Nutrient modulation in the management of disease-induced muscle wasting: evidence from human studies

Purpose of review: In addition to being essential for movement, skeletal muscles act as both a store and source of key macronutrients. As such, muscle is an important tissue for whole body homeostasis, undergoing muscle wasting in times of starvation, disease, and stress, for example, to provide energy substrates for other tissues. Yet, muscle wasting is also associated with disability, comorbidities, and mortality. As nutrition is so crucial to maintaining muscle homeostasis 'in health', it has been postulated that muscle wasting in cachexia syndromes may be alleviated by nutritional interventions. This review will highlight recent work in this area in relation to muscle kinetics, the acute metabolic (e.g. dietary protein), and longer-term effects of dietary interventions. Recent findings: Whole body and skeletal muscle protein synthesis invariably exhibit deranged kinetics (favouring catabolism) in wasting states; further, many of these conditions harbour blunted anabolic responses to protein nutrition compared with healthy controls. These derangements underlie muscle wasting. Recent trials of essential amino acid and protein-based nutrition have shown some potential for therapeutic benefit. Summary: Nutritional modulation, particularly of dietary amino acids, may have benefits to prevent or attenuate disease-induced muscle wasting. Nonetheless, there remains a lack of recent studies exploring these key concepts to make conclusive recommendations

Recent developments in deuterium oxide tracer approaches to measure rates of substrate turnover: implications for protein, lipid, and nucleic acid research

Purpose of review: Methods that inform on dynamic metabolism that can be applied to clinical populations to understand disease progression and responses to therapeutic interventions are of great importance. This review perspective will highlight recent advances, development, and applications of the multivalent stable isotope tracer deuterium oxide (D2O) to the study of substrate metabolism with particular reference to protein, lipids, and nucleic acids, and how these methods can be readily applied within clinical and pharmaceutical research. Recent findings: Advances in the application of D2O techniques now permit the simultaneous dynamic measurement of a range of substrates (i.e. protein, lipid, and nucleic acids, along with the potential for OMICs methodologies) with minimal invasiveness further creating opportunities for long-term ‘free living’ measures that can be used in clinical settings. These techniques have recently been applied to ageing populations and further in cancer patients revealing altered muscle protein metabolism. Additionally, the efficacy of numerous drugs in improving lipoprotein profiles and controlling cellular proliferation in leukaemia have been revealed. Summary: D2O provides opportunities to create a more holistic picture of in-vivo metabolic phenotypes, providing a unique platform for development in clinical applications, and the emerging field of personalized medicine

A 4-week, lifestyle-integrated, home-based exercise training programme elicits improvements in physical function and lean mass in older men and women: a pilot study

Background: Developing alternative exercise programmes that can alleviate certain barriers to exercise such as psychological, environmental or socio-economical barriers, but provide similar physiological benefits e.g. increases in muscle mass and strength, is of grave importance. This pilot study aimed to assess the efficacy of an unsupervised, 4-week, whole-body home-based exercise training (HBET) programme, incorporated into daily living activities, on skeletal muscle mass, power and strength. Methods: Twelve healthy older volunteers (63±3 years, 7 men: 5 women, BMI: 29±1 kg/m²) carried out the 4-week “lifestyle-integrated” HBET of 8 exercises, 3x12 repetitions each, every day. Before and after HBET, a number of physical function tests were carried out: unilateral leg extension 1-RM (one- repetition maximum), MVC (maximal voluntary contraction) leg extension, lower leg muscle power (via Nottingham Power Rig), handgrip strength and SPPBT (short physical performance battery test). A D3-Creatine method was used for assessment of whole-body skeletal muscle mass, and ultrasound was used to measure the quadriceps cross-sectional area (CSA) and vastus lateralis muscle thickness. Results: Four weeks HBET elicited significant (p<0.05) improvements in leg muscle power (276.7±38.5 vs. 323.4±43.4 W), maximal voluntary contraction (60°: 154.2±18.4 vs. 168.8±15.2 Nm, 90°: 152.1±10.5 vs. 159.1±11.4 Nm) and quadriceps CSA (57.5±5.4 vs. 59.0±5.3 cm2), with a trend for an increase in leg strength (1-RM: 45.7±5.9 vs. 49.6±6.0 kg, P=0.08). This was despite there being no significant differences in whole-body skeletal muscle mass, as assessed via D3-Creatine. Conclusions: This study demonstrates that increases in multiple aspects of muscle function can be achieved in older adults with just 4-weeks of “lifestyle-integrated” HBET, with a cost-effective means. This training mode may prove to be a beneficial alternative for maintaining and/or improving muscle mass and function in older adults

The effects of elective abdominal surgery on protein turnover: A meta-analysis of stable isotope techniques to investigate postoperative catabolism

Background & aimsElective surgery induces skeletal muscle wasting driven by an imbalance between muscle protein synthesis and breakdown. From examination of diverse stable isotope tracer techniques, the dynamic processes driving this imbalance are unclear. This meta-analysis aimed to elucidate the mechanistic driver(s) of postoperative protein catabolism through stable isotope assessment of protein turnover before and after abdominal surgery.MethodsMeta-analysis was performed of randomized controlled trials and cohort studies in patients undergoing elective abdominal surgery that contained measurements of whole-body or skeletal muscle protein turnover using stable isotope tracer methodologies pre- and postoperatively. Postoperative changes in protein synthesis and breakdown were assessed through subgroup analysis of tracer methodology and perioperative care.ResultsSurgery elicited no overall change in protein synthesis [standardized mean difference (SMD) ?0.47, 95% confidence interval (CI): ?1.32, 0.39, p = 0.25]. However, subgroup analysis revealed significant suppressions via direct-incorporation methodology [SMD -1.53, 95%CI: ?2.89, ?0.17, p = 0.03] within skeletal muscle. Changes of this nature were not present among arterio-venous [SMD 0.61, 95%CI: ?1.48, 2.70, p = 0.58] or end-product [SMD -0.09, 95%CI: ?0.81, 0.64, p = 0.82] whole-body measures. Surgery resulted in no overall change in protein breakdown [SMD 0.63, 95%CI: ?0.06, 1.32, p = 0.07]. Yet, separation by tracer methodology illustrated significant increases in urinary end-products (urea/ammonia) [SMD 0.70, 95%CI: 0.38, 1.02, p < 0.001] that were not present among arterio-venous measures [SMD 0.67, 95%CI: ?1.05, 2.38, p = 0.45].ConclusionsElective abdominal surgery elicits suppressions in skeletal muscle protein synthesis that are not reflected on a whole-body level. Lack of uniform changes across whole-body tracer techniques are likely due to contribution from tissues other than skeletal muscle

The Fall of Stringy de Sitter

Kachru, Kallosh, Linde, & Trivedi recently constructed a four-dimensional de Sitter compactification of IIB string theory, which they showed to be metastable in agreement with general arguments about de Sitter spacetimes in quantum gravity. In this paper, we describe how discrete flux choices lead to a closely-spaced set of vacua and explore various decay channels. We find that in many situations NS5-brane meditated decays which exchange NSNS 3-form flux for D3-branes are comparatively very fast.Comment: 35 pp (11 pp appendices), 5 figures, v3. fixed minor typo

Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age-related anabolic resistance to exercise in humans

Ageing is associated with impaired hypertrophic responses to resistance exercise training (RET). Here we investigated the aetiology of ‘anabolic resistance’ in older humans. Twenty healthy male individuals, 10 younger (Y; 23 ± 1 years) and 10 older (O; 69 ± 3 years), performed 6 weeks unilateral RET (6 × 8 repetitions, 75% of one repetition maximum (1-RM), 3 times per week). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom%; thereafter 50 ml week−1), further bilateral VL muscle biopsies were taken at 3 and 6 weeks to quantify muscle protein synthesis (MPS) via gas chromatography–pyrolysis–isotope ratio mass spectrometry. After RET, 1-RM increased in Y (+35 ± 4%) and O (+25 ± 3%; P < 0.01), while MVC increased in Y (+21 ± 5%; P < 0.01) but not O (+6 ± 3%; not significant (NS)). In comparison to Y, O displayed blunted RET-induced increases in muscle thickness (at 3 and 6 weeks, respectively, Y: +8 ± 1% and +11 ± 2%, P < 0.01; O: +2.6 ± 1% and +3.5 ± 2%, NS). While ‘basal’ longer term MPS was identical between Y and O (∼1.35 ± 0.1% day−1), MPS increased in response to RET only in Y (3 weeks, Y: 1.61 ± 0.1% day−1; O: 1.49 ± 0.1% day−1). Consistent with this, O exhibited inferior ribosomal biogenesis (RNA:DNA ratio and c-MYC induction: Y: +4 ± 2 fold change; O: +1.9 ± 1 fold change), translational efficiency (S6K1 phosphorylation, Y: +10 ± 4 fold change; O: +4 ± 2 fold change) and anabolic hormone milieu (testosterone, Y: 367 ± 19; O: 274 ± 19 ng dl−1 (all P < 0.05). Anabolic resistance is thus multifactorial

A novel D2O tracer method to quantify RNA turnover as a biomarker of de novo ribosomal biogenesis, in vitro, in animal models, and in human skeletal muscle

Current methods to quantify in vivo RNA dynamics are limited. Here, we developed a novel stable isotope (D2O) methodology to quantify RNA synthesis (i.e., ribosomal biogenesis) in cells, animal models, and humans. First, proliferating C2C12 cells were incubated in D2O-enriched media and myotubes ±50 ng/ml IGF-I. Second, rat quadriceps (untrained, n = 9; 7-wk interval-“like” training, n = 13) were collected after ~3-wk D2O (70 atom %) administration, with body-water enrichment monitored via blood sampling. Finally, 10 (23 ± 1 yr) men consumed 150-ml D2O followed by 50 ml/wk and undertook 6-wk resistance exercise (6 × 8 repetitions, 75% 1-repetition maximum 3/wk) with body-water enrichment monitored by saliva sampling and muscle biopsies (for determination of RNA synthesis) at 0, 3, and 6 wk. Ribose mole percent excess (r-MPE) from purine nucleotides was analyzed via GC-MS/MS. Proliferating C2C12 cell r-MPE exhibited a rise to plateau, whereas IGF-I increased myotube RNA from 76 ± 3 to 123 ± 3 ng/μl and r-MPE by 0.39 ± 0.1% (both P < 0.01). After 3 wk, rat quadriceps r-MPE had increased to 0.25 ± 0.01% (P < 0.01) and was greater with running exercise (0.36 ± 0.02%; P < 0.01). Human muscle r-MPE increased to 0.06 ± 0.01 and 0.13 ± 0.02% at 3/6 wk, respectively, equating to synthesis rates of ~0.8%/day, increasing with resistance exercise to 1.7 ± 0.3%/day (P < 0.01) and 1.2 ± 0.1%/day (P < 0.05) at 3/6 wk, respectively. Therefore, we have developed and physiologically validated a novel technique to explore ribosomal biogenesis in a multimodal fashion

DAZAP1, an RNA-binding protein required for development and spermatogenesis, can regulate mRNA translation

DAZ-associated protein 1 (DAZAP1) is an RNA-binding protein required for normal growth, development, and fertility in mice. However, its molecular functions have not been elucidated. Here we find that Xenopus laevis and human DAZAP1, which are each expressed as short and long forms, act as mRNA-specific activators of translation in a manner that is sensitive to the number of binding sites present within the 3′ UTR. Domain mapping suggests that this conserved function is mainly associated with C-terminal regions of DAZAP1. Interestingly, we find that the expression of xDAZAP1 and its polysome association are developmentally controlled, the latter suggesting that the translational activator function of DAZAP1 is regulated. However, ERK phosphorylation of DAZAP1, which can alter protein interactions with its C terminus, does not play a role in regulating its ability to participate in translational complexes. Since relatively few mRNA-specific activators have been identified, we explored the mechanism by which DAZAP1 activates translation. By utilizing reporter mRNAs with internal ribosome entry sites, we establish that DAZAP1 stimulates translation initiation. Importantly, this activity is not dependent on the recognition of the 5′ cap by initiation factors, showing that it functions downstream from this frequently regulated event, but is modulated by changes in the adenylation status of mRNAs. This suggests a function in the formation of “end-to-end” complexes, which are important for efficient initiation, which we show to be independent of a direct interaction with the bridging protein eIF4G

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

Pathogenesis and treatment of chronic pulmonary disease