Prevent Muscle Wasting Research Articles

Effect of acute transcranial magnetic stimulation on intracellular signalling in human skeletal muscle.

To investigate the potential of an acute bout of transcranial electrical stimulation to induce anabolic signalling. Experimental intervention on healthy subjects. Ten healthy subjects, 5 women and 5 men (mean age (standard deviation (SD) 32 years (SD 4)). The quadriceps muscle was stimulated at a frequency of 10 Hz for 10 s, followed by 20 s of rest, repeated 40 times over 20 min. Electromyography and force data were collected for all transcranial electrical stimulation sequences. Muscle biopsies were obtained from the vastus lateralis muscle before and 1 and 3 h after stimulation. One bout of transcranial electrical stimulation decreased phosphorylation of AKT at Thr308 (1 h: -29%, 3 h: -38%; p < 0.05) and mTOR phosphorylation at Ser2448 (1 h: -10%; ns, 3 h: -21%; p < 0.05), both in the anabolic pathway. Phosphorylation of AMPK, ACC and ULK1 were not affected. c-MYC gene expression was unchanged following transcranial electrical stimulation, but rDNA transcription decreased (1 h: -28%, 3 h: -19%; p < 0.05). PGC1α-ex1b mRNA increased (1 h: 2.3-fold, 3 h: 2.6-fold; p < 0.05), which also correlated with vastus lateralis electromyography activity, while other PGC-1α variants were unchanged. Acute transcranial electrical stimulation of skeletal muscle in weight-bearing healthy individuals did not induce anabolic signalling, and some signs of impaired muscle anabolism were detected, suggesting limited potential in preventing muscle wasting.

Molecular Mechanisms of Anthocyanins as A Potential Nutraceutical for Muscle Regeneration

Anthocyanins, natural pigments belonging in the flavonoid group that can be found in different types of plants, are popular bioactive compounds with various beneficial properties. In the topic of skeletal muscle, overtraining, or pathological conditions can cause excessive ROS production and chronic inflammation, leading to degradation in function, mass, and regenerative capacity. There are two sides of ROS induced inflammation. Although inflammation is needed during skeletal muscle regeneration, chronic inflammation leads to detrimental effects. Thus, in the case of imbalance of ROS in chronic inflammation, further antioxidant supplementation might be required to counter the excessive ROS. Anthocyanins, as a nutraceutical, have the potential to improve muscle function and its regenerative capacity through its redox control, increasing protein synthesis, decreasing the breakdown of muscle protein, regulating mitochondria function, regulating autophagy, preventing apoptosis, improving gut dysbiosis, and inducing myogenesis. Here, we discussed and summarized the potential molecular mechanisms of anthocyanins as a nutraceutical to promote skeletal muscle regeneration and prevent muscle wasting. Keywords: anthocyanins, muscle regeneration, nutraceutical, skeletal muscle Corresponding Author: Astrid Feinisa Khairani Division of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran Address: Jalan Raya Bandung - Sumedang Km 21.6, Jatinangor, Sumedang, West Java, Indonesia, 45363 Email address: astrid.khairani@unpad.ac.id Tel: +62-22-7795594

Weight reduction and possible implications for the rehabilitation of horses with ambulatory difficulties

SummaryEquine musculoskeletal injuries, or other causes of reduced movement, can have a poor prognosis partially due to the secondary complications that may develop during recovery or rehabilitation. These can include supporting limb laminitis due to excessive weightbearing on healthy limbs and also problems associated with ventilation or perfusion due to prolonged recumbency. The risk of these complications is reported to increase with increasing body weight. While many methods have been attempted to reduce load and prevent complications, there is no current standard practice when managing horses with ambulatory difficulties. One critical consideration with load reduction devices is maintaining sufficient mobility to allow for blood flow and the prevention of muscle wasting. One of the most challenging obstacles with any weight reduction method or device is preventing pressure sores/ulcers or other tissue trauma because load is redistributed away from the limbs and onto regions of the body unaccustomed to weightbearing. Reported methods to aid in recovery and rehabilitation include rescue slings, forced recumbency, flotation tanks, water treadmills and aquatic therapy. While these methods have been successful in some horses, significant complications have also been reported. If too much weight is removed, muscle wasting or osteopenia occurs; conversely, if insufficient weight is lifted blood flow is hindered. The optimal load reduction is not known because each individual horse will have different requirements depending on the severity of the injury. The goal would be to restore normal weight distribution on the noninjured limbs, while supporting the weight that would normally be placed on the injured limb.

Skeletal Muscle Depletion Predicts the Prognosis of Patients With Hepatocellular Carcinoma Treated With Radiotherapy.

Background: Sarcopenia is gaining attention as a poor prognostic factor for various types of malignancies. This study evaluated the prevalence and prognostic significance of sarcopenia and its association with survival in hepatocellular carcinoma (HCC) patients who underwent radiotherapy (RT) to the primary site.Materials and Methods: Between January 2009 and November 2016, 156 patients with HCC that underwent RT to the liver were retrospectively studied. Sarcopenia was defined as an L3 skeletal muscle index of <49 cm2/m2 for men and <41 cm2/m2 for women as proposed by Korean-specific cut-off value. Sarcopenia was identified pre- and post-RT (within 3 months from the end of RT).Results: Pre-RT sarcopenia occurred in 99 (63.5%) patients and was significantly associated with higher levels of protein induced by vitamin K absence or antagonist-II (PIVKA-II), lower percentage of overweight/obesity (body-mass index), higher percentage of previous systemic chemotherapy, and lower total RT dose. At a median follow-up of 9.3 months, median overall survival (OS) was significantly lower in patients with pre-RT sarcopenia than in those without (7.1 vs. 15.3 months, p < 0.001). In multivariate analysis [reporting hazard ratio (HR): 95% confidence interval (CI)], albumin-bilirubin score (2.35: 1.33–4.17; p = 0.003), total dose (0.44: 0.27–0.71; p = 0.001), and pre-RT sarcopenia (2.38: 1.53–3.70; p < 0.001) were independent OS prognostic factors. Among patients without pre-RT sarcopenia, 20 newly developed sarcopenia after RT and showed significantly lower OS compared to those without sarcopenia after RT (n = 35) (median 14.1 vs. 17.5 months, p = 0.018). Multivariate logistic regression analysis [reporting odds ratio (OR)] demonstrated older age (310.190; p = 0.007), Child-Pugh classification B or C (15.239; p = 0.047), higher alpha-fetoprotein (128.486; p = 0.008), higher PIVKA-II (118.536; p = 0.027), and larger planning target volume (51.310; p = 0.026) as significant factors for newly developed post-RT sarcopenia.Conclusion: Newly developed sarcopenia after RT, as well as pre-RT sarcopenia, were associated with poor survival for HCC patients who underwent RT to the liver. This result suggests the possibility that early intervention such as nutritional support and exercise therapies before and during RT could prevent muscle wasting and may be effective in improving the prognosis of HCC patients.

Repetitive vascular occlusion stimulus (RVOS) versus standard care to prevent muscle wasting in critically ill patients (ROSProx):a study protocol for a pilot randomised controlled trial

BackgroundForty per cent of critically ill patients are affected by intensive care unit-acquired weakness (ICU-AW), to which skeletal muscle wasting makes a substantial contribution. This can impair outcomes in hospital, and can cause long-term physical disability after hospital discharge. No effective mitigating strategies have yet been identified.Application of a repetitive vascular occlusion stimulus (RVOS) a limb pressure cuff inducing brief repeated cycles of ischaemia and reperfusion, can limit disuse muscle atrophy in both healthy controls and bed-bound patients recovering from knee surgery. We wish to determine whether RVOS might be effective in mitigating against muscle wasting in the ICU. Given that RVOS can also improve vascular function in healthy controls, we also wish to assess such effects in the critically ill. We here describe a pilot study to assess whether RVOS application is safe, tolerable, feasible and acceptable for ICU patients.MethodsThis is a randomised interventional feasibility trial. Thirty-two ventilated adult ICU patients with multiorgan failure will be recruited within 48 h of admission and randomised to either the intervention arm or the control arm. Intervention participants will receive RVOS twice daily (except only once on day 1) for up to 10 days or until ICU discharge.Serious adverse events and tolerability (pain score) will be recorded; feasibility of trial procedures will be assessed against pre-specified criteria and acceptability by semi-structured interview. Together with vascular function, muscle mass and quality will be assessed using ultrasound and measures of physical function at baseline, on days 6 and 11 of study enrolment, and at ICU and hospital discharge. Blood and urine biomarkers of muscle metabolism, vascular function, inflammation and DNA damage/repair mechanism will also be analysed. The Health questionnaire will be completed 3 months after hospital discharge.DiscussionIf this study demonstrates feasibility, the derived data will be used to inform the design (and sample size) of an appropriately-powered prospective trial to clarify whether RVOS can help preserve muscle mass/improve vascular function in critically ill patients.Trial registrationISRCTN Registry, ISRCTN44340629. Registered on 26 October 2017.

Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting

Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.

Can L-carnitine supplementation and exercise improve muscle complications in patients with liver cirrhosis who receive branched-chain amino acid supplementation?

The aim of this study was to elucidate the efficacy of the combination of L-carnitine and exercise, reported to prevent muscle wasting, for muscle complications (function, volume, and cramping) in patients with liver cirrhosis (LC) who received branched-chain amino acid supplementation. From December 2017 to April 2018, 18 patients with LC who had been given branched-chain amino acid granule supplementation (12.45 g/day) were enrolled (mean age 68.4±10.8 years; 10 males and eight females; Child-Pugh A : B=9 : 9). After evaluating the average number of daily steps, oral L-carnitine supplementation (1000 mg/day) and additional exercise (plus 2000 steps/day) were added for 6 months. Every 4 weeks, a pedometer, a hand dynamometer, ergometer, and bioelectrical impedance analysis were used to evaluate daily steps, muscle function and muscle volume, and muscle cramps were recorded using a numerical rating scale. Average steps and serum levels of total and free carnitine were increased from before treatment to the final measurement (1883.5±1211.6 vs. 3165.1±1800.0/day, 62.6±16.5 vs. 110.9±28.6 μmol/l, and 47.7±15.2 vs. 83.2±21.5 μmol/l, respectively; P<0.01), whereas there were no significant changes in the ratios of handgrip strength, leg strength, and muscle volume after 6 months [1.00±0.13 (P=0.991), 1.07±0.13 (P=0.073), and 0.992±0.036 (P=0.390), respectively]. However, the frequency of complaints of muscle cramping was reduced as compared with the start of therapy (baseline, 3 months, and 6 months: 6.3±4.8, 3.1±3.3, and 2.1±2.0, respectively) (P=0.025, Holm's method), whereas numerical rating scale did not show any significant improvement. L-Carnitine may have an important role for prevention of muscle wasting and reducing the frequency of muscle cramping.

Salidroside Attenuates Denervation-Induced Skeletal Muscle Atrophy Through Negative Regulation of Pro-inflammatory Cytokine

Skeletal muscle atrophy is associated with pro-inflammatory cytokines. Salidroside is a biologically active ingredient of Rhodiola rosea, which exhibits anti-inflammatory property. However, there is little known about the effect of salidroside on denervation-induced muscle atrophy. Therefore, the present study aimed to determine whether salidroside could protect against denervation-induced muscle atrophy and to clarify potential molecular mechanisms. Denervation caused progressive accumulation of inflammatory factors in skeletal muscle, especially interleukin 6 (IL6) and its receptor, and recombinant murine IL6 (rmIL6) local infusion could induce target muscle atrophy, suggesting that denervation induced inflammation in target muscles and the inflammation may trigger muscle wasting. Salidroside alleviated denervation-induced muscle atrophy and inhibited the production of IL6. Furthermore, the inhibition of phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the decreased levels of suppressor of cytokine signaling (SOCS3), muscle RING finger protein-1 (MuRF1), atrophy F-box (atrogin-1), microtubule-associated protein light chain 3 beta (LC3B) and PTEN-induced putative kinase (PINK1) were observed in denervated muscles that were treated with salidroside. Finally, all of these responses to salidroside were replicated in neutralizing antibody against IL6. Taken together, these results suggest that salidroside alleviates denervation-induced inflammation response, thereby inhibits muscle proteolysis and muscle atrophy. Therefore, it was assumed that salidroside might be a potential therapeutic candidate to prevent muscle wasting.

OR16-4 The Growth Hormone Axis in Relation to Muscle Weakness in the ICU: Effect of Early Macronutrient Deficit

Background: The activity of the growth hormone (GH) axis is altered by critical illness. In the acute phase, GH resistance, as reflected by increased GH and decreased insulin-like growth factor-I (IGF-I), mimics fasting-induced changes in health. Although early full feeding in ICU has long been assumed to prevent muscle wasting and weakness, the EPaNIC RCT observed fewer complications and faster recovery with accepting the macronutrient deficit in the first ICU week, as compared with early full feeding, including less acquired muscle weakness [1,2]. We previously observed that accepting the early macronutrient deficit attenuated rather than aggravated the rise in GH as compared with early full feeding [3]. We have now further characterized its impact on the GH axis, in relation to the risk of acquiring muscle weakness in ICU. Methods: This was a preplanned sub-analysis of the EPaNIC RCT. For 10 matched patients per group, serum GH was quantified every 10 min between 9 PM and 6 AM, followed by deconvolution analyses to estimate GH secretion. For 564 patients per group, matched for baseline characteristics, and for all patients investigated for muscle weakness (n=600), serum IGF-I, IGF binding protein 3 (IGFBP3) and IGFBP1 were measured upon ICU admission, at day 4 (if still in ICU), and on the last ICU day (LD). Matched healthy subjects (n=65) were included as controls. Groups were compared with Wilcoxon test or repeated-measures ANOVA. Associations between changes in concentrations from baseline to day 4 or LD for patients with shorter ICU stay (d4/LD) and risk of muscle weakness were assessed with nominal logistic regression analysis, adjusted for baseline risk factors, baseline hormone concentrations and randomization. Results: Upon ICU admission, patients revealed low IGF-I and IGFBP3 and high IGFBP1 as compared with controls (p<0.001). Tolerating an early macronutrient deficit in ICU decreased basal (non-pulsatile) GH secretion (p=0.005) without affecting pulsatile GH secretion. From admission to d4/LD IGF-I and IGFBP3 increased, whereas IGFBP1 decreased (all p<0.001) in the fully fed group. Compared to full feeding, tolerating the early macronutrient deficit prevented the rise in IGF-I (p<0.001), did not affect IGFBP3 and attenuated the decrease in IGFBP1 (p<0.001). A stronger rise in GH and IGF-I from admission to d4/LD was independently associated with a lower risk of acquiring muscle weakness (OR (95%CI) per ng/ml change 0.88 (0.81-0.96) for GH, p=0.001; 0.98 (0.97-0.99) for IGF-I, p=0.002). Conclusion: Tolerating the early macronutrient deficit suppresses basal but not pulsatile GH secretion and alters IGF-I bioavailability during critical illness. These effects may counteract the protection of the intervention against the development of muscle weakness. 1. Casaer et al. N Engl J Med 2011;365:506-17 2. Hermans et al. Lancet Respir Med 2013;1:621-9 3. Van Dyck et al. ENDO 2018;SUN601

Resistance Exercise Counteracts Tumor Growth in Two Carcinoma Rodent Models.

Although resistance exercise (RE) is now recognized as an adjuvant in cancer treatment because of its capacity to prevent muscle wasting, weakness, and cachexia, it is unknown whether RE can mitigate tumor development. Two solid adenocarcinoma models (Walker-256 and Ehrlich) were used to investigate the effects of RE on tumor cell proliferation, growth, and aggressiveness parameters in tumor-bearing animals' life span. Walker-256 tumor-bearing rats and Ehrlich tumor-bearing mice were subjected to RE, which consisted of climbing a ladder apparatus with loads tied to their tails. After 4 wk, animals were euthanized, and tumors were excised and assessed for tumor microenvironment evaluation such as cell proliferation and apoptosis determination, collagen deposit, and presence of malignant tumor morphology. Our data demonstrate that RE mitigated tumor growth and favored tumor end points such as lower Scarff-Bloom-Richardson histological grade tumor, denoting slow cell aberrant form and division, decreased tumor cell proliferation (evaluated by nucleus marked with antigen ki-67), and lower viable tumor area in both types of tumors studied. In addition, RE stimulated tumor microvessel density in Walker-256 tumor-bearing rats, but there was no change in their life span. RE may mitigate tumor growth and tumor malignancy parameters such as lower histopathological grade, assuming less nuclear pleomorphism and mitotic cells, smaller viable tumor area, and decreased tumor cell proliferation in both adenocarcinomas. In addition, RE induced tumor vascularization.

Effects of the amino acid derivatives, β-hydroxy-β-methylbutyrate, taurine, and N-methyltyramine, on triacylglycerol breakdown in fat cells.

Various amino acid (AA) metabolites are used as supplements to facilitate metabolic control and enhance responsiveness of insulin-sensitive tissues. β-hydroxy-β-methylbutyrate (HMB) is a leucine metabolite proposed to prevent muscle wasting and to mitigate insulin resistance. Taurine, commonly added to energizing drinks, is a metabolite of methionine and cysteine present in bile juice, and proposed to be involved in lipid digestion and to be pro-lipolytic in adipocytes. N-methyltyramine (NMT) is a phenylalanine metabolite found in orange juices at 0.1-3ppm while its effects on lipid mobilization remain controversial. Here, the putative lipolytic effects of these AA metabolites were studied and it was tested whether they could enhance insulin antilipolytic response in adipocytes. Release of glycerol and non-esterified fatty acids (NEFAs) was measured after a 2-h incubation of adipocytes obtained from control and diet-induced obese mice or from obese patients. In mouse, none of the tested AA derivatives was lipolytic from 1μM to 1mM. These compounds did not improve insulin antilipolytic effect or isoprenaline lipolytic action, except for 1mM NMT that impaired triacylglycerol breakdown in obese mice. In human adipocytes, HMB and taurine were not lipolytic, while NMT weakly activated glycerol and NEFA release at 1mM. However, 100μM NMT impaired isoprenaline-stimulated lipolysis in a manner that was hardly added to insulin antilipolytic effect. Since none of these AA derivatives acutely helped or replaced insulin antilipolytic effect in adipocytes, the present in vitro observations do not support their proposed insulin-sensitizing properties. Moreover, NMT, HMB, and taurine were not notably lipolytic.

Moderate Exercise Improves Experimental Cancer Cachexia by Modulating the Redox Homeostasis.

Cachexia is a debilitating syndrome that complicates the management of cancer patients. Muscle wasting, one of the main features of cachexia, is associated with hyper-activation of protein degradative pathways and altered mitochondrial function that could both result from impaired redox homeostasis. This study aimed to investigate the contribution of oxidative stress to cancer-induced cachexia in the presence or in the absence of moderate exercise training. Mice bearing the colon C26 carcinoma, either sedentary or exercised, were used. The former showed muscle wasting and redox imbalance, with the activation of an antioxidant response and with upregulation of markers of proteasome-dependent protein degradation and autophagy. Moderate exercise was able to relieve muscle wasting and prevented the loss of muscle strength; such a pattern was associated with reduced levels of Reactive Oxygen Species (ROS), carbonylated proteins and markers of autophagy and with improved antioxidant capacity. The muscle of sedentary tumor hosts also showed increased levels of molecular markers of mitophagy and reduced mitochondrial mass. Conversely, exercise in the C26 hosts led to increased mitochondrial mass. In conclusion, moderate exercise could be an effective non-pharmacological approach to prevent muscle wasting in cancer patients, decreasing muscle protein catabolism and oxidative stress and preserving mitochondria.

Glabridin inhibits dexamethasone-induced muscle atrophy

Prevention of muscle wasting is known to contribute to improving the quality of life and extending a healthy life. Recently, we have reported that licorice flavonoid oil containing glabridin, which is a prenylated isoflavone, enhances muscle mass in mice. In this study, we investigated the prevention effect of glabridin on dexamethasone-induced muscle atrophy and clarified its mechanism in cultured myotubes and in muscle of mice. Treatment with glabridin to C2C12 myotubes inhibited dexamethasone-induced protein degradation through dexamethasone-induced expression of ubiquitin ligases, MuRF1 and Cbl-b, but not atrogin-1. Mechanistically, glabridin inhibited nuclear translocation of the glucocorticoid receptor. Glabridin directly bound to the glucocorticoid receptor, resulting in the inhibition of binding between dexamethasone and the receptor protein. Glabridin also inhibited dexamethasone-induced phosphorylation of p38 and FoxO3a, as the upstream for the induction of ubiquitin ligases in C2C12 myotubes. Moreover, the glabridin-induced inhibition of protein degradation was eliminated by knockdown of the glucocorticoid receptor, but not by p38 knockdown. These data indicated that the inhibitory mechanism of glabridin against dexamethasone-induced muscle atrophy was mainly mediated by the inhibition of binding between dexamethasone and the glucocorticoid receptor in myotubes. Oral administration of glabridin prevented dexamethasone-induced protein degradation in the tibialis anterior muscle of mice. It was confirmed that glabridin inhibited dexamethasone-induced nuclear translocation of the glucocorticoid receptor and phosphorylation of FoxO3a in the muscle of mice. These findings suggest that glabridin is an effective food ingredient for the prevention of glucocorticoid-induced skeletal muscle atrophy.

Supplements with purported effects on muscle mass and strength.

Several supplements are purported to promote muscle hypertrophy and strength gains in healthy subjects, or to prevent muscle wasting in atrophying situations (e.g., ageing or disuse periods). However, their effectiveness remains unclear. This review summarizes the available evidence on the beneficial impacts of several popular supplements on muscle mass or strength. Among the supplements tested, nitrate and caffeine returned sufficient evidence supporting their acute beneficial effects on muscle strength, whereas the long-term consumption of creatine, protein and polyunsaturated fatty acids seems to consistently increase or preserve muscle mass and strength (evidence level A). On the other hand, mixed or unclear evidence was found for several popular supplements including branched-chain amino acids, adenosine triphosphate, citrulline, β-Hydroxy-β-methylbutyrate, minerals, most vitamins, phosphatidic acid or arginine (evidence level B), weak or scarce evidence was found for conjugated linoleic acid, glutamine, resveratrol, tribulus terrestris or ursolic acid (evidence level C), and no evidence was found for other supplements such as ornithine or α-ketoglutarate (evidence D). Of note, although most supplements appear to be safe when consumed at typical doses, some adverse events have been reported for some of them (e.g., caffeine, vitamins, α-ketoglutarate, tribulus terrestris, arginine) after large intakes, and there is insufficient evidence to determine the safety of many frequently used supplements (e.g., ornithine, conjugated linoleic acid, ursolic acid). In summary, despite their popularity, there is little evidence supporting the use of most supplements, and some of them have been even proven ineffective or potentially associated with adverse effects.

PROTEIN AND PHYSICAL ACTIVITY IN PREVENTION AND TREATMENT OF SARCOPENIA

There is continuous ageing in world population. Although life expectancy still increases there is no similar trend in maintaining quality of life. The number of disabilities due to age is expected to double in 2060. Muscle mass is one of the most important factors of health and nutrition in old age and it constant loss is characteristic for process of ageing. Muscle mass is controlled by number of different factors. The most important of which is balance between muscle protein synthesis and degradation. Ageing has no influence on muscle protein degradation so for maintaining muscle mass it is better to target muscle protein synthesis. Optimal protein dose in the meal is the minimal amount of protein effecting in maximal anabolic response. Threshold for anabolic response increase with age. This process, named anabolic resistance can be overwhelmed with high amount of protein in diet. Experts in the field of ageing and nutrition recommend 1,2-1,5 g/kg/d protein for the maintaining of muscle mass, 1,2-1,5 g/kg/d for older with additional risk factors, 2,0 g/kg/d for seriously ill and malnourished. Physical training has synergistic influence with diet protein. Physical training improves muscle performance, muscle strength and prevents muscle wasting. Physical training combined with increased amount of protein in diet results with increased muscle mass.

Hispaglabridin B, a constituent of liquorice identified by a bioinformatics and machine learning approach, relieves protein-energy wasting by inhibiting forkhead box O1.

Liquorice is the root of Glycyrrhiza glabra, which is a popular food in Europe and China that has previously shown benefits for skeletal fatigue and nutrient metabolism. However, the mechanism and active ingredients remain largely unclear. The aim of this study was to investigate the active ingredients of liquorice for muscle wasting and elucidate the underlying mechanisms. RNA-Seq and bioinformatics analysis were applied to predict the main target of liquorice. A machine learning model and a docking tool were used to predict active ingredients. Isotope labelling experiments, immunostaining, Western blots, qRT-PCR, ChIP-PCR and luciferase reporters were utilized to test the pharmacological effects in vitro and in vivo. The reverse effects were verified through recombination-based overexpression. The liposoluble constituents of liquorice improved muscle wasting by inhibiting protein catabolism and fibre atrophy. We further identified FoxO1 as the target of liposoluble constituents of liquorice. In addition, hispaglabridin B (HB) was predicted as an inhibitor of FoxO1. Further studies determined that HB improved muscle wasting by inhibiting catabolism in vivo and in vitro. HB also markedly suppressed the transcriptional activity of FoxO1, with decreased expression of the muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1. HB can serve as a novel natural food extract for preventing muscle wasting in chronic kidney disease and possibly other catabolic conditions.

Emerging outcome measures for nutrition trials in the critically ill.

Mortality has long been the gold-standard outcome measure for intensive care clinical trials. However, as the critical care community begins to understand and accept that survivorship is associated with functional disability and a health and socioeconomic burden, the clinical and research focus has begun to shift towards long-term physical function RECENT FINDINGS: To use mortality as a primary outcome measure, one would either have to choose an improbable effect (e.g. a difference of 5-10% in mortality as a result of a single intervention) or recruit a larger number of patients, the latter being unfeasible for most critical care trials.Outcome measures will need to match interventions. As an example, amino acids, or intermittent feeding, can stimulate muscle protein synthesis, and so prevention of muscle wasting may seem an appropriate outcome measure when assessing the effectiveness of these interventions. Testing the effectiveness of these interventions requires the development of novel outcome measures that are targeted and acceptable to patients. We describe advancements in dual-energy X-ray absorptiometry scanning, bio-impedence analysis, MRI and muscle ultrasound in this patient group that are beginning to address this development need. New approaches to outcome assessment are beginning to appear in post-ICU research, which promise to improve our understanding of nutrition and exercise interventions on skeletal muscle structure, composition and function, without causing undue suffering to the patient.

Morin suppresses cachexia-induced muscle wasting by binding to ribosomal protein S10 in carcinoma cells

Cachexia, observed in most cancer patients, is a syndrome that includes wasting of bodily energy reserves and is characterized by muscle atrophy and fat loss. We have previously demonstrated that isoflavones, such as genistein and daidzein, prevent muscle wasting in tumor-bearing mice. In this study, we examined the effect of morin, a flavonoid, on cachexia. The wet weight and myofiber size of muscles in Lewis lung carcinoma (LLC) cell-bearing mice fed a normal diet were decreased, compared with those in control mice fed a normal diet. In contrast, intake of morin prevented the reduction of muscle wet weight and myofiber size. Moreover, the tumor weight in mice fed the morin diet was lower than that in mice fed the normal diet. Both cell viability and protein synthetic ability of LLC cells were reduced by treatment with morin, but C2C12 myotubes were not affected. Binding assay using morin-conjugated magnetic beads identified ribosomal protein S10 (RPS10) as a target protein of morin. Consistent with the result of morin treatment, knockdown of RPS10 suppressed LLC cell viability. These results suggest that morin indirectly prevents muscle wasting induced by cancer cachexia by suppressing cancer growth via binding to RPS10.

Exogenous Delta-Like 1 Homolog (DLK1)-Fc Treatment Attenuates Muscle Atrophy in Both Dexamethasone and High-Fat Diet–Induced Obesity Mice Models

Skeletal muscle degeneration is accelerated in elderly patients with diabetes and the imbalance between muscle growth and wasting can lead to metabolic dysfunction. DLK1 is a member of the EGF-like family and essential for skeletal muscle development and regeneration. To identify whether exogenous DLK1 treatment can prevent muscle wasting, we assessed muscle mass as well as muscle differentiation and atrophy markers in two different models: dexamethasone and high fat diet (HFD)-induced obesity mice models (n=7-8 per each group). In the dexamethasone model, mice were divided into (1) control, (2) dexamethasone treatment (1mg/Kg, 2 weeks), and (3) DLK1 (0.8mg/Kg, 2 weeks) and dexamethasone treatment groups. In the HFD model, mice were divided into (1) control, (2) HFD (60% calories from fat, 8 weeks), and (3) HFD with DLK1 treatment (0.8mg/Kg, 8 weeks) groups. The expressions of genes related to muscle differentiation and atrophy were determined using RT-PCR. We observed that dexamethasone reduced muscle mass and markedly increased atrophy makers including atrogin-1 and murf-1. DLK1 treatment attenuated these degenerative changes. Furthermore, the level of myostatin, which inhibits muscle cell growth, was reduced in DLK1 treatment group compared to dexamethasone group. Additionally, compared to HFD group, DLK1 inhibited muscle atrophy by increasing the differentiation marker: myoD, and decreasing the atrophy markers: mysotatin, atrogin-1, and murf-1. Taken together, these results suggest that DLK1 attenuates both dexamethasone and HFD-induced muscle atrophy in mice by suppressing the downstream signaling of myostatin/atrogin-1/murf-1 pathway. The increased expression of myoD indicates that DLK1 treatment can also improve the quality of muscle formation. Our study implies that DLK1 could be a promising candidate in the treatment of aging or diabetes-related sarcopenia, characterized by muscle atrophy and dysfunction. Disclosure J. Lee: None. M. Lee: None. H. Jung: None. J. Lee: None. Y. Cho: None. J. Bae: None. Y. Lee: None. B. Lee: None. E. Kang: None. B. Cha: None.

Knockout of USP19 Deubiquitinating Enzyme Prevents Muscle Wasting by Modulating Insulin and Glucocorticoid Signaling.

Muscle atrophy arises because of many chronic illnesses, as well as from prolonged glucocorticoid treatment and nutrient deprivation. We previously demonstrated that the USP19 deubiquitinating enzyme plays an important role in chronic glucocorticoid- and denervation-induced muscle wasting. However, the mechanisms by which USP19 exerts its effects remain unknown. To explore this further, we fasted mice for 48 hours to try to identify early differences in the response of wild-type and USP19 knockout (KO) mice that could yield insights into the mechanisms of USP19 action. USP19 KO mice manifested less myofiber atrophy in response to fasting due to increased rates of protein synthesis. Insulin signaling was enhanced in the KO mice, as revealed by lower circulating insulin levels, increased insulin-stimulated glucose disposal and phosphorylation of Akt and S6K in muscle, and improved overall glucose tolerance. Glucocorticoid signaling, which is essential in many conditions of atrophy, was decreased in KO muscle, as revealed by decreased expression of glucocorticoid receptor (GR) target genes upon both fasting and glucocorticoid treatment. This decreased GR signaling was associated with lower GR protein levels in the USP19 KO muscle. Restoring the GR levels in USP19-deficient muscle was sufficient to abolish the protection from myofiber atrophy. Expression of GR target genes also correlated with that of USP19 in human muscle samples. Thus, USP19 modulates GR levels and in so doing may modulate both insulin and glucocorticoid signaling, two critical pathways that control protein turnover in muscle and overall glucose homeostasis.