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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.

Recently it has been postulated that there is an atypical facioscapulohumeral muscular dystrophy (FSHD) phenotype with isolated axial myopathy. Involvement of paraspinal and limb muscles was evaluated in six patients with molecularly proven FSHD and a predominant bent spine phenotype. Consistent with the camptocormia phenotype, the most severely affected muscles in all six patients were the thoracic and lumbar spinal tract together with hamstrings. MRI disclosed severe axial muscle degeneration but mostly subclinical involvement of limb muscles. The involvement of hip extensor muscles in FSHD might considerably contribute to the clinical phenotype of camptocormia due to axial muscle involvement.

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer 1 . Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength 2 . An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1 . EDA-A2-driven myotube atrophy involved activation of the non-canonical NFĸB pathway and was dependent on NFκB-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatin M (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatin M receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R–NIK signalling mediates cancer-associated muscle atrophy in an OSM–OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss. Gene expression analysis in muscle tissues showed upregulation of ectodysplasin A2 receptor in tumour-bearing mice and patients with cachectic cancer, and thus therapeutic targeting of relevant pathways may be beneficial in prevention of muscle loss.

Key Points Muscle atrophy frequently complicates the course of chronic kidney disease (CKD) and is associated with excess morbidity and mortality CKD-induced mechanisms that cause muscle atrophy include activation of the ubiquitin–proteasome system, caspase-3 and myostatin Triggers that activate proteolysis in CKD include metabolic acidosis, defects in insulin/insulin-like growth factor 1 (IGF-1) intracellular signalling, inflammation and catabolic responses to microRNAs Current strategies aimed at preventing muscle atrophy include correction of acidosis plus exercise; specific therapies that inhibit myostatin or signal transducer and activator of transcription 3 (Stat3) are being developed Muscle atrophy frequently complicates the course of chronic kidney disease (CKD) and is associated with excess morbidity and mortality. In this Review, the authors describe how CKD stimulates catabolic pathways that interfere with cellular protein metabolism and discuss how knowledge of these pathways might enable the development of therapies to block muscle wasting in catabolic conditions. In patients with chronic kidney disease (CKD), loss of cellular proteins increases the risks of morbidity and mortality. Persistence of muscle protein catabolism in CKD results in striking losses of muscle proteins as whole-body protein turnover is great; even small but persistent imbalances between protein synthesis and degradation cause substantial protein loss. No reliable methods to prevent CKD-induced muscle wasting currently exist, but mechanisms that control cellular protein turnover have been identified, suggesting that therapeutic strategies will be developed to suppress or block protein loss. Catabolic pathways that cause protein wasting include activation of the ubiquitin–proteasome system (UPS), caspase-3, lysosomes and myostatin (a negative regulator of skeletal muscle growth). These pathways can be initiated by complications associated with CKD, such as metabolic acidosis, defective insulin signalling, inflammation, increased angiotensin II levels, abnormal appetite regulation and impaired microRNA responses. Inflammation stimulates cellular signalling pathways that activate myostatin, which accelerates UPS-mediated catabolism. Blocking this pathway can prevent loss of muscle proteins. Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications.

Diaphragm weakness is highly prevalent in critically ill patients. It may exist prior to ICU admission and may precipitate the need for mechanical ventilation but it also frequently develops during the ICU stay. Several risk factors for diaphragm weakness have been identified; among them sepsis and mechanical ventilation play central roles. We employ the term critical illness-associated diaphragm weakness to refer to the collective effects of all mechanisms of diaphragm injury and weakness occurring in critically ill patients. Critical illness-associated diaphragm weakness is consistently associated with poor outcomes including increased ICU mortality, difficult weaning, and prolonged duration of mechanical ventilation. Bedside techniques for assessing the respiratory muscles promise to improve detection of diaphragm weakness and enable preventive or curative strategies. Inspiratory muscle training and pharmacological interventions may improve respiratory muscle function but data on clinical outcomes remain limited.

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Sarcopenia (severe muscle depletion) is a prevalent muscle abnormality in patients with cirrhosis that confers poor prognosis both pre- and post-liver transplantation. The pathogenesis of sarcopenia is multifactorial and results from an imbalance between protein synthesis and breakdown. Nutritional, metabolic, and biochemical abnormalities seen in chronic liver disease alter whole body protein homeostasis. Hyperammonemia, increased autophagy, proteasomal activity, lower protein synthesis, and impaired mitochondrial function play an important role in muscle depletion in cirrhosis. Factors including cellular energy status, availability of metabolic substrates (e.g., branched-chain amino acids), alterations in the endocrine system (insulin resistance, circulating levels of insulin, insulin-like growth factor-1, corticosteroids, and testosterone), cytokines, myostatin, and exercise are involved in regulating muscle mass. A favored atrophy of type II fast-twitch glycolytic fibers seems to occur in patients with cirrhosis and sarcopenia. Identification of muscle biological abnormalities and underlying mechanisms is required to plan clinical trials to reverse sarcopenia through modulation of specific mechanisms. Accordingly, a combination of nutritional, physical, and pharmacological interventions might be necessary to reverse sarcopenia in cirrhosis. Moderate exercise should be combined with appropriate energy and protein intake, in accordance with clinical guidelines. Interventions with branched chain amino acids, testosterone, carnitine, or ammonia-lowering therapies should be considered individually. Various factors such as dose, type, duration of supplementations, etiology of cirrhosis, amount of dietary protein intake, and compliance with supplementation and exercise should be the focus of future large randomized controlled trials investigating both prevention and treatment of sarcopenia in this patient population.

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.

Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein degradation such as the ubiquitin proteasome system and dysregulated autophagy. Furthermore, it is characterized by the preferential loss of myosin, a distinct feature of the condition. While many risk factors for ICUAW have been identified, effective interventions to offset these changes remain elusive. In addition, our understanding of the mechanisms underlying the long-term, sustained weakness observed in a subset of patients after discharge is minimal. Herein, we discuss the various proposed pathways involved in the pathophysiology of ICUAW, with a focus on the mechanisms underpinning skeletal muscle wasting and impaired contractility, and the animal models used to study them. Furthermore, we will explore the contributions of inflammation, steroid use, and paralysis to the development of ICUAW and how it pertains to those with the corona virus disease of 2019 (COVID-19). We then elaborate on interventions tested as a means to offset these decrements in muscle function that occur as a result of critical illness, and we propose new strategies to explore the molecular mechanisms of ICUAW, including serum-related biomarkers and 3D human skeletal muscle culture models.

Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin–proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo . Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.