The T allele of TCF7L2 rs7903146 is associated with decreased glucose tolerance after bed rest in healthy older adults.

Inpatient populations are at increased risk of hyperglycemia due to factors such as medications, physical inactivity and underlying illness, which increases morbidity and mortality. Unfortunately, clinicians have limited tools available to prospectively identify those at greatest risk. We evaluated the ability of 10 common genetic variants associated with development of type 2 diabetes to predict impaired glucose metabolism. Our research model was a simulated inpatient hospital stay (7 day bed rest protocol, standardized diet, and physical inactivity) in a cohort of healthy older adults (n = 31, 65 ± 8 years) with baseline fasting blood glucose < 100 mg/dL. Participants completed a standard 75 g oral glucose tolerance test (OGTT) at baseline and post-bed rest. Bed rest increased 2-h OGTT blood glucose and insulin independent of genetic variant. In multiple regression modeling, the transcription factor 7-like 2 (TCF7L2) rs7903146 T allele predicted increases in 2-h OGTT blood glucose (p = 0.039). We showed that the TCF7L2 rs7903146 T allele confers risk for loss of glucose tolerance in nondiabetic older adults following 7 days of bed rest.

Leucine augments specific skeletal muscle mitochondrial respiratory pathways during recovery following 7 days of physical inactivity in older adults.

In older adults, leucine mitigated the loss of insulin sensitivity associated with muscular disuse. Leucine supplementation increased mitochondrial respiration and reduced a marker of oxidative stress following periods of disuse and rehabilitation.

The effect of acute sleep deprivation on skeletal muscle protein synthesis and the hormonal environment.

Chronic sleep loss is a potent catabolic stressor, increasing the risk of metabolic dysfunction and loss of muscle mass and function. To provide mechanistic insight into these clinical outcomes, we sought to determine if acute sleep deprivation blunts skeletal muscle protein synthesis and promotes a catabolic environment. Healthy young adults (N = 13; seven male, six female) were subjected to one night of total sleep deprivation (DEP) and normal sleep (CON) in a randomized cross-over design. Anabolic and catabolic hormonal profiles were assessed across the following day. Postprandial muscle protein fractional synthesis rate (FSR) was assessed between 13:00 and 15:00 and gene markers of muscle protein degradation were assessed at 13:00. Acute sleep deprivation reduced muscle protein synthesis by 18% (CON: 0.072 ± 0.015% vs. DEP: 0.059 ± 0.014%·h-1 , p = .040). In addition, sleep deprivation increased plasma cortisol by 21% (p = .030) and decreased plasma testosterone by 24% (p = .029). No difference was found in the markers of protein degradation. A single night of total sleep deprivation is sufficient to induce anabolic resistance and a procatabolic environment. These acute changes may represent mechanistic precursors driving the metabolic dysfunction and body composition changes associated with chronic sleep deprivation.

Optimizing Adult Protein Intake During Catabolic Health Conditions.

The DRIs define a range of acceptable dietary intakes for each nutrient. The range is defined from the minimum intake to avoid risk of inadequacy (i.e., the RDA) up to an upper limit (UL) based on a detectable risk of adverse effects. For most nutrients, the minimum RDA is based on alleviating a clear deficiency condition, whereas higher intakes are often recommended to optimize specific health outcomes. Evidence is accumulating that similar logic should be applied to dietary recommendations for protein. Although the RDA for protein of 0.8 g/kg body weight is adequate to avoid obvious inadequacies, multiple studies provide evidence that many adults may benefit from protein quantity, quality, and distribution beyond guidelines currently defined by the RDA. Further, the dietary requirement for protein is a surrogate for the constituent amino acids and, in particular, the 9 considered to be indispensable. Leucine provides an important example of an essential amino acid where the RDA of 42 mg/kg body weight is significantly less than the 100-110 mg/kg required to optimize metabolic regulation and skeletal muscle protein synthesis. This review will highlight the benefits of higher protein diets to optimize health during aging, inactivity, bed rest, or metabolic dysfunction such as type 2 diabetes.

Countering disuse atrophy in older adults with low-volume leucine supplementation.

Older adults are at increased risk of being bedridden and experiencing negative health outcomes including the loss of muscle tissue and functional capacity. We hypothesized that supplementing daily meals with a small quantity (3-4 g/meal) of leucine would partially preserve lean leg mass and function of older adults during bed rest. During a 7-day bed rest protocol, followed by 5 days of inpatient rehabilitation, healthy older men and women (67.8 ± 1.1 yr, 14 men; 6 women) were randomized to receive isoenergetic meals supplemented with leucine (LEU, 0.06 g/kg/meal; n = 10) or an alanine control (CON, 0.06 g/kg/meal; n = 10). Outcomes were assessed at baseline, following bed rest, and after rehabilitation. Body composition was measured by dual-energy X-ray absorptiometry. Functional capacity was assessed by knee extensor isokinetic and isometric dynamometry, peak aerobic capacity, and the short physical performance battery. Muscle fiber type, cross-sectional area, signaling protein expression levels, and single fiber characteristics were determined from biopsies of the vastus lateralis. Leucine supplementation reduced the loss of leg lean mass during bed rest (LEU vs. CON: -423 vs. -1035 ± 143 g; P = 0.008) but had limited impact on strength or endurance-based functional outcomes. Similarly, leucine had no effect on markers of anabolic signaling and protein degradation during bed rest or rehabilitation. In conclusion, providing older adults with supplemental leucine has minimal impact on total energy or protein consumption and has the potential to partially counter some, but not all, of the negative effects of inactivity on muscle health.NEW & NOTEWORTHY Skeletal muscle morphology and function in older adults was significantly compromised by 7 days of disuse. Leucine supplementation partially countered the loss of lean leg mass but did not preserve muscle function or positively impact changes at the muscle fiber level associated with bed rest or rehabilitation. Of note, our data support a relationship between myonuclear content and adaptations to muscle atrophy at the whole limb and single fiber level.

Improving Dietary Protein Quality Reduces the Negative Effects of Physical Inactivity on Body Composition and Muscle Function.

BACKGROUND: Brief periods of physical inactivity can compromise muscle health. Increasing dietary protein intake is potentially beneficial but complicated by difficulties reconciling anabolic potential with a realistic food volume and energy intake. We sought to determine whether increasing dietary protein quality could reduce the negative effects of physical inactivity. METHODS: Twenty healthy, older men and women completed 7 days of bed rest followed by 5 days of rehabilitation. Volunteers consumed a mixed macronutrient diet (MIXED: N = 10; 68 ± 2 years; 1,722 ± 29 kcal/day; 0.97 ± 0.01 g protein/kg/day) or an isoenergetic, whey-augmented, higher protein quality diet (WHEY: N = 10; 69 ± 1 years; 1,706 ± 23 kcal/day; 0.90 ± 0.01 g protein/kg/day). Outcomes included body composition, blood glucose, insulin, and a battery of physical function tests. RESULTS: During bed rest, both groups experienced a 20% reduction in knee extension peak torque (p < .05). The WHEY diet partially protected leg lean mass (-1,035 vs. -680 ± 138 g, MIXED vs. WHEY; p = .08) and contributed to a greater loss of body fat (-90 vs. -233 ± 152 g, MIXED vs. WHEY; p < .05). Following rehabilitation, knee extension peak torque in the WHEY group fully recovered (-10.0 vs. 2.2 ± 4.1 Nm, MIXED vs. WHEY; p = .05). Blood glucose, insulin, aerobic capacity, and Short Physical Performance Battery (SPPB) changes were similar in both dietary conditions (p > .05). CONCLUSIONS: Improving protein quality without increasing total energy intake has the potential to partially counter some of the negative effects of bed rest in older adults.

2,000 Steps/Day Does Not Fully Protect Skeletal Muscle Health in Older Adults During Bed Rest.

Physical activity in an inpatient setting is often limited to brief periods of walking. For healthy adults, public health agencies recommend a minimum of 150 min/week of moderate-intensity exercise. The authors sought to determine if meeting this activity threshold, in the absence of incidental activities of daily living, could protect skeletal muscle health during bed rest. Healthy older adults (68 ± 2 years) were randomized to 7-day bed rest with (STEP, n = 7) or without (CON, n = 10) a 2,000 steps/day intervention. Performing 2018 ± 4 steps/day did not prevent the loss of lean leg mass and had no beneficial effect on aerobic capacity, strength, or muscle fiber volume. However, the insulin response to an oral glucose challenge was preserved. Performing a block of 2,000 steps/day, in the absence of incidental activities of daily living, was insufficient to fully counter the catabolic effects of bed rest in healthy older adults.

Adopting a Mediterranean-Style Eating Pattern with Different Amounts of Lean Unprocessed Red Meat Does Not Influence Short-Term Subjective Personal Well-Being in Adults with Overweight or Obesity.

Background: Reducing red meat intake is commonly recommended. Limited observational studies suggest that healthy eating patterns with red meat are associated with improved quality of life. Objective: The secondary objectives of this randomized crossover controlled-feeding trial were to assess the effects of following a Mediterranean-style eating pattern (Med-Pattern) with different amounts of red meat on indexes of personal well-being (i.e., perceived quality of life, mood, and sleep) in overweight or obese adults. We hypothesized that following a Med-Pattern would improve these outcomes, independent of red meat intake amount. Methods: Forty-one participants [aged 46 ± 2 y; body mass index (kg/m2): 30.5 ± 0.6; n = 28 women, n = 13 men) were provided Med-Pattern foods for two 5-wk periods separated by 4 wk of self-selected eating. The Med-Red Pattern contained ∼500 g/wk (typical US intake), and the Med-Control Pattern contained ∼200 g/wk (commonly recommended intake in heart-healthy eating patterns) of lean, unprocessed beef or pork compensated with mainly poultry and dairy. Baseline and postintervention outcomes measured were perceived quality of life via the MOS 36-Item Short-Form Health Survey, version 2 (SF-36v2), daily mood states via the Profile of Mood States (POMS), sleep perceptions via the Pittsburgh Sleep Quality Index, and sleep patterns via actigraphy. Data were analyzed via a doubly repeated-measures ANOVA adjusted for age, sex, and body mass at each time point. Results: Following a Med-Pattern did not change domains of physical health, mental health, total mood disturbances, sleep perceptions, and sleep patterns but improved subdomains of physical health role limitations (SF-36v2: 93.6-96.7%; P = 0.038), vitality (SF-36v2: 57.9-63.0%; P = 0.020), and fatigue (POMS: 2.9-2.5 arbitrary units; P = 0.039). There were no differences between the Med-Red and Med-Control Patterns (time × pattern, P-interaction > 0.05). Conclusion: Following a Med-Pattern, independent of lean, unprocessed red meat intake, may not be an effective short-term strategy to meaningfully improve indexes of personal well-being in adults who are overweight or obese. This trial was registered at clinicaltrials.gov as NCT02573129.

A Mediterranean-style eating pattern with lean, unprocessed red meat has cardiometabolic benefits for adults who are overweight or obese in a randomized, crossover, controlled feeding trial.

Background: A Mediterranean-style eating pattern (Mediterranean Pattern) is often described as being low in red meat. Research shows that lean, unprocessed red meat can be incorporated into healthy eating patterns to improve cardiometabolic disease (CMD) risk factors. Objective: We assessed the effects of consuming different amounts of lean, unprocessed red meat in a Mediterranean Pattern on CMD risk factors. We hypothesized that consuming a Mediterranean Pattern would improve CMD risk factors and that red meat intake would not influence these improvements. Design: In an investigator-blinded, randomized, crossover, controlled feeding trial, 41 subjects [mean ± SD age: 46 ± 2 y; mean ± SD body mass index (kg/m2): 30.5 ± 0.6] were provided with a Mediterranean Pattern for two 5-wk interventions separated by 4 wk of self-selected eating. The Mediterranean Patterns contained ∼500 g [typical US intake (Med-Red)] and ∼200 g [commonly recommended intake in heart-healthy eating patterns (Med-Control)] of lean, unprocessed beef or pork per week. Red meat intake was compensated by poultry and other protein-rich foods. Baseline and postintervention outcomes included fasting blood pressure, serum lipids, lipoproteins, glucose, insulin, and ambulatory blood pressure. The presented results were adjusted for age, sex, and body mass at each time point (P < 0.05). Results: Total cholesterol decreased, but greater reductions occurred with Med-Red than with Med-Control (-0.4 ± 0.1 and -0.2 ±0.1 mmol/L, respectively, intervention × time = 0.045]. Low-density lipoprotein decreased with Med-Red but was unchanged with Med-Control [-0.3 ± 0.1 and -0.1 ± 0.1 mmol/L, respectively, intervention × time = 0.038], whereas high-density lipoprotein (HDL) concentrations decreased nondifferentially [-0.1 ± 0.0 mmol/L]. Triglycerides, total cholesterol:HDL, glucose, and insulin did not change with either Med-Red or Med-Control. All blood pressure parameters improved, except during sleep, independent of the red meat intake amount. Conclusions: Adults who are overweight or moderately obese may improve multiple cardiometabolic disease risk factors by adopting a Mediterranean-style eating pattern with or without reductions in red meat intake when red meats are lean and unprocessed. This trial was registered at clinicaltrials.gov as NCT02573129.

Whey protein supplementation 2 hours after a lower protein breakfast restores plasma essential amino acid availability comparable to a higher protein breakfast in overweight adults.

Amino acids from meals peak in the plasma at ~180 minutes postprandial. Conversely, amino acids from rapidly digestible whey protein appear in the plasma within 15 minutes and peak at 60 minutes postprandial. Therefore, we hypothesized that consuming a 20-g whey protein snack 2 hours after a standard mixed-macronutrient, lower protein breakfast (10 g) would result in peak and composite postprandial plasma essential amino acid (EAA) responses that were not different from consuming a 30-g protein breakfast alone. Using a randomized, crossover design, 12 subjects (6 men, 6 women; age: 29 ± 1 y; BMI: 26.0 ± 1.0 kg/m2; mean ± SE) completed three 330-minute trials in which they consumed breakfasts containing (i) 10 g of protein (10-PRO, control), (ii) 30 g of protein (30-PRO), and (iii) 10 g of protein followed by 20 g of whey protein isolate 120 minutes later (10/20-PRO). For both 30-PRO and 10/20-PRO, EAA peaked 180 minutes after breakfast, with greater peak concentrations for 10/20-PRO than 30-PRO (Tukey adjusted, P < .0001). Essential amino acid positive incremental areas under the curve (iAUCpos) over 300 minutes were not different between 30-PRO and 10/20-PRO. Consuming a rapidly digested whey protein snack 2 hours after a slowly digested, lower protein breakfast resulted in a greater peak plasma EAA concentration but comparable plasma EAA availability than consuming a single higher protein breakfast.

Within-day protein distribution does not influence body composition responses during weight loss in resistance-training adults who are overweight.

Background: Emerging research suggests that redistributing total protein intake from 1 high-protein meal/d to multiple moderately high-protein meals improves 24-h muscle protein synthesis. Over time, this may promote positive changes in body composition.Objective: We sought to assess the effects of within-day protein intake distribution on changes in body composition during dietary energy restriction and resistance training.Design: In a randomized parallel-design study, 41 men and women [mean ± SEM age: 35 ± 2 y; body mass index (in kg/m2): 31.5 ± 0.5] consumed an energy-restricted diet (750 kcal/d below the requirement) for 16 wk while performing resistance training 3 d/wk. Subjects consumed 90 g protein/d (1.0 ± 0.03 g · kg-1 · d-1, 125% of the Recommended Dietary Allowance, at intervention week 1) in either a skewed (10 g at breakfast, 20 g at lunch, and 60 g at dinner; n = 20) or even (30 g each at breakfast, lunch, and dinner; n = 21) distribution pattern. Body composition was measured pre- and postintervention.Results: Over time, whole-body mass (least-squares mean ± SE: -7.9 ± 0.6 kg), whole-body lean mass (-1.0 ± 0.2 kg), whole-body fat mass (-6.9 ± 0.5 kg), appendicular lean mass (-0.7 ± 0.1 kg), and appendicular fat mass (-2.6 ± 0.2 kg) each decreased. The midthigh muscle area (0 ± 1 cm2) did not change over time, whereas the midcalf muscle area decreased (-3 ± 1 cm2). Within-day protein distribution did not differentially affect these body-composition responses.Conclusion: The effectiveness of dietary energy restriction combined with resistance training to improve body composition is not influenced by the within-day distribution of protein when adequate total protein is consumed. This trial was registered at clinicaltrials.gov as NCT02066948.

Summary Points and Consensus Recommendations From the International Protein Summit.

The International Protein Summit in 2016 brought experts in clinical nutrition and protein metabolism together from around the globe to determine the impact of high-dose protein administration on clinical outcomes and address barriers to its delivery in the critically ill patient. It has been suggested that high doses of protein in the range of 1.2-2.5 g/kg/d may be required in the setting of the intensive care unit (ICU) to optimize nutrition therapy and reduce mortality. While incapable of blunting the catabolic response, protein doses in this range may be needed to best stimulate new protein synthesis and preserve muscle mass. Quality of protein (determined by source, content and ratio of amino acids, and digestibility) affects nutrient sensing pathways such as the mammalian target of rapamycin. Achieving protein goals the first week following admission to the ICU should take precedence over meeting energy goals. High-protein hypocaloric (providing 80%-90% of caloric requirements) feeding may evolve as the best strategy during the initial phase of critical illness to avoid overfeeding, improve insulin sensitivity, and maintain body protein homeostasis, especially in the patient at high nutrition risk. This article provides a set of recommendations based on assessment of the current literature to guide healthcare professionals in clinical practice at this time, as well as a list of potential topics to guide investigators for purposes of research in the future.

Assessment of Protein Turnover in Health and Disease.

To identify protein requirements, it is necessary to be familiar with basic physiology, practical methods, and dose response of protein delivery. This review evaluates available methodology, with emphasis on the limitations of existing techniques most often related to the underlying assumption. Historically, nitrogen balance has been the dominating technique. It is still the gold standard, although there are considerable problems related to the underlying assumptions to have reliable readings. When minimal requirements needed to be defined, the indicator amino acid oxidation technique came into practice. In situations of longer term steady states, it serves a purpose. In situations of disease or in aging, it has proven to be more problematic. More recently, whole-body protein turnover measurements have shown to be useful in situations where the underlying assumptions for the other techniques are not possible to meet.

How Many Nonprotein Calories Does a Critically Ill Patient Require? A Case for Hypocaloric Nutrition in the Critically Ill Patient.

Calculation of energy and protein doses for critically ill patients is still a matter of controversy. For more than 40 years of nutrition support, the total amount of nutrients to be delivered to these patients has been calculated based on expert recommendations, and this calculation is based on the administration of nonprotein calories in one attempt to ameliorate catabolic response and avoid the weight loss. New evidence suggests protein delivery is the most important intervention to improve clinical and metabolic outcomes. This article describes the metabolic rationale and the new evidence supporting a change in the approach of metabolic support of the critically ill, proposing a physiological-based intervention supported by the recognition of ancillary characteristics of the metabolic response to trauma and injury. A moderate dose of calories around 15 kcal/kg/d with a delivery of protein of 1.5 g/kg/d appears to be the new recommendation for many hypercatabolic patients in the first week following injury.

Protein Turnover and Metabolism in the Elderly Intensive Care Unit Patient.

Many intensive care unit (ICU) patients do not achieve target protein intakes particularly in the early days following admittance. This period of iatrogenic protein undernutrition contributes to a rapid loss of lean, in particular muscle, mass in the ICU. The loss of muscle in older (aged >60 years) patients in the ICU may be particularly rapid due to a perfect storm of increased catabolic factors, including systemic inflammation, disuse, protein malnutrition, and reduced anabolic stimuli. This loss of muscle mass has marked consequences. It is likely that the older patient is already experiencing muscle loss due to sarcopenia; however, the period of stay in the ICU represents a greatly accelerated period of muscle loss. Thus, on discharge, the older ICU patient is now on a steeper downward trajectory of muscle loss, more likely to have ICU-acquired muscle weakness, and at risk of becoming sarcopenic and/or frail. One practice that has been shown to have benefit during ICU stays is early ambulation and physical therapy (PT), and it is likely that both are potent stimuli to induce a sensitivity of protein anabolism. Thus, recommendations for the older ICU patient would be provision of at least 1.2-1.5 g protein/kg usual body weight/d, regular and early utilization of ambulation (if possible) and/or PT, and follow-up rehabilitation for the older discharged ICU patient that includes rehabilitation, physical activity, and higher habitual dietary protein to change the trajectory of ICU-mediated muscle mass loss and weakness.

Variation in Protein Origin and Utilization: Research and Clinical Application.

Muscle health can be rapidly compromised in clinical environments. Modifiable strategies to preserve metabolic homeostasis in adult patient populations include physical activity and pharmacologic support; however, optimizing dietary practices, or more specifically protein intake, is a necessary prerequisite for any other treatment strategy to be fully effective. Simply increasing protein intake is a well-intentioned but often unfocused strategy to protect muscle health in an intensive care setting. Protein quality is a frequently overlooked factor with the potential to differentially influence health outcomes. Quality can be assessed by a variety of techniques, with digestible indispensable amino acid score being the current and most comprehensive technique endorsed by the Food and Agriculture Organization. In practical terms, animal-based proteins are consistently scored higher in quality compared with incomplete proteins, regardless of the assessment method. Consequently, choosing parenteral and/or enteral feeding options that contain high-quality proteins, rich in the branched-chain amino acid leucine, may help establish a dietary framework with the potential to support clinical practice and improve health outcomes in critically ill patients.

11C-L-methyl methionine dynamic PET/CT of skeletal muscle: response to protein supplementation compared to L-[ring 13C6] phenylalanine infusion with serial muscle biopsy.

OBJECTIVE: The objective of this study was to determine if clinical dynamic PET/CT imaging with 11C-L-methyl-methionine (11C-MET) in healthy older women can provide an estimate of tissue-level post-absorptive and post-prandial skeletal muscle protein synthesis that is consistent with the more traditional method of calculating fractional synthesis rate (FSR) of muscle protein synthesis from skeletal muscle biopsies obtained during an infusion of L-[ring 13C6] phenylalanine (13C6-Phe). METHODS: Healthy older women (73 ± 5 years) completed both dynamic PET/CT imaging with 11C-MET and a stable isotope infusion of 13C6-Phe with biopsies to measure the skeletal muscle protein synthetic response to 25 g of a whey protein supplement. Graphical estimation of the Patlak coefficient Ki from analysis of the dynamic PET/CT images was employed as a measure of incorporation of 11 C-MET in the mid-thigh muscle bundle. RESULTS: Post-prandial values [mean ± standard error of the mean (SEM)] were higher than post-absorptive values for both Ki (0.0095 ± 0.001 vs. 0.00785 ± 0.001 min-1, p < 0.05) and FSR (0.083 ± 0.008 vs. 0.049 ± 0.006%/h, p < 0.001) in response to the whey protein supplement. The percent increase in Ki and FSR in response to the whey protein supplement was significantly correlated (r = 0.79, p = 0.015). CONCLUSIONS: Dynamic PET/CT imaging with 11C-MET provides an estimate of the post-prandial anabolic response that is consistent with a traditional, invasive stable isotope, and muscle biopsy approach. These results support the potential future use of 11C-MET imaging as a non-invasive method for assessing conditions affecting skeletal muscle protein synthesis.

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

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