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Background Skeletomuscular diseases result in significant muscle loss and decreased performance, paralleled by a loss in mitochondrial and oxidative capacity. Insulin and insulin‐like growth factor‐1 (IGF‐1) are two potent anabolic hormones that activate a host of signalling intermediates including the serine/threonine kinase AKT to influence skeletal muscle physiology. Defective AKT signalling is associated with muscle pathology, including cachexia, sarcopenia, and disuse; however, the mechanistic underpinnings remain unresolved. Methods To elucidate the role of AKT signalling in muscle mass and physiology, we generated both congenital and inducible mouse models of skeletal muscle‐specific AKT deficiency. To understand the downstream mechanisms mediating AKT's effects on muscle biology, we generated mice lacking AKT1/2 and FOXO1 (M‐AKTFOXO1TKO and M‐indAKTFOXO1TKO) to inhibit downstream FOXO1 signalling, AKT1/2 and TSC1 (M‐AKTTSCTKO and M‐indAKTTSCTKO) to activate mTORC1, and AKT1/2, FOXO1, and TSC1 (M‐QKO and M‐indQKO) to simultaneously activate mTORC1 and inhibit FOXO1 in AKT‐deficient skeletal muscle. Muscle proteostasis and physiology were assessed using multiple assays including metabolic labelling, mitochondrial function, fibre typing, ex vivo physiology, and exercise performance. Results Here, we show that genetic ablation of skeletal muscle AKT signalling resulted in decreased muscle mass and a loss of oxidative metabolism and muscle performance. Specifically, deletion of muscle AKT activity during development or in adult mice resulted in a significant reduction in muscle growth by 30–40% (P  < 0.0001; n = 12–20) and 15% (P < 0.01 and P < 0.0001; n = 20–30), respectively. Interestingly, this reduction in muscle mass was primarily due to an ~40% reduction in protein synthesis in both M‐AKTDKO and M‐indAKTDKO muscles (P < 0.05 and P < 0.01; n = 12–20) without significant changes in proteolysis or autophagy. Moreover, a significant reduction in oxidative capacity was observed in both M‐AKTDKO (P < 0.05, P < 0.01 and P < 0.001; n = 5–12) and M‐indAKTDKO (P < 0.05 and P < 0.01; n = 4). Mechanistically, activation and inhibition of mTORC1/FOXO1, respectively, but neither alone, were sufficient to restore protein synthesis, muscle oxidative capacity, and muscle function in the absence of AKT in vivo. In a mouse model of disuse‐induced muscle loss, simultaneous activation of mTORC1 and inhibition of FOXO1 preserved muscle mass following immobilization (~5–10% reduction in casted M‐indFOXO1TSCDKO muscles vs. ~30–40% casted M‐indControl muscles, P < 0.05 and P < 0.0001; n = 8–16). Conclusions Collectively, this study provides novel insights into the AKT‐dependent mechanisms that underlie muscle protein homeostasis, function, and metabolism in both normal physiology and disuse‐induced muscle wasting.

Cachexia is a multifactorial syndrome that presents with, among other characteristics, progressive loss of muscle mass and anti-cardiac remodeling effect that may lead to heart failure. This condition affects about 80% of patients with advanced cancer and contributes to worsening patients’ tolerance to anticancer treatments and to their premature death. Its pathogenesis involves an imbalance in metabolic homeostasis, with increased catabolism and inflammatory cytokines levels, leading to proteolysis and lipolysis, with insufficient food intake. A multimodal approach is indicated for patients with cachexia, with the aim of reducing the speed of muscle wasting and improving their quality of life, which may include nutritional, physical, pharmacologic, and psychological support. This review aims to outline the mechanisms of muscle loss, as well as to evaluate the current clinical evidence of the use of physical exercise in patients with cachexia.

Gracilaria chorda (GC) is a red algal species that is primarily consumed in Asia. Here, we investigated the effect of GC on obesity‐related skeletal muscle wasting. Furthermore, elucidating its impact on the activation of sirtuin 1 (SIRT1)/peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC1α) constituted a critical aspect in understanding the underlying mechanism of action. In this study, 6‐week‐old male C57BL/6 mice were fed a high‐fat diet (HFD) for 8 weeks to induce obesity, then continued on the HFD for another 8 weeks while orally administered GC. GC decreased ectopic fat accumulation in skeletal muscle and increased muscle weight, size, and function in obese mice. Furthermore, GC reduced skeletal muscle atrophy and increased hypertrophy in mice. We hypothesized that the activation of SIRT1/PGC1α by GC regulates skeletal muscle atrophy and hypertrophy. We observed that GC increased the expression of SIRT1 and PGC1α in skeletal muscle of mice and in C2C12 cells, which increased mitochondrial function and biogenesis. In addition, when C2C12 cells were treated with the SIRT1‐specific inhibitor EX‐527, no changes were observed in the protein levels of SIRT1 and PGC1α in the GC‐treated C2C12 cells. Therefore, GC attenuated obesity‐related muscle wasting by improving mitochondrial function and biogenesis through the activation of SIRT1/PGC1α in the skeletal muscle of mice. GC increased skeletal muscle weight and improved muscle function in obese mice. GC reduced skeletal muscle atrophy and increased hypertrophy in mice. GC increased the expression of SIRT1 and PGC1α in vivo and in vitro, which increased mitochondrial function and biogenesis.

Cancer cachexia consists of dramatic body weight loss with rapid muscle depletion due to imbalanced protein homeostasis. We found that the mRNA levels of apelin decrease in muscles from cachectic hepatoma-bearing rats and three mouse models of cachexia. Furthermore, apelin expression inversely correlates with MuRF1 in muscle biopsies from cancer patients. To shed light on the possible role of apelin in cachexia in vivo, we generated apelin 13 carrying all the last 13 amino acids of apelin in D isomers, ultimately extending plasma stability. Notably, apelin D-peptides alter cAMP-based signaling in vitro as the L-peptides, supporting receptor binding. In vitro apelin 13 protects myotube diameter from dexamethasone-induced atrophy, restrains rates of degradation of long-lived proteins and MuRF1 expression, but fails to protect mice from atrophy. D-apelin 13 given intraperitoneally for 13 days in colon adenocarcinoma C26-bearing mice does not reduce catabolic pathways in muscles, as it does in vitro. Puzzlingly, the levels of circulating apelin seemingly deriving from cachexia-inducing tumors, increase in murine plasma during cachexia. Muscle electroporation of a plasmid expressing its receptor APJ, unlike apelin, preserves myofiber area from C26-induced atrophy, supporting apelin resistance in vivo. Altogether, we believe that during cachexia apelin resistance occurs, contributing to muscle wasting and nullifying any possible peptide-based treatment.

Background Muscle wasting occurs in response to various physiological and pathological conditions, including ageing and Duchenne muscular dystrophy (DMD). Transforming growth factor‐β1 (TGF‐β1) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF‐β1 signalling is a promising therapeutic strategy for muscle‐wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane‐bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF‐β subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF‐β1 signalling. Methods Conventional and conditional Hjv knockout mice as well as mdx and aged mice transfected with Hjv overexpression vector were used to study the role of Hjv in muscle physiology and pathophysiology. qRT‐PCR, western blotting, and immunohistochemistry examinations were conducted to evaluate gene, protein, and structural changes in vivo and in vitro. Exercise endurance was determined using treadmill running test, and muscle force was detected by an isometric transducer. RNA interference, immunoprecipitation, and dual‐luciferase reporter assays were utilized to explore the mechanism by which Hjv regulates TGF‐β1 signalling in skeletal muscle. Results Conventional and conditional Hjv knockout mice displayed muscle atrophy, fibrosis, reduced running endurance, and muscle force. HJV was significantly down‐regulated in the muscles of DMD patients (n = 3, mean age: 11.7 ± 5.7 years) and mdx mice as well as in those of aged humans (n = 10, 20% women, mean age: 75.1 ± 9.5 years) and mice. Overexpression of Hjv rescued dystrophic and age‐related muscle wasting. Unlike its function in hepatic cells, the bone morphogenetic protein downstream phosphorylated p‐Smad1/5/8 signalling pathway was unchanged, but TGF‐β1, TGF‐β receptor II (TβRII), and p‐Smad2/3 expression were increased in Hjv‐deficient muscles. Mechanistically, loss of Hjv promoted activation of Smad3 signalling induced by TGF‐β1, whereas Hjv overexpression inhibited TGF‐β1/Smad3 signalling by directly interacting with TβRII on the muscle membrane. Conclusions Our findings identify an unrecognized role of HJV in skeletal muscle by regulating TGF‐β1/Smad3 signalling as a coreceptor for TβRII. Unlike the TGF‐β1/Smad3 pathway, HJV could be a reliable drug target as its expression is not widespread. Novel therapeutic strategies could potentially be devised to interfere only with the muscle function of HJV to treat DMD and age‐related muscle wasting.

Angiotensin (1-7) (Ang-(1-7)) is a bioactive heptapeptide with a short half-life and has beneficial effects in several tissues - among them, skeletal muscle - by preventing muscle atrophy. Dendrimers are promising vehicles for the protection and transport of numerous bioactive molecules. This work explored the use of a neutral, non-cytotoxic hydroxyl-terminated poly(amidoamine) (PAMAM-OH) dendrimer as an Ang-(1-7) carrier. Bioinformatics analysis showed that the Ang-(1-7)-binding capacity of the dendrimer presented a 2:1 molar ratio. Molecular dynamics simulation analysis revealed the capacity of neutral PAMAM-OH to protect Ang-(1-7) and form stable complexes. The peptide coverage ability of the dendrimer was between ~50% and 65%. Furthermore, an electrophoretic mobility shift assay demonstrated that neutral PAMAM-OH effectively bonded peptides. Experimental results showed that the Ang-(1-7)/PAMAM-OH complex, but not Ang-(1-7) alone, had an anti-atrophic effect when administered intraperitoneally, as evaluated by muscle strength, fiber diameter, myofibrillar protein levels, and atrogin-1 and MuRF-1 expressions. The results of the Ang-(1-7)/PAMAM-OH complex being intraperitoneally injected were similar to the results obtained when Ang-(1-7) was systemically administered through mini-osmotic pumps. Together, the results suggest that Ang-(1-7) can be protected for PAMAM-OH when this complex is intraperitoneally injected. Therefore, the Ang-(1-7)/PAMAM-OH complex is an efficient delivery method for Ang-(1-7), since it improves the anti-atrophic activity of this peptide in skeletal muscle.

Lung infection can evoke pulmonary and systemic inflammation, which is associated with systemic severe symptoms, such as skeletal muscle wasting. While N-chlorotaurine (also known as taurine chloramine; TauCl) has anti-inflammatory effects in cells, its effects against pulmonary and systemic inflammation after lung infection has not been elucidated. In the present study, we evaluated the anti-inflammatory effect of the taurine derivative, TauCl against Escherichia coli-derived lipopolysaccharide (LPS)-induced pneumonia in obese mice maintained on a high fat diet. In this study, TauCl was injected intraperitoneally 1 h before intratracheal LPS administration. While body weight was decreased by 7.5% after LPS administration, TauCl treatment suppressed body weight loss. TauCl also attenuated the increase in lung weight due to lung edema. While LPS-induced acute pneumonia caused an increase in cytokine/chemokine mRNA expression, including that of IL-1β, -6, TNF-α, MCP-1, TauCl treatment attenuated IL-6, and TNF-alpha expression, but not IL-1β and MCP-1. TauCl treatment partly attenuated the elevation of the serum cytokines. Furthermore, TauCl treatment alleviated skeletal muscle wasting. Importantly, LPS-induced expression of Atrogin-1, MuRF1 and IκB, direct or indirect targets for NFκB, were suppressed by TauCl treatment. These findings suggest that intraperitoneal TauCl treatment attenuates acute pneumonia-related pulmonary and systemic inflammation, including muscle wasting, in vivo.

This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 7th Cachexia Conference held in Kobe, Japan, in December 2013. This year, the main topics were the development of new methods and new biomarkers in the field of cachexia and wasting disorders with particular focus on inflammatory pathways, growth differentiation factor-15, myostatin, the ubiquitin proteasome-dependent pathway, valosin and the regulation of ubiquitin-specific protease 19 that is involved in the differentiation of myogenin and myosin heavy chain. This article presents highlights from the development of drugs that have shown potential in the treatment of wasting disorders, particularly the ghrelin receptor agonist anamorelin, the myostatin antagonist REGN1033, the selective androgen receptor modulators enobosarm and TEI-E0001, and the anabolic catabolic transforming agent espindolol. In addition, novel data on the prevalence and detection methods of muscle wasting/sarcopenia are presented, including the D3-creatine dilution method and several new biomarkers.

Background Patients with critical illness can lose more than 15% of muscle mass in one week, and this can have long-term detrimental effects. However, there is currently no synthesis of the data of intensive care unit (ICU) muscle wasting studies, so the true mean rate of muscle loss across all studies is unknown. The aim of this project was therefore to systematically synthetise data on the rate of muscle loss and to identify the methods used to measure muscle size and to synthetise data on the prevalence of ICU-acquired weakness in critically ill patients. Methods We conducted a systematic literature search of MEDLINE, PubMed, AMED, BNI, CINAHL, and EMCARE until January 2022 (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD420222989540. We included studies with at least 20 adult critically ill patients where the investigators measured a muscle mass-related variable at two time points during the ICU stay. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed the study quality using the Newcastle–Ottawa Scale. Results Fifty-two studies that included 3251 patients fulfilled the selection criteria. These studies investigated the rate of muscle wasting in 1773 (55%) patients and assessed ICU-acquired muscle weakness in 1478 (45%) patients. The methods used to assess muscle mass were ultrasound in 85% ( n  = 28/33) of the studies and computed tomography in the rest 15% ( n  = 5/33). During the first week of critical illness, patients lost every day −1.75% (95% CI −2.05, −1.45) of their rectus femoris thickness or −2.10% (95% CI −3.17, −1.02) of rectus femoris cross-sectional area. The overall prevalence of ICU-acquired weakness was 48% (95% CI 39%, 56%). Conclusion On average, critically ill patients lose nearly 2% of skeletal muscle per day during the first week of ICU admission.

Skeletal muscle dysfunction occurs in patients with chronic obstructive pulmonary disease (COPD) and affects both ventilatory and nonventilatory muscle groups. It represents a very important comorbidity that is associated with poor quality of life and reduced survival. It results from a complex combination of functional, metabolic, and anatomical alterations leading to suboptimal muscle work. Muscle atrophy, altered fiber type and metabolism, and chest wall remodeling, in the case of the respiratory muscles, are relevant etiological contributors to this process. Muscle dysfunction worsens during COPD exacerbations, rendering patients progressively less able to perform activities of daily living, and it is also associated with poor outcomes. Muscle recovery measures consisting of a combination of pulmonary rehabilitation, optimized nutrition, and other strategies are associated with better prognosis when administered in stable patients as well as after exacerbations. A deeper understanding of this process' pathophysiology and clinical relevance will facilitate the use of measures to alleviate its effects and potentially improve patients' outcomes. In this review, a general overview of skeletal muscle dysfunction in COPD is offered to highlight its relevance and magnitude to expert practitioners and scientists as well as to the average clinician dealing with patients with chronic respiratory diseases.