Muscle Protein Loss Research Articles

Ursolic acid ameliorates hypobaric hypoxia-induced skeletal muscle protein loss via upregulating Akt pathway: An experimental study using rat model.

Hypobaric hypoxic stress leads to oxidative stress, inflammation, and disturbance in protein turnover rate. Aggregately, this imbalance in redox homeostasis is responsible for skeletal muscle protein loss and a decline in physical performance. Hence, an urgent medical need is required to ameliorate skeletal muscle protein loss. The present study investigated the efficacy of ursolic acid (UA), a pentacyclic triterpene acid to ameliorate hypobaric hypoxia (HH)-induced muscle protein loss. UA is a naturally occurring pentacyclic triterpene acid present in several edible herbs and fruits such as apples. It contains skeletal muscle hypertrophy activity; still its potential against HH-induced muscle protein loss is unexplored. To address this issue, an in vivo study was planned to examine the beneficial effect of UA supplementation on HH-induced skeletal muscle loss. Male Sprague Dawley rats were exposed to HH with and without UA supplementation (20 mg/kg; oral) for 3 continuous days. The results described the beneficial role of UA as supplementation of UA with HH exposure attenuated reactive oxygen species production and oxidative protein damage, which indicate the potent antioxidant activity. Furthermore, UA supplementation enhanced Akt, pAkt, and p70S6kinase activity (Akt pathway) and lowered the pro-inflammatory cytokines in HH exposed rats. UA has potent antioxidant and anti-inflammatory activity, and it enhanced the protein content via upregulation of Akt pathway-related proteins against HH exposure. These three biological activities of UA make it a novel candidate for amelioration of HH-induced skeletal muscle damage and protein loss.

A model mimicking catabolic inflammatory disease; a controlled randomized study in humans.

ObjectiveInflammatory disease is catabolic and associated with insulin resistance, increased energy expenditure, lipolysis and muscle protein loss. The main contributors to these metabolic adaptations are inflammation, malnutrition and immobilisation. Controlled experimental models incorporating these central elements of hospitalisation are lacking. The aim of this study was to validate such a human experimental model.MethodsIn a randomized crossover design, six healthy young men underwent; (i) overnight fast (CTR), or (ii) exposure to systemic lipopolysaccharide (1 ng/kg) combined with 36-hour fast and bed rest (CAT). The difference in insulin sensitivity between CAT and CTR was the main outcome, determined by a hyperinsulinemic euglycemic glucose clamp. Palmitate, glucose, urea, phenylalanine and tyrosine tracers were infused to estimate metabolic shifts during interventions. Indirect calorimetry was used to estimate energy expenditure and substrate oxidation.ResultsInsulin sensitivity was 41% lower in CAT than in CTR (M-value, mg/kg/min): 4.3 ± 0.2 vs 7.3 ± 1.3, p<0.05. The median (min max) palmitate flux (μmol/min) was higher during CAT than in CTR (257.0 (161.7 365.4) vs 131.6 (92.3 189.4), p = 0.004), and protein kinetics did not differ between interventions. C-reactive peptide (mg/L) was elevated in CAT compared with CTR (30.57 ± 4.08 vs 1.03 ± 0.19, p<0.001). Energy expenditure increased by 6% during CAT compared with CTR (1869 ± 94 vs 1756 ± 58, p = 0.04), CAT having higher lipid oxidation rates (p = 0.01) and lower glucose oxidation rates (p = 0.03). Lipopolysaccharide caused varying abdominal discomfort 2 hours post-injection, which had disappeared the following day.ConclusionWe found that combined systemic inflammation, fasting and bed rest induced marked insulin resistance and increased energy expenditure and lipolysis, rendering this controlled experimental model suitable for anti-catabolic intervention studies, mimicking clinical conditions.

1,25-Dihydroxyvitamin D3 Inhibits Lipopolysaccharide-Induced Interleukin-6 Production by C2C12 Myotubes

Background and Objective: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits proinflammatory cytokines in microglial cells and monocytes. However, it is unclear whether 1,25(OH)2D3 inhibits proinflammatory cytokines in muscle cells. This study was conducted to investigate whether 1,25(OH)2D3 inhibits the production of proinflammatory cytokines, resulting in inhibition of the protein expression of E3 ubiquitin ligases and muscle protein loss. Materials and Methods: C2C12 myoblasts were proliferated in Dulbecco’s modified Eagle medium (DMEM) containing 10% fetal bovine serum, and myoblasts were differentiated into myotubes in DMEM containing 2% horse serum. Myotubes were treated with 1,25(OH)2D3 for 24 h, followed by lipopolysaccharide (LPS) stimulation for 48 h. Results: Interleukin (IL)-6 protein concentrations were higher in the culture supernatant following LPS stimulation compared to that without LPS stimulation (p < 0.001). However, the IL-6 concentration was significantly lower in C2C12 myotubes following 1,25(OH)2D3 treatment than in C2C12 myotubes without 1,25(OH)2D3 treatment (p < 0.001). The myosin heavy chain (MHC), muscle atrophy F-box, and muscle ring-finger protein-1 protein levels did not significantly differ (P = 0.324, 0.552, and 0.352, respectively). We could not compare tumor necrosis factor α (TNFα) protein levels because they were below the limit of detection of our assay in many supernatant samples, including in LPS-stimulated samples. Conclusions: 1,25(OH)2D3 inhibited increases in IL-6 protein concentrations in muscle cells stimulated by LPS, suggesting that 1,25(OH)2D3 inhibits inflammation in muscle cells. The findings suggest that 1,25(OH)2D3 can prevent or improve sarcopenia, which is associated with IL-6. The TNFα protein content could not be measured, and MHC was not decreased despite LPS stimulation of C2C12 myotubes. Further studies are needed to examine the effects of higher doses of LPS stimulation on muscle cells and use more sensitive methods for measuring TNFα protein to investigate the preventive effects of 1,25(OH)2D3 on increased TNFα and muscle proteolysis.

Sex-Related Differences After a Single Bout of Maximal Eccentric Exercise in Response to Acute Effects: A Systematic Review and Meta-analysis.

Morawetz, D, Blank, C, Koller, A, Arvandi, M, Siebert, U, and Schobersberger, W. Sex-related differences after a single bout of maximal eccentric exercise in response to acute effects: a systematic review and meta-analysis. J Strength Cond Res 34(9): 2697-2707, 2020-The most prominent effects after unaccustomed eccentric exercise are muscle damage, muscle soreness, strength loss, and higher concentrations of muscle proteins in the plasma. The aim of this systematic review is to evaluate sex-related differences in these acute effects. A systematic literature search in MEDLINE following the PRISMA guidelines was performed. Inclusion criteria were the difference in absolute outcomes between sexes in eccentric muscle strength, strength loss after eccentric exercise, blood concentrations of creatine kinase (CK), and delayed onset muscle soreness (DOMS). Results for maximal eccentric torque and CK data were pooled using a random-effect meta-analysis. A meta-regression was conducted to explain heterogeneity. Based on the 23 included trials, men showed significantly higher absolute eccentric strength. No sex-related differences were detected when normalizing strength for body mass, cross-sectional area of the muscle, or fat-free mass. Women displayed a tendency toward greater relative strength loss immediately after exercise. The absolute CK concentrations of men were significantly higher after exercise-induced muscle damage. No significant difference was found between sexes in DOMS. Untrained men and women display similar responses in all measures of relative muscle strength and DOMS. Apart from the enzymatic activity after exercise and the levels of absolute eccentric torque, there is no evidence for sex-related differences immediately after eccentric exercise. Therefore, eccentric training might have the same impact on men and women. One potential sex difference with practical relevance would be the possible difference in fatigue pattern immediately after eccentric exercise.

Mechanisms Regulating Muscle Protein Synthesis in CKD.

CKD induces loss of muscle proteins partly by suppressing muscle protein synthesis. Muscles of mice with CKD have increased expression of nucleolar protein 66 (NO66), as do muscle biopsy specimens from patients with CKD or those undergoing hemodialysis. Inflammation stimulates NO66 expression and changes in NF-κB mediate the response. Subtotal nephrectomy created a mouse model of CKD with BUN >80 mg/dl. Crossing NO66flox/flox with MCK-Cre mice bred muscle-specific NO66 (MCK-NO66) knockout mice. Experiments assessed the effect of removing NO66. Muscle-specific NO66 knockout in mice blocks CKD-induced loss of muscle mass and improves protein synthesis. NO66 suppression of ribosomal biogenesis via demethylase activity is the mechanism behind these responses. In muscle cells, expression of NO66, but not of demethylase-dead mutant NO66, decreased H3K4me3 and H3K36me3 and suppressed pre-rRNA expression. Knocking out NO66 increased the enrichment of H3K4me3 and H3K36me3 on ribosomal DNA. In primary muscle cells and in muscles of mice without NO66, ribosomal RNA, pre-rRNA, and protein synthesis all increased. CKD suppresses muscle protein synthesis via epigenetic mechanisms that NO66 mediates. Blocking NO66 could suggest strategies that counter CKD-induced abnormal muscle protein catabolism.

Nutritional Requirements for Sustaining Health and Performance During Exposure to Extreme Environments.

Dietary guidelines are formulated to meet minimum nutrient requirements, which prevent deficiencies and maintain health, growth, development, and function. These guidelines can be inadequate and contribute to disrupted homeostasis, lean body mass loss, and deteriorated performance in individuals who are working long, arduous hours with limited access to food in environmentally challenging locations. Environmental extremes can elicit physiological adjustments that alone alter nutrition requirements by upregulating energy expenditure, altering substrate metabolism, and accelerating body water and muscle protein loss. The mechanisms by which the environment, including high-altitude, heat, and cold exposure, alters nutrition requirements have been studied extensively. This contemporary review discusses physiological adjustments to environmental extremes, particularly when those adjustments alter dietary requirements.

Pharmacokinetics and pharmacodynamics of TTI-101, a STAT3 inhibitor that blocks muscle proteolysis in rats with chronic kidney disease.

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD), and there are no reliable preventive treatments. We uncovered a STAT3/CCAAT-enhancer-binding protein-δ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small-molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment for CKD-induced cachexia, we measured TTI-101 pharmacokinetics and pharmacodynamics in control and CKD rats that were orally administered TTI-101or its diluent. The following two groups of gavage-fed rats were studied: sham-operated control rats and CKD rats. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8, and 24 h) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS, and pharmacokinetic results were analyzed with the PKSolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations and time to maximal plasma levels (~1 h) were similar in sham-operated control rats and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced TTI-101 muscle levels in sham control rats and CKD rats that were not significantly different. CKD rats that received TTI-101 for 7 days had suppression of activated STAT3 and improved muscle grip strength; there also was a trend for increasing body and muscle weights. TTI-101 was tolerated at doses of 100 mg·kg-1·day-1 for 7 days. These results with TTI-101 in rats warrant its development as a treatment for cachexia in humans.

Muscle Phenotype, Proteolysis, and Atrophy Signaling During Reloading in Mice: Effects of Curcumin on the Gastrocnemius.

We hypothesized that curcumin may mitigate muscle protein degradation and loss through attenuation of proteolytic activity in limb muscles of mice exposed to reloading (7dR) following immobilization (7dI). In gastrocnemius of mice (female C57BL/6J, 10 weeks) exposed to recovery following a seven-day period of hindlimb immobilization with/without curcumin treatment, markers of muscle proteolysis (systemic troponin-I), atrophy signaling pathways and histone deacetylases, protein synthesis, and muscle phenotypic characteristics and function were analyzed. In gastrocnemius of reloading mice compared to unloaded, muscle function, structure, sirtuin-1, and protein synthesis improved, while proteolytic and signaling markers (FoxO1/3) declined. In gastrocnemius of unloaded and reloaded mice treated with curcumin, proteolytic and signaling markers (NF-kB p50) decreased and sirtuin-1 activity and hybrid fibers size increased (reloaded muscle), while no significant improvement was seen in muscle function. Treatment with curcumin elicited a rise in sirtuin-1 activity, while attenuating proteolysis in gastrocnemius of mice during reloading following a period of unloading. Curcumin attenuated muscle proteolysis probably via activation of histone deacetylase sirtuin-1, which also led to decreased levels of atrophy signaling pathways. These findings offer an avenue of research in the design of therapeutic strategies in clinical settings of patients exposed to periods of disuse muscle atrophy.

Metabolic aspects of muscle wasting during critical illness.

Purpose of reviewSkeletal muscle wasting during critical illness is the result of disturbed metabolism. No proven effective interventions targeting skeletal muscle mass and function during critical illness currently exist. This review summarizes recent advances regarding the complexity of metabolic factors involved and the challenge of establishing the clinical effects of metabolic interventions targeting the muscle.Recent findingsAlthough the catabolic state is limited to the acute phase of critical illness, its subsequent impact on muscle mass and function persists long after ICU discharge. Immobilization, inflammation and disturbed muscle energy and nutrient metabolism are key drivers of muscle protein loss. Current research focuses on the effects of enhanced protein provision, specific substrate delivery and physical exercise. Whilst some interventions have been successful at improving muscle mass, these effects do not always carry over into muscle function or strength.SummaryIncreased understanding of metabolic derangements during critical illness provides new potential targets for treatment. The potential of dietary protein to attenuate the muscle protein catabolic state has yet to be established in clinical trials. Basic research should focus on ways to further improve the anabolic potential of nutrition by unravelling mechanisms that regulate anabolic and catabolic pathways and energy metabolism.

Effect of flaxseed oil on muscle protein loss and carbohydrate oxidation impairment in a pig model after lipopolysaccharide challenge.

Flaxseed oil is rich in α-linolenic acid (ALA), which is the metabolic precursor of EPA and DHA. The present study investigated the effect of flaxseed oil supplementation on lipopolysaccharide (LPS)-induced muscle atrophy and carbohydrate oxidation impairment in a piglet model. Twenty-four weaned pigs were used in a 2 × 2 factorial experiment including dietary treatment (5 % maize oil v. 5 % flaxseed oil) and LPS challenge (saline v. LPS). On day 21 of treatment, the pigs were injected intraperitoneally with 100 μg/kg body weight LPS or sterile saline. At 4 h after injection, blood, gastrocnemius muscle and longissimus dorsi muscle were collected. Flaxseed oil supplementation increased ALA, EPA, total n-3 PUFA contents, protein:DNA ratio and pyruvate dehydrogenase complex quantity in muscles (P < 0·05). In addition, flaxseed oil reduced mRNA expression of toll-like receptor (TLR) 4 and nucleotide-binding oligomerisation domain protein (NOD) 2 and their downstream signalling molecules in muscles and decreased plasma concentrations of TNF-α, IL-6 and IL-8, and mRNA expression of TNF-α, IL-1β and IL-6 (P < 0·05). Moreover, flaxseed oil inclusion increased the ratios of phosphorylated protein kinase B (Akt) 1:total Akt1 and phosphorylated Forkhead box O (FOXO) 1:total FOXO1 and reduced mRNA expression of FOXO1, muscle RING finger (MuRF) 1 and pyruvate dehydrogenase kinase 4 in muscles (P < 0·05). These results suggest that flaxseed oil might have a positive effect on alleviating muscle protein loss and carbohydrates oxidation impairment induced by LPS challenge through regulation of the TLR4/NOD and Akt/FOXO signalling pathways.

Mitigation of Muscle Loss in Stressed Physiology: Military Relevance.

Military personnel may be exposed to circumstances (e.g., large energy deficits, sleep deprivation, cognitive demands, and environmental extremes) of external stressors during training and combat operations (i.e., operational stressors) that combine to degrade muscle protein. The loss of muscle protein is further exacerbated by frequent periods of severe energy deficit. Exposure to these factors results in a hypogonadal state that may contribute to observed decrements in muscle mass. In this review, lessons learned from studying severe clinical stressed states and the interventions designed to mitigate the loss of muscle protein are discussed in the context of military operational stress. For example, restoration of the anabolic hormonal status (e.g., testosterone, insulin, and growth hormone) in stressed physiological states may be necessary to restore the anabolic influence derived from dietary protein on muscle. Based on our clinical experiences, restoration of the normal testosterone status during sustained periods of operational stress may be advantageous. We demonstrated that in severe burn patients, pharmacologic normalization of the anabolic hormonal status restores the anabolic stimulatory effect of nutrition on muscle by improving the protein synthetic efficiency and limiting amino acid loss from skeletal muscle. Furthermore, an optimal protein intake, and in particular essential amino acid delivery, may be an integral ingredient in a restored anabolic response during the stress state. Interventions which improve the muscle net protein balance may positively impact soldier performance in trying conditions.

Citrulline and muscle protein homeostasis in three different models of hypercatabolism

Supplementation of enteral nutrition (EN) by specific amino acids (AAs) has been proposed to prevent muscle protein loss in intensive care unit (ICU) patients. Citrulline (Cit), which has been shown to stimulate muscle protein synthesis in other situations, may be of interest in this setting. Our aim was to assess the effect of Cit in three catabolic models relevant to critical illness: endotoxemia (LPS), traumatic brain injury (TBI), and TBI with infectious complications (TBI-Ec), which are characterized by different alterations in protein homeostasis. Fifty-eight male Sprague-Dawley rats (200-220g) were randomized to receive a standard diet ad libitum (CON, n=9) or to undergo catabolic injuries on day 0 (D0, n=49), and EN (Sondalis HP energy® 290kcal/kg/d) from day 1 (D1) combined with Cit (2g/kg/d) or isonitrogenous non-essential AAs (NEAAs) until day 3 (D3). Endotoxemia was induced by IP injection of LPS from E.coli (3mg/kg), TBI by hydraulic percussion, and infectious complications (TBI-Ec) by administration of luminescent E.coli on D1. Nitrogen balance (ΔN) and 3-methylhistidine (3-MHis) were measured daily. Muscle protein synthesis (MPS, measured by the SUnSET method) and mTORC1 activation (S6K-1 and 4E-BP1 phosphorylation) were measured on D3 2h after the arrest of enteral nutrition in soleus, extensor digitorum longus (EDL), gastrocnemius and tibialis muscles. ΔN was lower (p<0.001) in all three models of injury compared with basal and CON from D1 to D3, and more negative in the LPS-CIT (p<0.05) than in the LPS group. The 3-MHis/creatinine ratio was significantly increased on D1 in all groups compared with CON, and on D2 only in the LPS and TBI groups (p<0.0001, LPS and TBI vs. CON). MPS was similar in all groups in soleus and tibialis but significantly higher in EDL in LPS-CIT [LPS-CIT: 4.5±1.7 (mean±SD) vs. CON: 2.3±1.2; and vs. LPS-NEAA: 3.1±2.3] and in gastrocnemius (LPS-CIT vs. CON; p=0.05). S6K-1 phosphorylation in the EDL was also higher in LPS-CIT vs. CON (LPS-CIT: 0.94±0.51 CON: 0.42±0.28), but not in gastrocnemius. IL-6 plasma level was significantly higher in all the catabolic groups vs. CON (p<0.005) with no difference between treatments (Cit or NEAAs). In conclusion, the TBI model showed only a rise in muscle proteolysis, whereas the LPS model displayed a rise in both protein synthesis and proteolysis. Secondly, our results show that the Cit effect varies according to the type of injury and to the muscle under study. The stimulation of MPS rate and the mTOR pathway in LPS-treated rats contrasts with degraded ΔN, suggesting that the Cit effect on protein metabolism in critically ill rats is limited at the whole-body level.

P300 Mediates Muscle Wasting in Lewis Lung Carcinoma.

C/EBPβ is a key mediator of cancer-induced skeletal muscle wasting. However, the signaling mechanisms that activate C/EBPβ in the cancer milieu are poorly defined. Here, we report cancer-induced muscle wasting requires the transcriptional cofactor p300, which is critical for the activation of C/EBPβ. Conditioned media from diverse types of tumor cells as well as recombinant HSP70 and HSP90 provoked rapid acetylation of C/EBPβ in myotubes, particularly at its Lys39 residue. Overexpression of C/EBPβ with mutated Lys39 impaired Lewis lung carcinoma (LLC)-induced activation of the C/EBPβ-dependent catabolic response, which included upregulation of E3 ligases UBR2 and atrogin1/MAFbx, increased LC3-II, and loss of muscle proteins both in myotubes and mouse muscle. Silencing p300 in myotubes or overexpressing a dominant negative p300 mutant lacking acetyltransferase activity in mouse muscle attenuated LLC tumor-induced muscle catabolism. Administration of pharmacologic p300 inhibitor C646, but not PCAF/GCN5 inhibitor CPTH6, spared LLC tumor-bearing mice from muscle wasting. Furthermore, mice with muscle-specific p300 knockout were resistant to LLC tumor-induced muscle wasting. These data suggest that p300 is a key mediator of LLC tumor-induced muscle wasting whose acetyltransferase activity may be targeted for therapeutic benefit in this disease. SIGNIFICANCE: These findings demonstrate that tumor-induced muscle wasting in mice is abrogated by knockout, mutation of Lys39 or Asp1399, and pharmacologic inhibition of p300.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1331/F1.large.jpg.

OR-017 Supplementation of Ala-Gln inhibits protein breakdown of skeletal muscle in rats with altitude training through TNF-α/NF-κB/MuRF1 pathway

Objective Objective: To explore the effects of alanyl-glutamine（Ala-Gln）or glutamine（Gln） supplementation on protein metabolism in rat skeletal muscle during simulated altitude training，and compare the intervention of Gln or Ala-Gln to provide the necessary experimental basis for finding nutritional interventions to inhibit skeletal muscle protein degradation during altitude training.&#x0D; Methods Methods: Forty SD rats aged 6 weeks were randomly divided into normoxic control group（NC group，n=10），hypoxic exercise group（HE group， n=10），hypoxic exercise + glutamine + alanine group（HEG group，n=10）， hypoxic exercise + alanyl glutamine group（HEAG group，n=10）. Rats were subjected to 6 weeks of 13.6% hypoxic exposure and 90% lactic acid threshold intensity weight-bearing swimming（load weight of 2.1% of body weight）exercise training，30 minutes after the end of each training，the mixed solution of Ala and Gln was administered according to the dose of 0.75g/Kg body weight in HEG group，and the solution of Ala-Gln was administered in the HEAG group at a dose of 1.5 g/kg body weight. After 6 weeks，the contents of rat skeletal muscle total protein（Pro），myosin heavy chain（Myo），tumor necrosis factor-α（TNF-α），nuclear transcription factor-κB （NF-κB），NF-κB inhibitory protein α（IkBα），and mRNA expression of muscle atrophy box F gene（MAFbx），muscle ring finger gene 1（MuRF1），and inhibitor of kappa B kinase complex-beta（IKKβ）were measured.&#x0D; Results Results:（1）Compared with NC group，the content of Pro and Myo in skeletal muscle in HE group was significantly decreased（P&lt;0.05，P&lt;0.01），and the mRNA expression of MAFbx and MuRF1 in skeletal muscle was significantly increased（P&lt;0.05，P&lt; 0.01），the levels of TNF-α and NF-κB were significantly increased（P&lt;0.05），the content of IkBα was significantly decreased（P&lt;0.05），and the expression of IKKβ mRNA was significantly increased（P&lt;0.01）. （2）Compared with HE group，the content of Pro and Myo in skeletal muscle in HEG group increased，but there was no significant difference（P&gt;0.05）. The expression of MuRF1 mRNA and the content of TNF-α and NF-κB in skeletal muscle decreased，IkBα content increased，there were no significant difference，but mRNA expression of MAFbx and IKKβ was significantly decreased（P&lt;0.05， P&lt;0.01）. （3）Compared with HE group，the content of Pro and Myo in skeletal muscle in HEAG group increased significantly（P&lt;0.05），mRNA expression of IKKβ，MuRF1 and MAFb（P&lt;0.01）and TNF-α，NF-κB content（P&lt;0.05）in skeletal muscle was significantly decreased，and the IkBα content was significantly increased（P&lt;0.05）.&#x0D; Conclusions Conclusion:（1）Simulated altitude training can activate TNF-α/NF-κB/MuRF1 pathway and enhance the catabolism of skeletal muscle protein，which is one of the important mechanisms for the reduction of skeletal muscle protein content caused by altitude training. （2）Supplementation of Ala-Gln during altitude training can significantly reduce the activation of TNF-α/NF-κB/MuRF1 pathway in skeletal muscle，and reduce the catabolism of skeletal muscle protein during altitude training，which plays a very important role in preventing the loss of skeletal muscle protein caused by altitude training. supplementation of Gln monomer during altitude training has little inhibitory effect on the activation of TNF-α/NF-κB/MuRF1 pathway in skeletal muscle.

Dysregulated handling of dietary protein and muscle protein synthesis after mixed meal ingestion in maintenance hemodialysis patients

Rationale: Skeletal muscle mass loss is common in maintenance hemodialysis (MHD) patients. Regular ingestion of protein-rich meals are recommended to help offset muscle protein loss in MHD patients but little is known about the muscle anabolic potential of such a strategy.

Dysregulated Handling of Dietary Protein and Muscle Protein Synthesis After Mixed-Meal Ingestion in Maintenance Hemodialysis Patients

IntroductionSkeletal muscle loss is common in patients with renal failure who receive maintenance hemodialysis (MHD) therapy. Regular ingestion of protein-rich meals are recommended to help offset muscle protein loss in MHD patients, but little is known about the anabolic potential of this strategy.MethodsEight MHD patients (age: 56 ± 5 years; body mass index [BMI]: 32 ± 2 kg/m2) and 8 nonuremic control subjects (age: 50 ± 2 years: BMI: 31 ± 1 kg/m2) received primed continuous L-[ring-2H5]phenylalanine and L-[1-13C]leucine infusions with blood and muscle biopsy sampling on a nondialysis day. Participants consumed a mixed meal (546 kcal; 20-g protein, 59-g carbohydrates, 26-g fat) with protein provided as L-[5,5,5-2H3]leucine-labeled eggs.ResultsCirculating dietary amino acid availability was reduced in MHD patients (41 ± 5%) versus control subjects (61 ± 4%; P = 0.03). Basal muscle caspase-3 protein content was elevated (P = 0.03) and large neutral amino acid transporter 1 (LAT1) protein content was reduced (P = 0.02) in MHD patients versus control subjects. Basal muscle protein synthesis (MPS) was ∼2-fold higher in MHD patients (0.030 ± 0.005%/h) versus control subjects (0.014 ± 0.003%/h) (P = 0.01). Meal ingestion failed to increase MPS in MHD patients (absolute change from basal: 0.0003 ± 0.007%/h), but stimulated MPS in control subjects (0.009 ± 0.002%/h; P = 0.004).ConclusionsMHD patients demonstrated muscle anabolic resistance to meal ingestion. This blunted postprandial MPS response in MHD patients might be related to high basal MPS, which results in a stimulatory ceiling effect and/or reduced plasma dietary amino acid availability after mixed-meal ingestion.

Long-noncoding RNA Atrolnc-1 promotes muscle wasting in mice with chronic kidney disease.

BackgroundChronic kidney disease (CKD) is commonly associated with cachexia, a condition that causes skeletal muscle wasting and an unfavourable prognosis. Although mechanisms leading to cachexia have been intensively studied, the advance of biological knowledges and technologies encourages us to make progress in understanding the pathogenesis of this disorder. Long noncoding RNAs (lncRNAs) are defined as >200 nucleotides RNAs but lack the protein‐coding potential. LncRNAs are involved in the pathogenesis of many diseases, but whether they functionally involve in muscle protein loss has not been investigated.MethodsWe performed lncRNA array and identified an lncRNA, which we named Atrolnc‐1, remarkably elevated in atrophying muscles from mice with cachexia. We examined how overexpression or knockdown of Atrolnc‐1 could influence muscle protein synthesis and degradation. We also examined whether inhibition of Atrolnc‐1 ameliorates muscle wasting in mice with CKD.ResultsWe documented that Atrolnc‐1 expression is continuously increased in muscles of mice with fasting (5.4 fold), cancer (2.0 fold), or CKD (5.1 fold). We found that depressed insulin signalling stimulates the transcription factor C/EBP‐α binding to the promoter of Atrolnc‐1 and promotes the expression of Atrolnc‐1. In cultured C2C12 myotubes, overexpression of Atrolnc‐1 increases protein degradation (0.45±0.03 vs. 0.64±0.02, *p<0.05); Atrolnc‐1 knockdown significantly reduces the rate of protein degradation stimulated by serum depletion (0.61±0.03 vs. 0.47±0.02, *p<0.05). Using mass spectrometry and a lncRNA pull‐down assay, we identified that Atrolnc‐1 interacts with A20 binding inhibitor of NF‐κB‐1 (ABIN‐1). The interaction impairs function, resulting in enhanced NF‐κB activity plus MuRF‐1 transcription. This response is counteracted by CRISPR/dCas9 mediated overexpression. In muscles from normal mice, overexpression of Atrolnc‐1 stimulates a 2.7‐fold increase in MuRF‐1 expression leading to myofibers atrophy. In contrast, Atrolnc‐1 knockdown attenuates muscle wasting by 42% in mice with CKD via suppression of NF‐κB activity and MuRF‐1 expression.ConclusionsOur findings provide evidence that lncRNAs initiates the pathophysiological process of muscle wasting. The interaction between Atrolnc‐1 and NF‐κB signalling modulates muscle mass and proteolysis in CKD and perhaps other catabolic conditions.

Security Hunger-Strike Prisoners in the Emergency Department: Physiological and Laboratory Findings

BackgroundMedical treatment of hunger-strike patients, especially those in incarceration facilities, may pose clinical and treatment challenges for the treating physicians. ObjectiveThe aim of our study is to describe the epidemiology and clinical and laboratory characteristics of hunger-strike prisoners presenting to the emergency department (ED) and to describe etiologies of hospitalization and complications among this group. MethodWe retrospectively examined clinical and laboratory manifestations of 50 hunger-strike prisoners who were referred for evaluation to the ED after a longstanding fast. ResultsAfter a mean of 38 (28-44) days of a hunger strike, the most common complaints were chest pain and abdominal pain (14/60 [23.3%], 13/60 [21.6%], respectively). Mean weight loss percentage was 18.5%, and most patients were bradycardic (25/40 [62.5%]), and some hypothermic (16/50, [32%]). We describe several laboratory disturbances observed in these patients; leukopenia was the most common hematologic manifestation (31/50 [62%]), and a prolonged international normalized ratio was observed in 12/29 (41.3%) patients. We hospitalized 12% of the patients; the most common hospitalization cause was bradycardia (3/6 [50%]). ConclusionsOur study found that the most common clinical symptom was chest pain, which has not been previously reported among hunger strikers. We observed a substantial number of laboratory disturbances due to muscle wasting and protein loss and due to presumed vitamin and micronutrient deficiencies. We suggest monitoring electrocardiograms for heart rate, blood count, chemistry, coagulation tests, and vitamin levels.

Hormones and Muscle Atrophy.

The endocrine system is an essential regulator of muscle metabolism in both health and disease. Hormones such as growth hormone (GH), insulin-like growth factor-I (IGF-I) and androgens are the main regulators of muscle metabolism in both health and disease; have profound influences on muscle, acting as anabolic factors; and are important regulators of muscle mass. On the contrary, glucocorticoids have direct catabolic effects and induce muscle protein loss. Muscle wasting is a systemic response to fasting and several diseases like cancer, sepsis, renal and cardiac failure and trauma. Muscle atrophy also occurs in specific muscles with denervation, immobilization or inactivity. All of these conditions are characterized by significant changes in the endocrine environment. The aim of this review was to describe the role of endocrine system on the development of muscle atrophy. Understanding hormonal regulation of the skeletal muscle in these conditions might facilitate the development of hormone-mediated therapies for muscle atrophy.

Sarcopenia and Exercise “The State of the Art”

Skeletal muscle mass reduction might be a consequence of aging (sarcopenia), disease (cachexia) or inactivity (muscle atrophy). Studying the triggering factors leading to muscle loss is important in developing therapies to preserve muscle tissue function. The loss of skeletal muscle proteins is caused by an imbalance between the rate of their synthesis and degradation. Specifically, the conditions characterized by muscle loss involve an adaptation metabolism of increased protein degradation (cachexia), decreased muscle protein synthesis (inactivity), or alteration in both (sarcopenia). Sarcopenia and exercise is the main topic chosen for this review. This is a huge health problem, poorly discussed in the current literature and the aim of this review is to explain and help readers to better understand the differences between “sarcopenia”, “cachexia”, “muscle atrophy” and the relative beneficial effects of exercise used as a possible therapeutic intervention. Sarcopenia is a component of the fragility syndrome and indicates a significant health issue related to the progressive decline of muscle tissue quality and strength. Exercise is associated with improved life quality, reduced health problems, and prolonged lifespan. The latter suggests that exercise should be considered a fundamental point in the treatment of pathological skeletal muscle mass reduction. The present scientific contribution also seeks to emphasize to the scientific community the positive effects of the adapted physical activity in the elderly as a possible non-pharmacologic treatment to prevent or treat muscle atrophy.