One week of bed rest leads to substantial muscle atrophy and induces whole-body insulin resistance in the absence of skeletal muscle lipid accumulation

Short ( < 10 days) periods of muscle disuse, often necessary for recovery from illness or injury, lead to various negative health consequences. The current study investigated mechanisms underlying disuse-induced insulin resistance, taking into account muscle atrophy. Ten healthy, young males (age: 23 ± 1 years; BMI: 23.0 ± 0.9 kg · m−2) were subjected to 1 week of strict bed rest. Prior to and after bed rest, lean body mass (dual-energy X-ray absorptiometry) and quadriceps cross-sectional area (CSA; computed tomography) were assessed, and peak oxygen uptake (VO2peak) and leg strength were determined. Whole-body insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Additionally, muscle biopsies were collected to assess muscle lipid (fraction) content and various markers of mitochondrial and vascular content. Bed rest resulted in 1.4 ± 0.2 kg lean tissue loss and a 3.2 ± 0.9% decline in quadriceps CSA (both P < 0.01). VO2peak and one-repetition maximum declined by 6.4 ± 2.3 (P < 0.05) and 6.9 ± 1.4% (P < 0.01), respectively. Bed rest induced a 29 ± 5% decrease in whole-body insulin sensitivity (P < 0.01). This was accompanied by a decline in muscle oxidative capacity, without alterations in skeletal muscle lipid content or saturation level, markers of oxidative stress, or capillary density. In conclusion, 1 week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet–induced insulin resistance

Protein type, protein dose, and age modulate dietary protein digestion and phenylalanine absorption kinetics and plasma phenylalanine availability in humans

This is the final version. Available from the publisher via the DOI in this record.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/m2): 24.8 ± 3.3] who consumed various quantities of intrinsically l-[1-13C]-phenylalanine-labeled whey (n = 137), casein (n = 393), or milk (n = 72) protein and received intravenous infusions of l-[ring-2H5]-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 < 0.001). The postprandial availability of dietary protein-derived phenylalanine in the circulation increased with the ingestion of greater protein doses (P < 0.05). Protein digestion and phenylalanine absorption kinetics were attenuated in older when compared with young individuals, with 45% ± 10% vs. 51% ± 14% of dietary protein-derived phenylalanine appearing in the circulation, respectively (P = 0.001). 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

Interventional strategies to combat muscle disuse atrophy in humans: Focus on neuromuscular electrical stimulation and dietary protein

Numerous situations, such as the recovery from illness or rehabilitation after injury, necessitate a period of muscle disuse in otherwise healthy individuals. Even a few days of immobilization or bed rest can lead to substantial loss of skeletal muscle tissue and compromise metabolic health. The decline in muscle mass is attributed largely to a decline in postabsorptive and postprandial muscle protein synthesis rates. Reintroduction of some level of muscle contraction by the application of neuromuscular electrical stimulation (NMES) can augment both postabsorptive and postprandial muscle protein synthesis rates and, as such, prevent or attenuate muscle loss during short-term disuse in various clinical populations. Whereas maintenance of habitual dietary protein consumption is a prerequisite for muscle mass maintenance, supplementing dietary protein above habitual intake levels does not prevent muscle loss during disuse in otherwise healthy humans. Combining the anabolic properties of physical activity (or surrogates) with appropriate nutritional support likely further increases the capacity to preserve skeletal muscle mass during a period of disuse. Therefore, effective interventional strategies to prevent or alleviate muscle disuse atrophy should include both exercise (mimetics) and appropriate nutritional support

Skeletal muscle atrophy during short-term disuse: Implications for age-related sarcopenia

Situations such as the recovery from injury and illness can lead to enforced periods of muscle disuse or unloading. Such circumstances lead to rapid skeletal muscle atrophy, loss of functional strength and a multitude of related negative health consequences. The elderly population is particularly vulnerable to the acute challenges of muscle disuse atrophy. Any loss of skeletal muscle mass must be underpinned by a chronic imbalance between muscle protein synthesis and breakdown rates. It is recognized that muscle atrophy during prolonged ( > 10 days ) disuse is brought about primarily by declines in post-absorptive and post-prandial muscle protein synthesis rates, without a clear contribution from changes in muscle protein breakdown. Few data are available on the impact of short-term disuse ( < 10 days ) on muscle protein turnover in humans. However, indirect evidence indicates that considerable muscle atrophy occurs during this early phase, and is likely attributed to a rapid increase in muscle protein breakdown accompanied by the characteristic decline in muscle protein synthesis. Short-term disuse atrophy is of particular relevance in the development of sarcopenia, as it has been suggested that successive short periods of muscle disuse, due to sickness or injury, accumulate throughout an individual's lifespan and contributes considerably to the net muscle loss observed with aging. Research is warranted to elucidate the physiological and molecular basis for rapid muscle loss during short periods of disuse. Such mechanistic insight will allow the characterization of nutritional, exercise and/or pharmacological interventions to prevent or attenuate muscle loss during periods of disuse and therefore aid in the treatment of age-related sarcopenia

Electrical stimulation for investigating and improving neuromuscular function in vivo : Historical perspective and major advances

This historical review summarizes the major advances – particularly from the last 50 years – in transcutaneous motor-level electrical stimulation, which can be used either as a tool to investigate neuromuscular function and its determinants (electrical stimulation for testing; EST) or as a therapeutic/training modality to improve neuromuscular and physical function (neuromuscular electrical stimulation; NMES). We focus on some of the most important applications of electrical stimulation in research and clinical settings, such as the investigation of acute changes, chronic adaptations and pathological alterations of neuromuscular function with EST, as well as the enhancement, preservation and restoration of muscle strength and mass with NMES treatment programs in various populations. For both EST and NMES, several major advances converge around understanding and optimizing motor unit recruitment during electrically-evoked contractions, also taking into account the influence of stimulation site (e.g., muscle belly vs nerve trunk) and type (e.g., pulse duration, frequency, and intensity). This information is equally important both in the context of mechanistic research of neuromuscular function as well as for clinicians who believe that improvements in neuromuscular function are required to provide health-related benefits to their patients

Neuromuscular electrical stimulation prior to presleep protein feeding stimulates the use of protein-derived amino acids for overnight muscle protein synthesis

Short periods of muscle disuse result in substantial skeletal muscle atrophy. Recently, we showed that both neuromuscular electrical stimulation (NMES) as well as presleep dietary protein ingestion represent effec-tive strategies to stimulate muscle protein synthesis rates. In this study, we test our hypothesis that NMES can augment the use of presleep protein-derived amino acids for overnight muscle protein synthesis in older men. Twenty healthy, older [69 1 (SE) yr] men were subjected to 24 h of bed rest, starting at 8:00 AM. In the evening, volunteers were subjected to 70-min 1-legged NMES, while the other leg served as nonstimulated control (CON). Immediately following NMES, 40 g of intrinsically L-[1-13C]-phenylalanine labeled protein was ingested prior to sleep. Blood samples were taken throughout the night, and muscle biopsies were obtained from both legs in the evening and the following morning (8 h after protein ingestion) to assess dietary protein-derived L-[1-13C]-phenylalanine enrichments in myofibrillar protein. Plasma phenylalanine concentrations and plasma L-[1-13C]-phenylalanine enrichments increased signifi-cantly following protein ingestion and remained elevated for up to 6 h after protein ingestion (P 0.05). During overnight sleep, myofibrillar protein-bound L-[1-13C]-phenylalanine enrichments (MPE) increased to a greater extent in the stimulated compared with the control leg (0.0344 0.0019 vs. 0.0297 0.0016 MPE, respectively; P 0.01), representing 18 6% greater incorpora-tion of presleep protein-derived amino acids in the NMES com-pared with CON leg. In conclusion, application of NMES prior to presleep protein feeding stimulates the use of dietary protein-derived amino acids for overnight muscle protein synthesis in older men

Intermittent versus continuous enteral nutrition attenuates increases in insulin and leptin during short-term bed rest

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 < 0.001) which reached a peak of 369 ± 225 pmol L−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

Substantial skeletal muscle loss occurs during only 5 days of disuse

Aim The impact of disuse on the loss of skeletal muscle mass and strength has been well documented. Given that most studies have investigated muscle atrophy after more than 2 weeks of disuse, few data are available on the impact of shorter periods of disuse. We assessed the impact of 5 and 14 days of disuse on skeletal muscle mass, strength and associated intramuscular molecular signalling responses

A single session of neuromuscular electrical stimulation does not augment postprandial muscle protein accretion

The loss of muscle mass and strength that occurs with aging, termed sarcopenia, has been ( at least partly ) attributed to an impaired muscle protein synthetic response to food intake. Previously, we showed that neuromuscular electrical stimulation ( NMES ) can stimulate fasting muscle protein synthesis rates and prevent muscle atrophy during disuse. We hypothesized that NMES prior to protein ingestion would increase postprandial muscle protein accretion. Eighteen healthy elderly ( 69 ± 1 yr ) males participated in this study. After a 70-min unilateral NMES protocol was performed, subjects ingested 20 g of intrinsically l-[1-13C]phenylalanine-labeled casein. Plasma samples and muscle biopsies were collected to assess postprandial mixed muscle and myofibrillar protein accretion as well as associated myocellular signaling during a 4-h postprandial period in both the control ( CON ) and stimulated ( NMES ) leg. Protein ingestion resulted in rapid increases in both plasma phenylalanine concentrations and l-[1-13C]phenylalanine enrichments, which remained elevated during the entire 4-h postprandial period ( P 0.05 ). In agreement, no differences were observed in the postprandial rise in myofibrillar protein bound l-[1-13C]phenylalanine enrichments between the CON and NMES legs ( 0.0115 ± 0.0014 vs. 0.0133 ± 0.0013 MPE, respectively, P > 0.05 ). Significant increases in mTOR and P70S6K phosphorylation status were observed in the NMES-stimulated leg only ( P < 0.05 ). We conclude that a single session of NMES prior to food intake does not augment postprandial muscle protein accretion in healthy older men

Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly

Objective Protein supplementation increases gains in lean body mass following prolonged resistance-type exercise training in frail older adults. We assessed whether the greater increase in lean body mass can be attributed to muscle fiber type specific hypertrophy with concomitant changes in satellite cell (SC) content. Design A total of 34 frail elderly individuals (77 ± 1 years, n = 12 male adults) participated in this randomized, double-blind, placebo-controlled trial with 2 arms in parallel. Intervention Participants performed 24 weeks of progressive resistance-type exercise training (2 sessions per week) during which they were supplemented twice-daily with milk protein (2 × 15 g) or a placebo. Methods Muscle biopsies were taken at baseline, and after 12 and 24 weeks of intervention, to determine type I and type II muscle fiber specific cross-sectional area (CSA), SC content, and myocellular characteristics. Results In the placebo group, a trend for a 20% ± 11% increase in muscle fiber CSA was observed in type II fibers only (P =.051), with no increase in type I muscle fiber CSA. In the protein group, type I and II muscle fiber CSA increased by 23% ± 7% and 34% ± 10% following 6 months of training, respectively (P .05). No changes in myonuclear content and SC contents were observed over time in either group (both P > .05). Regression analysis showed that changes in myonuclear content and domain size are predictive of muscle fiber hypertrophy. Conclusions Protein supplementation augments muscle fiber hypertrophy following prolongedresistance-type exercise training in frail older people, without changes in myonuclear and SC content