basal or post-prandial muscle protein synthesis rates in this population.Objective: To assess the basal and post-prandial muscle protein synthesis rates between healthy and sarcopenic older men.Design: A total of 15 healthy (69 +/- 1 y) and 15 sarcopenic (81 +/- 1 y) older men ingested a leucine-enriched whey protein nutritional supplement containing 21 g of protein, 9 g of carbohydrate, and 3 g of fat. Stable isotope methodology combined with frequent collection of blood and muscle samples was applied to assess basal and post-prandial muscle protein fractional synthetic rates. Handgrip strength, muscle mass, and gait speed were assessed to identify sarcopenia, according to international criteria. Results: Basal mixed muscle protein fractional synthetic rates (FSR) averaged 0.040 +/- 0.005 and 0.032 +/- 0.003%/h (mean +/- SEM) in the sarcopenic and healthy group, respectively (P = 0.14). Following protein ingestion, FSR increased significantly to 0.055 +/- 0.004 and 0.053 +/- 0.004%/h in the post-prandial period in the sarcopenic (P = 0.003) and healthy groups (P Conclusions: Basal muscle protein synthesis rates are not lower in sarcopenic older men compared to healthy older men. The ingestion of 21 g of a leucine-enriched whey protein effectively increases muscle protein synthesis rates in both sarcopenic and healthy older men. (C) 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Context: An impaired muscle protein synthetic response to feeding likely contributes to muscle loss with aging. There are few data available on the effect of the macronutrient composition of clinical supplements on the postprandial muscle protein synthetic response in older subjects. Objective: The objective of the study was to determine the impact of the macronutrient composition of a nutritional supplement on the postprandial muscle protein synthetic response in older men. Methods: A total of 45 nonsarcopenic older men ( aged 69 ± 1 y; body mass index 25.7 ± 0.3 kg/m2 ) were randomly assigned to ingest 21 g of leucine-enriched whey protein with carbohydrate ( 9 g ) and fat ( 3 g ) ( Pro-En ), an isonitrogenous amount of 21 g of leucine-enriched whey protein without carbohydrate and fat ( Pro ), or an isocaloric mixture ( 628 kJ ) containing carbohydrate and fat only ( En ). Stable isotope tracer methodology was applied to assess the basal as well as the postprandial muscle protein synthesis rates in the three groups. Results: Ingestion of protein in the Pro-En and Pro groups significantly increased muscle protein synthesis rates when compared with the basal rates ( from 0.032 ± 0.003%/h to 0.05%/h 3 ± 0.004%/h and 0.040%/h ± 0.003%/h to 0.049%/h ± 0.003%/h, respectively; P < .05 ), whereas ingestion of carbohydrate and fat did not increase muscle protein synthesis rates in the En group ( from 0.039%/h ± 0.004%/h to 0.040%/h ± 0.003%/h; P = .60 ). Despite the greater postprandial rise in circulating insulin concentration in the Pro-En group, no significant differences were observed in postprandial muscle protein synthesis rates between the Pro-En and Pro groups ( P = .32 ). Postprandial muscle protein synthesis rates were higher in the Pro-En vs En group ( P = .01 ). Conclusion: The ingestion of a nutritional supplement containing 21 g of leucine-enriched whey protein significantly raises muscle protein synthesis rates in nonsarcopenic older men, but coingestion of carbohydrate and fat does not modulate the postprandial muscle protein synthetic response to protein ingestion in older men.

Dietary nitrate (NO3(-)) supplementation has been proposed as an emerging treatment strategy for type 2 diabetes. We hypothesized that ingestion of a single bolus of dietary NO3(-) ingestion improves oral glucose tolerance in patients with type 2 diabetes. Seventeen men with type 2 diabetes (glycated hemoglobin, 7.3% ± 0.2%) participated in a randomized crossover experiment. The subjects ingested a glucose beverage 2.5 hours after consumption of either sodium NO3(-) (0.15 mmol NaNO3(-) · kg(-1)) or a placebo solution. Venous blood samples were collected before ingestion of the glucose beverage and every 30 minutes thereafter during a 2-hour period to assess postprandial plasma glucose and insulin concentrations. The results show that plasma NO3(-) and nitrite levels were increased after NaNO3(-) as opposed to placebo ingestion (treatment-effect, P = .001). Despite the elevated plasma NO3(-) and nitrite levels, ingestion of NaNO3(-) did not attenuate the postprandial rise in plasma glucose and insulin concentrations (time × treatment interaction, P = .41 for glucose, P = .93 for insulin). Despite the lack of effect on oral glucose tolerance, basal plasma glucose concentrations measured 2.5 hours after NaNO3(-) ingestion were lower when compared with the placebo treatment (7.5 ± 0.4 vs 8.3 ± 0.4 mmol/L, respectively; P = .04). We conclude that ingestion of a single dose of dietary NO3(-) does not improve subsequent oral glucose tolerance in patients with type 2 diabetes.

Skeletal muscle wasting occurs in patients following trauma, burns, surgical complications and/or sepsis. This inevitable phenomenon affects the whole body as a result of the progressive loss of skeletal muscle mass and strength leading to such higher clinical outcomes as morbidity and mortality. The accelerated degradation of muscle proteins may be caused by insufficient protein intake or infectious and traumatic stress. Indeed, the anabolic and catabolic protein kinases that may be responsible for governing changes in muscle mass are becoming better defined. However, most work in this area is based on cell and animal models, especially in relation to muscle protein turnover. Generally, in vivo human work on muscle loss is performed in models using head-down tilt bed rest, casting, unilateral leg suspension and/or knee immobilization of the leg muscles of healthy younger participants (Phillips et al. 2009). Intervention studies in catabolic patient groups are lacking. Therefore, there is a need to clarify the molecular and cellular mechanisms underlying changes in muscle protein turnover during wasting conditions as observed in critically ill patients, during bed rest, or in sarcopaenic elderly. From a clinical perspective, this will provide novel insights to develop more effective therapeutic strategies to preserve skeletal muscle mass in these patient groups. In a study in a recent issue of The Journal of Physiology, Constantin and colleagues (2011) sought to fill this research gap. Their paper provides novel insights into the molecular mechanisms underlying skeletal muscle wasting in critically ill patients. Key factors that seem to control muscle protein synthesis as well as proteases involved in muscle protein breakdown were investigated. Muscle biopsies were collected from 10 critically ill patients (aged 34–85 years) and 10 age- and sex- matched sedentary, healthy controls. Intramuscular signalling proteins involved in translation initiation of muscle protein synthesis were determined during their stay in the Intensive Care Unit. The study reported an increase in muscle mRNA expression of the anabolic signalling proteins Akt, GSK3, mTORC1, p70S6K and 4E-BP1, which was paralleled by a diminished phosphorylated state in the same signalling proteins. The fact that phosphorylation of p70S6K, a downstream target of mTORC1, was reduced may be of primary importance, as this could be representative of a reduced sensitivity to anabolic stimuli that may exist in critically ill patients. Specifically, the increase in p70S6K phosphorylation, a proxy for activation, has repeatedly been suggested to be indicative of acute muscle protein synthetic response, and might even predict the extent of muscle mass that is gained after resistance training and/or by the provision of amino acids (West et al. 2010). Of course, acute studies simply supply the obligatory framework for long-term intervention studies and thus further work is necessary to examine whether the same holds true in a critically ill subject population. The opposite arm of muscle protein synthesis in the net muscle protein balance equation is muscle protein breakdown (Phillips et al. 2009). Therefore, markers of muscle protein breakdown were studied by Constantin and co-workers (Constantin et al. 2011). They demonstrated higher gene expression and protein levels of the 20S proteasome and the E3-ligases MAFbx and MuRF1 in critically ill patients. Moreover, lysosomal cathepsins were elevated. Therefore, in this study they show that the main proteolytic systems were activated in the muscle. Interestingly, it was reported that mRNA expression and protein concentration of calpain-3, a muscle specific protease, was reduced in the muscle during critical illness. The significance of this finding is not entirely clear as others observed similar effects in certain types of muscular dystrophies as discussed by Constantin and colleagues (2011). It is worth highlighting as well that muscle myostatin mRNA expression was significantly higher in critically ill patients, which corresponded with an increase in myostatin protein expression when compared with the control group. It has been established that myostatin inhibits the phosphorylation of Akt, which eventually leads to muscle protein breakdown. This may be of significance since Akt is an upstream signalling protein of mTORC1, a fundamental control site for the regulation of muscle protein synthesis in humans. Admittedly, static ‘snapshots’ of muscle mRNA expression and protein phosphorylation are not always indicative of dynamic processes, such as muscle protein synthesis and breakdown (Greenhaff et al. 2008). However, the use of a kinetic measurement, as in contemporary stable isotope methodology, requires at least 3–5 h of tracer infusion to accurately measure muscle protein synthesis rates and thus may not be possible in some critically ill patient groups. Moreover, direct determination of muscle protein breakdown can be analytically challenging, and sometimes requires a mathematician to handle the data and ensure accurate results. Constantin et al. (2011) are to be congratulated for taking a step into a subject population that is difficult to study. The workers were able to study critically ill patients in a fasting state. The next logical step would be to examine fed-state responses that could provide valuable information that is needed to assess the impact of food administration on skeletal muscle mass maintenance in critically ill patients. What we know thus far is that feeding of amino acids has a beneficial effect in elderly people, a population that is characterized by accelerated loss of skeletal muscle mass. The latter has been attributed to a blunted muscle protein synthetic response to amino acid and/or protein administration. It remains to be determined if the feeding induced stimulation of muscle protein synthesis rates and/or inhibition of muscle protein breakdown rates are altered in critically ill patients. Our research group has recently infused a cow with amino acid tracers to obtain intrinsically labelled milk proteins (van Loon et al. 2009). Ingestion of these labelled milk proteins can be used as a tool to determine the muscle protein synthetic response in vivo in humans. Furthermore, this may be a valuable tool to determine dynamic measurements of anabolism in a population of subjects where contemporary stable isotope methodology may not be applied easily. Accordingly, dynamic direct measurements of muscle anabolism will allow for another step towards understanding the phenotypic responses of critically ill patients. Ultimately, this information may be fundamental for developing more effective therapeutic strategies for this clinical population.

Rationale: Pancreatic cancer related cachexia and skeletal muscle wasting is related to poor outcome. Body muscle mass can be assessed by CT-imaging. Intermuscular adipose tissue and/or intermyofibrillar fat accumulation (reflected by the “radiation attenuation”) are increased in cancer patients independent of sarcopenia, and might be indicators of muscle loss and muscle quality. This study aimed to assess the impact of fat accumulation in muscle on postoperative outcome in surgical patients with pancreatic cancer. Methods: A prospective cohort of 192 pancreatic cancer patients operated between 2008 2013 was analysed by CTimage analysis at the L3 level to measure cross-sectional surface area of (1) skeletal muscle, (2) intermuscular adipose tissue, (3) visceral adipose tissue; the mean muscle radiation attenuation, reflecting intermyofibrillar fat, was defined by the average muscle radiation attenuation in Hounsfield units. Results: Low muscle radiation attenuation, indicating high intermyofibrillar fat, was associated with low survival compared with middle and high muscle attenuation (median survival 46.5, 77.1, and 67.1 weeks, respectively; p < 0.001) and was associated with an increased risk of major complications (OR: 2.3, 95%CI: 1.4 5.6). Muscle attenuation index was negatively correlated with intermuscular adipose tissue (rp = 0.68, p < 0.001). Increased visceral adipose tissue was associated with development of pancreatic fistula (OR: 2.5, 95%CI: 1.1 6.1) and post-operative infections (OR: 2.7, 95%CI: 1.4 5.2). Conclusion: A reduced muscle radiation attenuation is associated with reduced survival and increased severe postoperative complications. The strong correlation between intermyofibrillar fat and intermuscular adipose tissue suggests a common mechanism of origin, warranting further investigation. Preoperative CT-image analysis of body tissue compartments likely is clinically useful to identify high-risk patients.