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Adverse experiences (e.g., acute stress) and alcohol misuse can both impair skeletal muscle homeostasis, resulting in reduced protein synthesis and greater protein breakdown. Exposure to acute stress is a significant risk factor for engaging in alcohol misuse. However, little is known about how these factors together might further affect skeletal muscle health. To that end, this study investigated the effects of acute stress exposure followed by a period of binge-patterned alcohol drinking on signaling factors along mouse skeletal muscle protein synthesis (MPS) and degradation (MPD) pathways. Young adult male C57BL/6J mice participated in the Drinking in the Dark paradigm, where they received 2–4 h of access to 20% ethanol (alcohol group) or water (control group) for four days to establish baseline drinking levels. Three days later, half of the mice in each group were either exposed to a single episode of uncontrollable tail shocks (acute stress) or remained undisturbed in their home cages (no stress). Three days after stress exposure, mice received 4 h of access to 20% ethanol (alcohol) to model binge-patterned alcohol drinking or water for ten consecutive days. Immediately following the final episode of alcohol access, mouse gastrocnemius muscle was extracted to measure changes in relative protein levels along the Akt-mTOR MPS, as well as the ubiquitin-proteasome pathway (UPP) and autophagy MPD pathways via Western blotting. A single exposure to acute stress impaired Akt singling and reduced rates of MPS, independent of alcohol access. This observation was concurrent with a potent increase in heat shock protein seventy expression in the muscle of stressed mice. Alcohol drinking did not exacerbate stress-induced alterations in the MPS and MPD signaling pathways. Instead, changes in the MPS and MPD signaling factors due to alcohol access were primarily observed in non-stressed mice. Taken together, these data suggest that exposure to a stressor of sufficient intensity may cause prolonged disruptions to signaling factors that impact skeletal muscle health and function beyond what could be further induced by periods of alcohol misuse. [ABSTRACT FROM AUTHOR]

Sarcopenic obesity is characterized by concurrent obesity and muscle wasting (sarcopenia) and is common in the elderly. Sarcopenic obesity has steadily increased as the aging population has grown and is an increasing public health burden. Both obesity and sarcopenia independently increase health risks of the elderly, but sarcopenic obesity has a greater effect on metabolic disease than either obesity or sarcopenia alone. The metabolic mechanisms of obesity and sarcopenia are strongly interconnected, and obesity and sarcopenia form a vicious cycle, with each pathology exacerbating the other. The pathogenesis of sarcopenic obesity is more complex than either disease alone and remains incompletely understood, underscoring the significant unmet clinical need for effective sarcopenic obesity treatments. We aimed to determine the efficacy and underlying regulatory mechanisms of Gamma-aminobutyric acid (GABA) in sarcopenic obesity in high-fat-diet-fed obese aged mice and alterations in related mechanisms to determine the potential of GABA as a therapeutic modality for sarcopenic obesity. In this study, we used young (3 months) and aged (20 months) mice to evaluate age-related sarcopenic obesity. The daily administration of GABA for 8 weeks resulted in decreased fat mass and increased muscle mass and strength in aged mice. GABA also enhanced energy expenditure in both adipose tissue and skeletal muscle. In addition, GABA promoted muscle synthesis and decreased muscle degradation by activating the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. These findings demonstrate that GABA has potential uses in preventing age-related sarcopenic obesity and related metabolic diseases. [ABSTRACT FROM AUTHOR]

Adverse experiences (e.g., acute stress) and alcohol misuse can both impair skeletal muscle homeostasis, resulting in reduced protein synthesis and greater protein breakdown. Exposure to acute stress is a significant risk factor for engaging in alcohol misuse. However, little is known about how these factors together might further affect skeletal muscle health. To that end, this study investigated the effects of acute stress exposure followed by a period of binge-patterned alcohol drinking on signaling factors along mouse skeletal muscle protein synthesis (MPS) and degradation (MPD) pathways. Young adult male C57BL/6J mice participated in the Drinking in the Dark paradigm, where they received 2–4 h of access to 20% ethanol (alcohol group) or water (control group) for four days to establish baseline drinking levels. Three days later, half of the mice in each group were either exposed to a single episode of uncontrollable tail shocks (acute stress) or remained undisturbed in their home cages (no stress). Three days after stress exposure, mice received 4 h of access to 20% ethanol (alcohol) to model binge-patterned alcohol drinking or water for ten consecutive days. Immediately following the final episode of alcohol access, mouse gastrocnemius muscle was extracted to measure changes in relative protein levels along the Akt-mTOR MPS, as well as the ubiquitin-proteasome pathway (UPP) and autophagy MPD pathways via Western blotting. A single exposure to acute stress impaired Akt singling and reduced rates of MPS, independent of alcohol access. This observation was concurrent with a potent increase in heat shock protein seventy expression in the muscle of stressed mice. Alcohol drinking did not exacerbate stress-induced alterations in the MPS and MPD signaling pathways. Instead, changes in the MPS and MPD signaling factors due to alcohol access were primarily observed in non-stressed mice. Taken together, these data suggest that exposure to a stressor of sufficient intensity may cause prolonged disruptions to signaling factors that impact skeletal muscle health and function beyond what could be further induced by periods of alcohol misuse.

Sarcopenic obesity is characterized by concurrent obesity and muscle wasting (sarcopenia) and is common in the elderly. Sarcopenic obesity has steadily increased as the aging population has grown and is an increasing public health burden. Both obesity and sarcopenia independently increase health risks of the elderly, but sarcopenic obesity has a greater effect on metabolic disease than either obesity or sarcopenia alone. The metabolic mechanisms of obesity and sarcopenia are strongly interconnected, and obesity and sarcopenia form a vicious cycle, with each pathology exacerbating the other. The pathogenesis of sarcopenic obesity is more complex than either disease alone and remains incompletely understood, underscoring the significant unmet clinical need for effective sarcopenic obesity treatments. We aimed to determine the efficacy and underlying regulatory mechanisms of Gamma-aminobutyric acid (GABA) in sarcopenic obesity in high-fat-diet-fed obese aged mice and alterations in related mechanisms to determine the potential of GABA as a therapeutic modality for sarcopenic obesity. In this study, we used young (3 months) and aged (20 months) mice to evaluate age-related sarcopenic obesity. The daily administration of GABA for 8 weeks resulted in decreased fat mass and increased muscle mass and strength in aged mice. GABA also enhanced energy expenditure in both adipose tissue and skeletal muscle. In addition, GABA promoted muscle synthesis and decreased muscle degradation by activating the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. These findings demonstrate that GABA has potential uses in preventing age-related sarcopenic obesity and related metabolic diseases.

Type 1 diabetes mellitus is an autoimmune disease caused by the destruction of pancreatic beta cells. Many patients with type 1 diabetes experience skeletal muscle wasting. Although the link between type 1 diabetes and muscle wasting is not clearly known, insulin insufficiency and hyperglycemia may contribute to decreased muscle mass. In this study, we investigated the therapeutic effect of the ethanolic extract of Schisandrae chinensis Fructus (SFe) on muscle wasting in streptozotocin (STZ)-induced diabetic mice. STZ-diabetic C57BL/6 mice (blood glucose level ≥300 mg/dL) were orally administered SFe (250 or 500 mg/kg/day) for 6 weeks. We observed that SFe administration did not change blood glucose levels but increased gastrocnemius muscle weight, cross-sectional area, and grip strength in STZ-induced diabetic mice. Administration of SFe (500 mg/kg) decreased the expression of atrophic factors, such as MuRF1 and atrogin-1, but did not alter the expression of muscle synthetic factors. Further studies showed that SFe administration decreased the expression of KLF15 and p-CREB, which are upstream molecules of atrophic factors. Examination of the expression of molecules involved in autophagy–lysosomal pathways (e.g., p62/SQSTM1, Atg7, Beclin-1, ULK-1, LC3-I, and LC3-II) revealed that SFe administration significantly decreased the expression of p62/SQSTM1, LC3-I, and LC3-II; however, no changes were observed in the expression of Atg7, Beclin-1, or ULK-1. Our results suggest that SFe ameliorated muscle wasting in STZ-induced diabetic mice by decreasing protein degradation via downregulation of the CREB-KLF15-mediated UPS system and the p62/SQSTM1-mediated autophagy–lysosomal pathway.

The purpose of this research was to investigate the prophylactic effects of glutamine on muscle protein synthesis and degradation in rats with ethanol-induced liver injury. For the first 2 weeks, Wistar rats were divided into two groups and fed a control (n = 16) or glutamine-containing diet (n = 24). For the following 6 weeks, rats fed the control diet were further divided into two groups (n = 8 per group) according to whether their diet contained no ethanol (CC) or did contain ethanol (CE). Rats fed the glutamine-containing diet were also further divided into three groups (n = 8 per group), including a GG group (glutamine-containing diet without ethanol), GE group (control diet with ethanol), and GEG group (glutamine-containing diet with ethanol). After 6 weeks, results showed that hepatic fatty change, inflammation, altered liver function, and hyperammonemia had occurred in the CE group, but these were attenuated in the GE and GEG groups. Elevated intestinal permeability and a higher plasma endotoxin level were observed in the CE group, but both were lower in the GE and GEG groups. The level of a protein synthesis marker (p70S6K) was reduced in the CE group but was higher in both the GE and GEG groups. In conclusion, glutamine supplementation might elevate muscle protein synthesis by improving intestinal health and ameliorating liver damage in rats with chronic ethanol intake.

We investigated the effects ofSarcodon aspratus,Agaricus bisporus, andLentinula edodesaqueous extracts on the tenderization of bovinelongissimus dorsimuscle. Meat quality and muscle protein degradation were examined as well. Beef chunks were marinated in distilled water (control), 5%S. aspratus(SA), 5%A. bisporus(AB), or 5%L. edodes(LE) extracts. SA was shown to have a higher enzymatic activity (p < 0.001) and water-holding capacity than LE (p < 0.01). SA and AB extracts exhibited lower shear force values compared with the control (p < 0.05). SA, AB, and LE showed superior muscle proteolytic effects compared with the control. SA demonstrated the ability to degrade myosin heavy chains and actin, which was not observed after AB and LE extract treatments. This suggests that SA extract may affect tenderization. Taken together, our results show that aqueous extract ofS. aspratusaffects the tenderness of the bovinelongissimus dorsimuscle. Effects of mushroom extract on textural properties and muscle protein degradation of bovine longissimus dorsi muscle. [ABSTRACT FROM PUBLISHER]

Supplementation of branched-chain amino acids (BCAA) has been demonstrated to promote skeletal muscle mass gain, but the mechanisms underlying this observation are still unknown. Since the regulation of muscle mass depends on a dynamic equilibrium (fasted losses-fed gains) in protein turnover, the aim of this study was to investigate the effects of BCAA supplementation on muscle protein synthesis and degradation in fed/fasted states and the related mechanisms. Fourteen 26- (Experiment 1) and 28-day-old (Experiment 2) piglets were fed reduced-protein diets without or with supplemental BCAA. After a four-week acclimation period, skeletal muscle mass and components of anabolic and catabolic signaling in muscle samples after overnight fasting were determined in Experiment 1. Pigs in Experiment 2 were implanted with carotid arterial, jugular venous, femoral arterial and venous catheters, and fed once hourly along with the intravenous infusion of NaH13CO3 for 2 h, followed by a 6-h infusion of [1-13C]leucine. Muscle leucine kinetics were measured using arteriovenous difference technique. The mass of most muscles was increased by BCAA supplementation. During feeding, BCAA supplementation increased leucine uptake, protein synthesis, protein degradation and net transamination. The greater increase in protein synthesis than in protein degradation resulted in elevated protein deposition. Protein synthesis was strongly and positively correlated with the intramuscular net production of α-ketoisocaproate (KIC) and protein degradation. Moreover, BCAA supplementation enhanced the fasted-state phosphorylation of protein translation initiation factors and inhibited the protein-degradation signaling of ubiquitin-proteasome and autophagy-lysosome systems. In conclusion, supplementation of BCAA to reduced-protein diet increases fed-state protein synthesis and inhibits fasted-state protein degradation, both of which could contribute to the elevation of skeletal muscle mass in piglets. The effect of BCAA supplementation on muscle protein synthesis is associated with the increase in protein degradation and KIC production in the fed state. [ABSTRACT FROM AUTHOR]

Supplementation of branched-chain amino acids (BCAA) has been demonstrated to promote skeletal muscle mass gain, but the mechanisms underlying this observation are still unknown. Since the regulation of muscle mass depends on a dynamic equilibrium (fasted losses–fed gains) in protein turnover, the aim of this study was to investigate the effects of BCAA supplementation on muscle protein synthesis and degradation in fed/fasted states and the related mechanisms. Fourteen 26- (Experiment 1) and 28-day-old (Experiment 2) piglets were fed reduced-protein diets without or with supplemental BCAA. After a four-week acclimation period, skeletal muscle mass and components of anabolic and catabolic signaling in muscle samples after overnight fasting were determined in Experiment 1. Pigs in Experiment 2 were implanted with carotid arterial, jugular venous, femoral arterial and venous catheters, and fed once hourly along with the intravenous infusion of NaH13CO3 for 2 h, followed by a 6-h infusion of [1-13C]leucine. Muscle leucine kinetics were measured using arteriovenous difference technique. The mass of most muscles was increased by BCAA supplementation. During feeding, BCAA supplementation increased leucine uptake, protein synthesis, protein degradation and net transamination. The greater increase in protein synthesis than in protein degradation resulted in elevated protein deposition. Protein synthesis was strongly and positively correlated with the intramuscular net production of α-ketoisocaproate (KIC) and protein degradation. Moreover, BCAA supplementation enhanced the fasted-state phosphorylation of protein translation initiation factors and inhibited the protein-degradation signaling of ubiquitin-proteasome and autophagy-lysosome systems. In conclusion, supplementation of BCAA to reduced-protein diet increases fed-state protein synthesis and inhibits fasted-state protein degradation, both of which could contribute to the elevation of skeletal muscle mass in piglets. The effect of BCAA supplementation on muscle protein synthesis is associated with the increase in protein degradation and KIC production in the fed state.

Background: Atrophy of skeletal muscle in cancer cachexia has been attributed to a tumour-produced highly glycosylated peptide called proteolysis-inducing factor (PIF). The action of PIF is mediated through a high-affinity membrane receptor in muscle. This study investigates the ability of peptides derived from the 20 N-terminal amino acids of the receptor to neutralise PIF action both in vitro and in vivo.Methods: Proteolysis-inducing factor was purified from the MAC16 tumour using an initial pronase digestion, followed by binding on DEAE cellulose, and the pronase was inactivated by heating to 80°C, before purification of the PIF using affinity chromatography. In vitro studies were carried out using C(2)C(12) murine myotubes, while in vivo studies employed mice bearing the cachexia-inducing MAC16 tumour.Results: The process resulted in almost a 23,000-fold purification of PIF, but with a recovery of only 0.004%. Both the D- and L-forms of the 20mer peptide attenuated PIF-induced protein degradation in vitro through the ubiquitin-proteosome proteolytic pathway and increased expression of myosin. In vivo studies showed that neither the D- nor the L-peptides significantly attenuated weight loss, although the D-peptide did show a tendency to increase lean body mass.Conclusion: These results suggest that the peptides may be too hydrophilic to be used as therapeutic agents, but confirm the importance of the receptor in the action of the PIF on muscle protein degradation. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC50 ~1.2 nM) reversed the loss of body weight (≈5-7% increase in body mass) and muscle mass (~10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38±1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21±1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics. [ABSTRACT FROM AUTHOR]

Background & Aim of the study The goal of this study was to investigate muscle protein degradation (MPD) and find possible biohumoral indicator of MPD in patients with chronic heart failure (CHF). Plasma 3-methylhistidine concentration (3MEH) could be high in clinically stable CHF with normal renal function and blood urea levels (BU) could be a proxy of 3MEH in clinical environments. Methods In 38 outpatients with stable CHF (30 males and 8 females; 56.4±10.6 yrs) and 17 healthy subjects (13 males and 4 females) we determined 3MEH, BU and creatinine (CR) concentrations in peripheral venous blood. The tests were made at 8 am, after a meat-free diet on the previous day. Results Compared to controls, patients had higher concentrations of plasma 3MEH (9.5±4.8 vs 3.7±1.1 μmol/L; p<0.001) blood BU (45.65±2 vs 29.88±2.38 mg/dl; p<0.001) serum CR (1.043±0.02 vs 0.892±0.03; p=0.002). Moreover, 3MEH was positively correlated with BU (r=+0.49; p<0.001), resting VO2/Kg (n=24, r=+0.48; p=0.02), NYHA functional class (r=+0.32; p<0.05) in the studied patients. It was found that with a BU threshold of 38mg/dl, BU can predict 3MEH levels higher than 6μmol/L with 68% probability. Conclusions The study showed a high prevalence of MPD in stable CHF. BU can positively predict MPD in 70% of patients. [ABSTRACT FROM AUTHOR]

Loss of muscle protein is a serious complication of catabolic diseases and contributes substantially to patients' morbidity and mortality. This muscle loss is mediated largely by the activation of the ubiquitin–proteasome system; however, caspase-3 catalyzes an initial step in this process by cleaving actomyosin into small protein fragments that are rapidly degraded by the proteasome-dependent proteolytic pathway. We hypothesized that X-chromosome linked inhibitor of apoptosis protein (XIAP), an endogenous caspase-3 inhibitor, would block this first step in the cleavage of actomyosin that would make XIAP a candidate for treating muscle wasting. To determine if XIAP could attenuate muscle protein degradation, we used a recombinant lentivirus (Len-XIAP) encoding the full-length human XIAP cDNA to express XIAP in vivo. In muscle of streptozotocin-treated insulin-deficient mice, total muscle protein degradation, caspase-3 activity, and myofibril destruction were increased while XIAP was decreased. Overexpression of XIAP in these mice attenuated the excessive muscle protein degradation. Increased proteasome activity, caspase-3 activity and myofibril protein breakdown were all reduced. The ability of XIAP to prevent the loss of muscle protein suggests that XIAP could be a therapeutic reagent for muscle atrophy in catabolic diseases.Gene Therapy (2007) 14, 711–720. doi:10.1038/sj.gt.3302927; published online 22 February 2007 [ABSTRACT FROM AUTHOR]

Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg−1) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2α phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-κB (NF-κB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia.British Journal of Cancer (2007) 96, 1216–1222. doi:10.1038/sj.bjc.6603704 www.bjcancer.com Published online 27 January 2007 [ABSTRACT FROM AUTHOR]

Abstract: The ubiquitin–proteasome proteolytic pathway plays a major role in degradation of myofibrillar proteins in skeletal muscle during cancer cachexia. The end-product of this pathway is oligopeptides and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II (TPPII) together with various aminopeptidases to form tripeptides and amino acids. To investigate if a relationship exists between the activity of the proteasome and TPPII, functional activities have been measured in gastrocnemius muscle of mice bearing the MAC16 tumour, and with varying extents of weight loss. TPPII activity was quantitated using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin, while proteasome activity was determined as the ‘chymotrypsin-like’ enzyme activity. Both proteasome proteolytic activity and TPPII activity increased in parallel with increasing weight loss, reaching a maximum at 16% weight loss, after which there was a progressive decrease in activity for both proteases with increasing weight loss. In murine myotubes, proteolysis-inducing factor, which is a sulphated glycoprotein produced by cachexia-inducing tumours, induced an increase in activity of both proteasome and TPPII, with an identical dose–response curve, and both activities were inhibited by eicosapentaenoic acid. These results suggest that the activities of both the proteasome and TPPII are regulated in a parallel manner in cancer cachexia, and that both are induced by the same factor and probably have the same intracellular signalling pathways and transcription factors. [Copyright &y& Elsevier]

Maintenance of skeletal muscle mass and function is an incredibly nuanced balance of anabolism and catabolism that can become distorted within different pathological conditions. In this paper we intend to discuss the distinct intracellular signaling events that regulate muscle protein atrophy for a given clinical occurrence. Aside from the common outcome of muscle deterioration, several conditions have at least one or more distinct mechanisms that creates unique intracellular environments that facilitate muscle loss. The subtle individuality to each of these given pathologies can provide both researchers and clinicians with specific targets of interest to further identify and increase the efficacy of medical treatments and interventions. Above shows varying signaling pathways that regulate both skeletal muscle anabolism and catabolism. Focal Adhesion Kinase (FAK) is shown activate mammalian target of rapamycin (mTOR) in response to mechanical load through the phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT) pathway. Insulin or insulin-like growth factor (IGF) stimulation can activate mTOR through the same cascade. Also shown are the catabolic pathways related to inflammatory cytokines such as tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). TNF-α receptor 1 (TNFR1) ligand binding activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and c-Jun N-terminal kinase (JNK) pathway increasing rates of proteolysis. Protein Kinase R (PKR) can also stimulate the activation of NF-kB. IL-6 receptor binding activates the Janus Kinase (JAK) Signal Transducer and Activator of Transcription (STAT) signaling that can increase rates of muscle loss. Transforming Growth Factor-beta (TGF-β) receptor binding facilitates small mothers against decapentaplegic (SMAD) homologs 2 and 3 (SMAD2/3) phosphorylation, and subsequent SMAD 4 phosphorylation, upregulating genes related to collagen synthesis and fibrosis. Additionally, glucocorticoid (GC) receptor activation, dimerization, and DNA binding subsequently facilitates increases in FOXO expression which can increase the expression of UPS related E3 ligases. During low energy availability, increased 5' adenosine monophosphate-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) phosphorylation induces the activation of autophagy related processes. [Display omitted] • The ubiquitin-proteasome is involved in muscle degradation in cachexia and unloading. • Co-morbid conditions such as obesity and PAD increase ROS and muscle loss with ageing. • Without co-morbidities, anabolic resistance leads to muscle loss in ageing. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus is an autoimmune disease caused by the destruction of pancreatic beta cells. Many patients with type 1 diabetes experience skeletal muscle wasting. Although the link between type 1 diabetes and muscle wasting is not clearly known, insulin insufficiency and hyperglycemia may contribute to decreased muscle mass. In this study, we investigated the therapeutic effect of the ethanolic extract of Schisandrae chinensis Fructus (SFe) on muscle wasting in streptozotocin (STZ)-induced diabetic mice. STZ-diabetic C57BL/6 mice (blood glucose level ≥300 mg/dL) were orally administered SFe (250 or 500 mg/kg/day) for 6 weeks. We observed that SFe administration did not change blood glucose levels but increased gastrocnemius muscle weight, cross-sectional area, and grip strength in STZ-induced diabetic mice. Administration of SFe (500 mg/kg) decreased the expression of atrophic factors, such as MuRF1 and atrogin-1, but did not alter the expression of muscle synthetic factors. Further studies showed that SFe administration decreased the expression of KLF15 and p-CREB, which are upstream molecules of atrophic factors. Examination of the expression of molecules involved in autophagy–lysosomal pathways (e.g., p62/SQSTM1, Atg7, Beclin-1, ULK-1, LC3-I, and LC3-II) revealed that SFe administration significantly decreased the expression of p62/SQSTM1, LC3-I, and LC3-II; however, no changes were observed in the expression of Atg7, Beclin-1, or ULK-1. Our results suggest that SFe ameliorated muscle wasting in STZ-induced diabetic mice by decreasing protein degradation via downregulation of the CREB-KLF15-mediated UPS system and the p62/SQSTM1-mediated autophagy–lysosomal pathway. [ABSTRACT FROM AUTHOR]

The purpose of this research was to investigate the prophylactic effects of glutamine on muscle protein synthesis and degradation in rats with ethanol-induced liver injury. For the first 2 weeks, Wistar rats were divided into two groups and fed a control (n = 16) or glutamine-containing diet (n = 24). For the following 6 weeks, rats fed the control diet were further divided into two groups (n = 8 per group) according to whether their diet contained no ethanol (CC) or did contain ethanol (CE). Rats fed the glutamine-containing diet were also further divided into three groups (n = 8 per group), including a GG group (glutamine-containing diet without ethanol), GE group (control diet with ethanol), and GEG group (glutamine-containing diet with ethanol). After 6 weeks, results showed that hepatic fatty change, inflammation, altered liver function, and hyperammonemia had occurred in the CE group, but these were attenuated in the GE and GEG groups. Elevated intestinal permeability and a higher plasma endotoxin level were observed in the CE group, but both were lower in the GE and GEG groups. The level of a protein synthesis marker (p70S6K) was reduced in the CE group but was higher in both the GE and GEG groups. In conclusion, glutamine supplementation might elevate muscle protein synthesis by improving intestinal health and ameliorating liver damage in rats with chronic ethanol intake. [ABSTRACT FROM AUTHOR]

Increased global demand for adequate protein nutrition against a backdrop of climate change and concern for animal agriculture sustainability necessitates new and more efficient approaches to livestock growth and production. Anabolic growth is achieved when rates of new synthesis exceed turnover, producing a positive net protein balance. Conversely, deterioration or atrophy of lean mass is a consequence of a net negative protein balance. During early life and periods of growth, muscle mass is driven by increases in protein synthesis at the level of mRNA translation. Throughout life, muscle mass is further influenced by degradative processes such as autophagy and the ubiquitin proteasome pathway. Multiple signal transduction networks guide and coordinate these processes alongside quality control mechanisms to maintain protein homeostasis (proteostasis). Genetics, hormones, and environmental stimuli each influence proteostasis control, altering capacity and/or efficiency of muscle growth. An overview of recent findings and current methods to assess muscle protein balance and proteostasis is presented. Current efforts to identify novel control points have the potential through selective breeding design or development of hormetic strategies to better promote growth and health span during environmental stress. [ABSTRACT FROM AUTHOR]

Supplementation of branched-chain amino acids (BCAA) has been demonstrated to promote skeletal muscle mass gain, but the mechanisms underlying this observation are still unknown. Since the regulation of muscle mass depends on a dynamic equilibrium (fasted losses-fed gains) in protein turnover, the aim of this study was to investigate the effects of BCAA supplementation on muscle protein synthesis and degradation in fed/fasted states and the related mechanisms. Fourteen 26- (Experiment 1) and 28-day-old (Experiment 2) piglets were fed reduced-protein diets without or with supplemental BCAA. After a four-week acclimation period, skeletal muscle mass and components of anabolic and catabolic signaling in muscle samples after overnight fasting were determined in Experiment 1. Pigs in Experiment 2 were implanted with carotid arterial, jugular venous, femoral arterial and venous catheters, and fed once hourly along with the intravenous infusion of NaH 13 CO₃ for 2 h, followed by a 6-h infusion of [1- 13 C]leucine. Muscle leucine kinetics were measured using arteriovenous difference technique. The mass of most muscles was increased by BCAA supplementation. During feeding, BCAA supplementation increased leucine uptake, protein synthesis, protein degradation and net transamination. The greater increase in protein synthesis than in protein degradation resulted in elevated protein deposition. Protein synthesis was strongly and positively correlated with the intramuscular net production of α-ketoisocaproate (KIC) and protein degradation. Moreover, BCAA supplementation enhanced the fasted-state phosphorylation of protein translation initiation factors and inhibited the protein-degradation signaling of ubiquitin-proteasome and autophagy-lysosome systems. In conclusion, supplementation of BCAA to reduced-protein diet increases fed-state protein synthesis and inhibits fasted-state protein degradation, both of which could contribute to the elevation of skeletal muscle mass in piglets. The effect of BCAA supplementation on muscle protein synthesis is associated with the increase in protein degradation and KIC production in the fed state., Competing Interests: The authors declare no conflict of interest.