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Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the ph...
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The objective of the current study was to investigate the effects of over-conditioning around calving on gene expression of key components of mammalian target of rapamycin (mTOR) pathway and ubiquitin-proteasome system (UPS) in skeletal muscle as well as the AA profiles in both serum and muscle of periparturient cows. Fifteen weeks ante partum, 38...
Citations
... In addition, myostatin and Akt signaling induce protein degradation through muscle loss-related genes such as MuRF-1 and MAFbx through the FOXO pathway [27,28,29]. As shown in Figure 6, the expression of myostatin in the DEX group, in which DEX induced muscle atrophy, increased significantly more than in the Normal group (myostatin, 1.50 fold). ...
... In addition, myostatin and Akt signaling induce protein degradation through muscle loss-related genes such as MuRF-1 and MAFbx through the FOXO pathway [27][28][29]. As shown in Figure 6, the expression of myostatin in the DEX group, in which DEX induced muscle atrophy, increased significantly more than in the Normal group (myostatin, 1.50 fold). ...
Background and Objectives: Muscle atrophy occurs when protein degradation exceeds protein synthesis, resulting in imbalanced protein homeostasis, compromised muscle contraction, and a reduction in muscle mass. The incidence of muscle atrophy is increasingly recognized as a significant worldwide public health problem. The aim of the current study was to evaluate the effect of whey peptide (WP) on muscle atrophy induced by dexamethasone (DEX) in mice. Materials and Methods: C57BL/6 mice were divided into six groups, each consisting of nine individuals. WPs were orally administered to C57BL/6 mice for 6 weeks. DEX was administered for 5–6 weeks to induce muscle atrophy (intraperitoneal injection, i.p.). Results: Microcomputer tomography (CT) analysis confirmed that WP significantly increased calf muscle volume and surface area in mice with DEX-induced muscle atrophy, as evidenced by tissue staining. Furthermore, it increased the area of muscle fibers and facilitated greater collagen deposition. Moreover, WP significantly decreased the levels of serum biomarkers associated with muscle damage, kidney function, and inflammatory cytokines. WP increased p-mTOR and p-p70S6K levels through the IGF-1/PI3K/Akt pathway, while concurrently decreasing protein catabolism via the FOXO pathway. Furthermore, the expression of proteins associated with myocyte differentiation increased noticeably. Conclusions: These results confirm that WP reduces muscle atrophy by regulating muscle protein homeostasis. Additionally, it is believed that it helps to relieve muscle atrophy by regulating the expression of myocyte differentiation factors. Therefore, we propose that WP plays a significant role in preventing and treating muscle wasting by functioning as a supplement to counteract muscle atrophy.
... During sepsis, the consumption of cysteine increases twofold [8]. Amino acids are also implicated in the repair of the intestinal mucosa and in the provision of energy to bolster the innate defence of the gut [9,10]. Stress therefore leads to increased demand for amino acids by the gut and the liver. ...
Background
A defining feature of prolonged critical illness is muscle wasting, leading to impaired recovery. Supplementation with a tailored blend of amino acids may bolster the innate gut defence, promote intestinal mucosa repair and limit muscle loss.
Methods
This was a monocentric, randomized, double-blind, placebo-controlled study that included patients with sepsis or acute respiratory distress syndrome. Patients received a specific combination of five amino acids or placebo mixed with enteral feeding for 21 days. Markers of renal function, gut barrier structure and functionality were collected at baseline and 1, 2, 3 and 8 weeks after randomization. Muscle structure and function were assessed through MRI measurements of the anterior quadriceps volume and by twitch airway pressure. Data were compared between groups relative to the baseline.
Results
Thirty-five critically ill patients were randomized. The amino acid blend did not impair urine output, blood creatinine levels or creatinine clearance. Plasma citrulline levels increased significantly along the treatment period in the amino acid group (difference in means [95% CI] 5.86 [1.72; 10.00] nmol/mL P = 0.007). Alanine aminotransferase and alkaline phosphatase concentrations were lower in the amino acid group than in the placebo group at one week (ratio of means 0.5 [0.29; 0.86] ( P = 0.015) and 0.73 [0.57; 0.94] ( P = 0.015), respectively). Twitch airway pressure and volume of the anterior quadriceps were greater in the amino acid group than in the placebo group 3 weeks after randomization (difference in means 10.6 [0.99; 20.20] cmH 2 0 ( P = 0.035) and 3.12 [0.5; 5.73] cm ³ /kg ( P = 0.022), respectively).
Conclusions
Amino acid supplementation increased plasma citrulline levels, reduced alanine aminotransferase and alkaline phosphatase levels, and improved twitch airway pressure and anterior quadriceps volume.
Trial registration ClinicalTrials.gov, NCT02968836. Registered November 21, 2016.
... The large scatter has been observed before by our research group [9,10,14], but also by others in septic patients [1] and burn patients [22]. This higher variation has also been observed in the expression of the genes involved in protein synthesis [23]. The present results confirm the larger variation in critically ill patients, although this was not the prime objective of the study, since the patient groups and control groups were not equal in size. ...
(1) Background: Muscle protein synthesis in critically ill patients is, on average, normal despite dramatic muscle loss, but the variation is much larger than in controls. Here, we evaluate if this variation is due to 1) heterogeneity in synthesis rates, 2) morphological variation or infiltrating cells, or 3) heterogeneity in the synthesis of different protein fractions. (2) Methods: Muscle biopsies were taken from both legs of critically ill patients (n = 17). Mixed and mitochondrial protein synthesis rates and morphologies were evaluated in both legs. Synthesis rates of myosin and actin were determined in combined biopsies and compared with controls. (3) Results: Muscle protein synthesis rates had a large variability in the patients (1.4–10.8%/day). No differences in mixed and mitochondrial protein synthesis rates between both legs were observed. A microscopic examination revealed no morphological differences between the two legs or any infiltrating inflammatory cells. The synthesis rates for myosin were lower and for actin they were higher in the muscles of critically ill patients, compared with the controls. (4) Conclusions: The large variation in muscle protein synthesis rates in critically ill patients is not the result of heterogeneity in synthesis rates, nor due to infiltrating cells. There are differences in the synthesis rates of different proteins, but these do not explain the larger variations.
... This impairs muscle function, especially strength and endurance. At the same time, insulin has an anabolic effect on muscle by increasing protein synthesis and inhibiting protein breakdown (98,103), so that insulin resistance leads to disturbed protein homeostasis with increased protein breakdown and reduced protein synthesis, resulting in muscle atrophy and weakness (27,37). Importantly, insulin resistance has been reported to be a predictor for ICUAW (47). ...
Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem.
... Interestingly, IL-6 has been proven to drive the systemic compensatory anti-inflammatory response syndrome, by inhibiting TNFα release and stimulating IL-10 [71]. In skeletal muscle, IL-6 is involved in myogenesis, lipid metabolism, glucose uptake and both protein synthesis and degradation [72][73][74]. Skeletal muscle cellular niche has been recognized itself as a myokine secretor organ and even a potential regulator of immune system [75]. In mechanically ventilated patients who developed myopathy, the inflammation-induced acute phase response resulted in a marked increase in IL-6 production in skeletal muscle [76]. ...
... The overall elevated proteolysis rate can also be clinically identified fro increases in urinary 3-methyl histidine excretion, an index of myofibril protein breakdow [30]. Concurrent with the increased expression of the 20S, the muscle-specific ubiqui ligases, MAFbx and MuRF1, are also up-regulated in critical illness [28,31], suggesti that an upstream control of the components of the ubiquitin-proteasome pathway exi ( Figure 2). Several cytokines that increase oxidative stress have received attention as p tential underlying triggers to up-regulation of the UPP [32]. ...
... Indeed, a recent study provided evidence of remarkably high TN α and IL-6 expression levels in muscles of critically ill patients [28]. Such increases mig be reasonably predictable to reduce insulin receptor substrate-1 (IRS-1) binding [3 Concurrent with the increased expression of the 20S, the muscle-specific ubiquitin ligases, MAFbx and MuRF1, are also up-regulated in critical illness [28,31], suggesting that an upstream control of the components of the ubiquitin-proteasome pathway exists ( Figure 2). Several cytokines that increase oxidative stress have received attention as potential underlying triggers to up-regulation of the UPP [32]. ...
Muscle fatigue (MF) declines the capacity of muscles to complete a task over time at a constant load. MF is usually short-lasting, reversible, and is experienced as a feeling of tiredness or lack of energy. The leading causes of short-lasting fatigue are related to overtraining, undertraining/deconditioning, or physical injury. Conversely, MF can be persistent and more serious when associated with pathological states or following chronic exposure to certain medication or toxic composites. In conjunction with chronic fatigue, the muscle feels floppy, and the force generated by muscles is always low, causing the individual to feel frail constantly. The leading cause underpinning the development of chronic fatigue is related to muscle wasting mediated by aging, immobilization, insulin resistance (through high-fat dietary intake or pharmacologically mediated Peroxisome Proliferator-Activated Receptor (PPAR) agonism), diseases associated with systemic inflammation (arthritis, sepsis, infections, trauma, cardiovascular and respiratory disorders (heart failure, chronic obstructive pulmonary disease (COPD))), chronic kidney failure, muscle dystrophies, muscle myopathies, multiple sclerosis, and, more recently, coronavirus disease 2019 (COVID-19). The primary outcome of displaying chronic muscle fatigue is a poor quality of life. This type of fatigue represents a significant daily challenge for those affected and for the national health authorities through the financial burden attached to patient support. Although the origin of chronic fatigue is multifactorial, the MF in illness conditions is intrinsically linked to the occurrence of muscle loss. The sequence of events leading to chronic fatigue can be schematically denoted as: trigger (genetic or pathological) -> molecular outcome within the muscle cell -> muscle wasting -> loss of muscle function -> occurrence of chronic muscle fatigue. The present review will only highlight and discuss current knowledge on the molecular mechanisms that contribute to the upregulation of muscle wasting, thereby helping us understand how we could prevent or treat this debilitating condition.
... [3][4][5] Of note, both CIM and CIP show a particular high prevalence in septic patients. 6,7 Loss of muscle mass due to an imbalance in myofibrillar breakdown and compensatory protein synthesis is the most prominent observation in weak patients, [8][9][10] which results in a preferential loss of myosin and a shift in muscle fibre type composition. [11][12][13] Impaired muscle force generation in the critically ill is not merely a consequence of the muscle wasting but is also related to mechanisms that affect the muscles' bioenergetic state and the excitation-contraction coupling. ...
Background:
Prolonged critically ill patients frequently develop debilitating muscle weakness that can affect both peripheral nerves and skeletal muscle. In-depth knowledge on the temporal contribution of neural and muscular components to muscle weakness is currently incomplete.
Methods:
We used a fluid-resuscitated, antibiotic-treated, parenterally fed murine model of prolonged (5 days) sepsis-induced muscle weakness (caecal ligation and puncture; n = 148). Electromyography (EMG) measurements were performed in two nerve-muscle complexes, combined with histological analysis of neuromuscular junction denervation, axonal degeneration, and demyelination. In situ muscle force measurements distinguished neural from muscular contribution to reduced muscle force generation. In myofibres, imaging and biomechanics were combined to evaluate myofibrillar contractile calcium sensitivity, sarcomere organization, and fibre structural properties. Myosin and actin protein content and titin gene expression were measured on the whole muscle.
Results:
Five days of sepsis resulted in increased EMG latency (P = 0.006) and decreased EMG amplitude (P < 0.0001) in the dorsal caudal tail nerve-tail complex, whereas only EMG amplitude was affected in the sciatic nerve-gastrocnemius muscle complex (P < 0.0001). Myelin sheath abnormalities (P = 0.2), axonal degeneration (number of axons; P = 0.4), and neuromuscular junction denervation (P = 0.09) were largely absent in response to sepsis, but signs of axonal swelling [higher axon area (P < 0.0001) and g-ratio (P = 0.03)] were observed. A reduction in maximal muscle force was present after indirect nerve stimulation (P = 0.007) and after direct muscle stimulation (P = 0.03). The degree of force reduction was similar with both stimulations (P = 0.2), identifying skeletal muscle, but not peripheral nerves, as the main contributor to muscle weakness. Myofibrillar calcium sensitivity of the contractile apparatus was unaffected by sepsis (P ≥ 0.6), whereas septic myofibres displayed disorganized sarcomeres (P < 0.0001) and altered myofibre axial elasticity (P < 0.0001). Septic myofibres suffered from increased rupturing in a passive stretching protocol (25% more than control myofibres; P = 0.04), which was associated with impaired myofibre active force generation (P = 0.04), linking altered myofibre integrity to function. Sepsis also caused a reduction in muscle titin gene expression (P = 0.04) and myosin and actin protein content (P = 0.05), but not the myosin-to-actin ratio (P = 0.7).
Conclusions:
Prolonged sepsis-induced muscle weakness may predominantly be related to a disruption in myofibrillar cytoarchitectural structure, rather than to neural abnormalities.
... 18 The increase in anabolic hormones such as insulin acts on the MuRF1 and MAFbx regulatory mechanism, decreasing their expression levels and, consequently, the muscular atrophy. 19 Recently, therapeutic approaches to extensive BIs have aimed to reverse hypermetabolic responses and catabolic states. To do so, investments must be made in anabolic agents, such as growth hormones, insulin, IGF-1, testosterone, and oxandrolone 20 and anticatabolic agents such as adrenergic antagonists (propranolol or metoprolol), which reduce supraphysiological thermogenesis, cardiac work, resting energy expenditure, peripheral lipolysis, and efficiency of muscle protein synthesis. ...
Background
Burn injuries (BIs) due to scalding are one of the most common accidents among children. BIs greater than 40% of total body surface area are considered extensive and result in local and systemic response. We sought to assess morphological and myogenic mechanisms through both short- and long-term intensive insulin therapies that affect the skeletal muscle after extensive skin BI in young rats.
Materials and methods
Wistar rats aged 21 d were distributed into four groups: control (C), control with insulin (C + I), scald burn injury (SI), and SI with insulin (SI + I). The SI groups were submitted to a 45% total body surface area burn, and the C + I and SI + I groups received insulin (5 UI/Kg/d) for 4 or 14 d. Glucose tolerance and the homeostatic model assessment of insulin resistance index were determined. Gastrocnemius muscles were analyzed for histopathological, morphometric, and immunohistochemical myogenic parameters (Pax7, MyoD, and MyoG); in addition, the expression of genes related to muscle atrophy (MuRF1 and MAFbx) and its regulation (IGF-1) were also assessed.
Results
Short-term treatment with insulin favored muscle regeneration by primary myogenesis and decreased muscle atrophy in animals with BIs, whereas the long-term treatment modulated myogenesis by increasing the MyoD protein. Both treatments improved histopathological parameters and secondary myogenesis by increasing the MyoG protein.
Conclusions
Treatment with insulin benefits myogenic parameters during regeneration and modulates MuRF1, an important mediator of muscle atrophy.
... Several studies have reported changes in inflammatory responses following exercise in typically healthy, physically inactive adults and populations with mild-to-moderate diseases (eg idiopathic inflammatory myopathies and cancer) (Pedersen, 2009;Loell and Lundberg, 2011;Philippou et al, 2012;LaVoy et al, 2016;Monteiro-Junior et al, 2018;Silva et al, 2018). In this context, Jespersen et al (2011) demonstrated that serum levels of IL-8 was consistently elevated in critically ill adults. However, Winkelman et al (2015) did not find significant differences in IL-8 serum levels pre-to post-activity among mechanically ventilated patients who received a once-daily 20-minute progressive mobility intervention. ...
Background/Aims A growing body of evidence has demonstrated that early mobilisation
is beneficial for patients in the intensive care unit. The aim of this prospective study was
to investigate the acute effect of an early passive cycling exercise session on serum
interleukin-8 and interleukin-10 levels in critically ill patients.
Methods A total of 11 haemodynamically stable and deeply sedated (Richmond Agitation
and Sedation Scale -4) adult patients within the first 48 hours of mechanical ventilation
received a single 20-minute session of passive cycle ergometer. Serum interleukin-8 and
interleukin-10 levels were measured at baseline, immediately after the intervention and
60 minutes after the intervention.
Findings Interleukin-8 decreased significantly 60 minutes after the passive cycle
ergometer session compared to baseline (P=0.001). The serum levels of interleukin-10
increased immediately after the end of the 20 minutes and at 60 minutes after the
intervention (P<0.001).
Conclusions A single 20-minute session of passive cycle ergometer seems to have a
positive effect in inflammatory response in critically ill patients
... Several studies have reported changes in inflammatory responses following exercise in typically healthy, physically inactive adults and populations with mild-to-moderate diseases (eg idiopathic inflammatory myopathies and cancer) (Pedersen, 2009;Loell and Lundberg, 2011;Philippou et al, 2012;LaVoy et al, 2016;Monteiro-Junior et al, 2018;Silva et al, 2018). In this context, Jespersen et al (2011) demonstrated that serum levels of IL-8 was consistently elevated in critically ill adults. However, Winkelman et al (2015) did not find significant differences in IL-8 serum levels pre-to post-activity among mechanically ventilated patients who received a once-daily 20-minute progressive mobility intervention. ...
Background/aims
A growing body of evidence has demonstrated that early mobilisation is beneficial for patients in the intensive care unit. The aim of this prospective study was to investigate the acute effect of an early passive cycling exercise session on serum interleukin-8 and interleukin-10 levels in critically ill patients.
Methods
A total of 11 haemodynamically stable and deeply sedated (Richmond Agitation and Sedation Scale-4) adult patients within the first 48 hours of mechanical ventilation received a single 20-minute session of passive cycle ergometer. Serum interleukin-8 and interleukin-10 levels were measured at baseline, immediately after the intervention and 60 minutes after the intervention.
Findings
Interleukin-8 levels decreased significantly 60 minutes after the passive cycle ergometer session compared to baseline (P=0.001). The serum levels of interleukin-10 increased immediately after the end of the 20 minutes and at 60 minutes after the intervention (P<0.001).
Conclusions
A single 20-minute session of passive cycle ergometer seems to have a positive effect on the inflammatory response in critically ill patients.
