Sarcopenia in chronic liver disease: mechanisms and countermeasures

Abstract

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with cirrhosis and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and posttransplant complications. In chronic liver disease (CLD), sarcopenia is most commonly defined through the measurement of the skeletal muscle index of the third lumbar spine. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover, which likely occurs due to a decrease in muscle protein synthesis and an elevation in muscle protein breakdown. This imbalance is assumed to arise due to several factors including accelerated starvation, hyperammonemia, amino acid deprivation, chronic inflammation, excessive alcohol intake, and physical inactivity. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to mitochondrial dysfunction and an increase in myostatin expression. Currently, the use of nutritional interventions such as late-evening snacks, branched-chain amino acid supplementation, and physical activity have been proposed to help the management and treatment of sarcopenia. However, little evidence exists to comprehensively support their use in clinical settings. Several new pharmacological strategies, including myostatin inhibition and the nutraceutical Urolithin A, have recently been proposed to treat age-related sarcopenia and may also be of use in CLD. This review highlights the potential molecular mechanisms contributing to sarcopenia in CLD alongside a discussion of existing and potential new treatment strategies.

INTRODUCTION

Loss of skeletal muscle mass, quality, and strength, defined as sarcopenia, is a key component of malnutrition in cirrhosis (1, 2). The term “sarcopenia” was first proposed in 1989 to describe an age-related loss of muscle mass (3) but is now widely used to describe a loss of muscle mass and strength that occurs due to causes other than aging, including chronic inflammatory disease states (4). In contrast, the term cachexia is also used to describe a metabolic syndrome, which is associated with loss of muscle mass, with or without the presence of fat loss (5). Although the term cachexia has been linked with malnutrition within liver cirrhosis, the vast range of literature chooses to focus on the incorporation of the term sarcopenia. The prevalence of sarcopenia within patients with chronic liver disease (CLD) is estimated at ∼25%–70%, with higher rates identified among males (6). The presence of sarcopenia imposes significant clinical complications and has been associated with increased mortality (7), reduced quality of life (QoL) (8), increased length of hospital stays (9), and development of complications such as infections, both pre- and postliver transplant (LT) (10). Ultimately, sarcopenia inflicts a significant economic burden with increased health-care costs in patients with sarcopenic awaiting LT in comparison with patients with no sarcopenia (11).

Despite the known clinical problems associated with sarcopenia, the mechanisms that contribute to the development of this condition are still poorly understood. Current hypotheses suggest that a state of accelerated catabolism (12), hyperammonemia (13), and physical inactivity (14) may underpin impairments in muscle protein turnover. Specifically, these factors are thought to lead to a decrease in muscle protein synthesis (MPS) and an increase in muscle protein breakdown (MPB), although conclusive evidence is lacking (15). It is thus perhaps unsurprising that there are limited effective therapies to counteract sarcopenia in patients with CLD (15). To date, most treatment options have focused on supporting muscle anabolism through the use of physical activity (16) and nutritional interventions such as late-evening snacks (LES) and branched-chain amino acid (BCAA) supplementation (17). Therefore, this review provides an overview of the current understanding of sarcopenia in CLD, with a particular focus on liver cirrhosis and the molecular mechanisms potentially involved. We will also discuss the merits of current and emerging interventions to target sarcopenia.

DIAGNOSIS OF SARCOPENIA IN CHRONIC LIVER DISEASE

In age-related sarcopenia, the criteria for diagnosis have been agreed in Europe by the European Working Group on Sarcopenia in Older People (EWGSOP) (4). These criteria, updated in 2019, now include low muscle strength as the primary criterion, with low muscle quantity or quality and low physical performance as additional qualifying criteria (1). The presence of all three defines severe sarcopenia. Within CLD, there are currently no standardized definitions or cutoff values specific to liver-related sarcopenia (18). This is likely a consequence of the significant heterogeneity in the methods utilized to assess and define sarcopenia (Table 1) (18). This variability generates a major challenge and a degree of uncertainty that limits the assessment of sarcopenia in routine clinical care (19). Furthermore, many retrospective studies that have investigated the prevalence of sarcopenia only utilize one measure of sarcopenia, most commonly the measurement of muscle mass (10), potentially underestimating the prevalence and severity in this patient group.

Table 1.

Overview of modes used to assess sarcopenia in CLD

	Mode of Assessment
Prescreen assessment	SARC-F Questionnaire
Muscle mass	MAMC, DEXA, BIA, Ultrasound, CT, MRI
Muscle strength	HGS, isokinetic dynamometry
Physical performance	SPPB, gait speed, Timed Up and Go, 6MWD, CPET, LFI

BIA, bioelectrical impedance analysis; CLD, chronic liver disease; CPET, cardiopulmonary exercise test; CT, computed tomography; DEXA, dual-energy X-ray absorptiometry; HGS, handgrip strength; LFI, liver frailty index; MAMC, midarm muscle circumference; MRI, magnetic resonance imaging; 6MWD, 6-minute walk distance; SARC-F, simple five-item questionnaire; SPPB, short physical performance battery.

The most common measure of muscle mass in patients with CLD is the skeletal muscle mass index (SMI) of the third lumbar vertebrae (L3), imaged through computed tomography (CT) (15). Although SMI incorporates the measure of the psoas, paraspinal, and abdominal muscles at L3, the measurement of psoas muscle index (PMI) also obtained through CT imaging may be used (20, 21). Although CT scans are expensive and irradiating, abdominal imaging is often completed in the routine assessment of transplant candidates and cancer screening (7, 20), thereby allowing identification of sarcopenia without the need for additional imaging. However, the application of SMI in a clinical setting remains limited due to a lack of standardized definitions and sex-specific cutoff values. Nonetheless, recent work by Carey et al. (22) sought to generate specific SMI cutoff values for sarcopenia in patients with CLD. The authors reported these cutoffs as <50 cm²/m² and <39 cm²/m² in men and women with CLD, respectively. Importantly, these cutoff values were shown to correlate with LT waitlist mortality (22) and are considered to be the most robust definition of sarcopenia within patients with CLD to date (18). In contrast, when compared with the use of SMI, the use of PMI was unable to identify LT list patients with a higher mortality risk (20).

As mentioned earlier, the latest EWGSOP update shows appreciation of the importance of muscle strength and physical performance (1). As a result, the use of self-reported questionnaires that evaluate aspects of sarcopenia such as the simple five-item questionnaire (SARC-F) can be used to screen for the risk of sarcopenia development (23). The SARC-F incorporates questions that evaluate an individual’s muscle strength, ability to walk, rise from chairs, climb stairs, and the incidence of falls and has shown to be a valid assessment of sarcopenia risk (23). Additionally, high SARC-F scores have been more frequently identified with the progression of CLD (24). After the risk of sarcopenia has been identified, further assessment of muscle strength should be conducted. The use of handgrip strength (HGS) assessment has been identified as a key, reproducible measure of sarcopenia and is now typically incorporated in clinical assessments (25). HGS forms part of the recommended diagnostic criteria for patients with liver failure in both the European Association for the Study of Liver (EASL) and the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines (25, 26). HGS is seen as a valuable tool as it is a quick, validated, and cost-effective measure of muscle strength, which can be conducted at the bedside in patients with CLD, and correlates with mortality (27). In addition to muscle strength, measures of physical performance, and muscle function, including the 6-min walk distance (6MWD) (28), the short physical performance battery test (SPPB) (29), and gait speed (30) are all practical as a measure of sarcopenia in CLD. In patients with cirrhosis awaiting liver transplantation, a distance of <250 m achieved within the 6MWD (28) and each 1-unit decrease in SPPB score (29) are associated with an increase in mortality risk, while a reduced gait speed is associated with an increased risk of complications, such as hepatic encephalopathy (HE), gastrointestinal bleeding, and infections (30).

CLINICAL IMPACT OF SARCOPENIA WITHIN CHRONIC LIVER DISEASE

Sarcopenia has consistently been identified as a predictor of mortality risk, both pre-LT (7, 31) and post-LT (21). It has been shown that the addition of sarcopenia to the model for end-stage liver disease (MELD) scoring system improves the predictive accuracy of mortality, particularly in patients with MELD scores below 15 (31). Sarcopenia is also associated with several poor clinical outcomes including a risk of decompensation (32), HE (33), increased risk of infection (i.e., sepsis) (6, 7, 10), duration of mechanical ventilation, duration of hospital admission, and length of admission to intensive care post-LT (9, 34). It is therefore unsurprising that patients with sarcopenic have increased hospital costs in comparison to those associated with nonsarcopenic patients (11).

Although sarcopenia has clear implications for overall health outcomes, it is also associated with a reduction in QoL in patients with liver cirrhosis (8). Recent research found that patients with CLD with “presarcopenia,” defined as a loss of muscle mass without subsequent decreases in muscle strength and performance (4), experience greater reductions in QoL in comparison with patients with CLD without sarcopenia (8). One of the most frequently reported symptoms of CLD is sleep disturbance (35), which can have a large impact upon many aspects of QoL including fatigue (36). Sleep disturbances are often associated with the presence of HE and are believed to cause CLD owing to several mechanisms, which include alterations in the metabolism of melatonin and glucose (37) and disturbances to the intestinal microbiome (36). However, it is largely unclear whether the poor QoL identified within patients with CLD is because of muscle loss or functional disabilities (8). Furthermore, it is possible that factors such as clinical characteristics, disease severity, and cirrhosis-specific complications also contribute to reductions in QoL (38).

Although LTs are thought to reverse complications such as ascites and portal hypertension, sarcopenia may remain, or even worsen, post LT (39, 40). Indeed, previous research identified the presence of post-LT sarcopenia in both individuals with and without pre-LT sarcopenia, whereas only 6.1% of patients experienced a reversal of sarcopenia post LT (40). Alongside changes in muscle mass, patients often experience an increase in body weight post LT (39). This is largely attributed to an increase in fat mass (41), and a slower, incomplete restoration of muscle mass (39). These changes are thought to closely resemble the onset of sarcopenic-obesity, identified frequently in nonalcoholic fatty liver disease (NAFLD) (42). Collectively, current data highlight the need for better nutritional and functional assessment and the implementation of interventions before and after LT to reduce sarcopenia.

MECHANISMS OF MUSCLE LOSS IN CHRONIC LIVER DISEASE

Alterations in Muscle Protein Turnover and Anabolic Resistance

Skeletal muscle protein exists in a constant state of turnover, with simultaneous synthesis and breakdown (43). Alterations in muscle protein turnover occur daily owing to a number of environmental stimuli, such as the ingestion of dietary protein (44) and physical activity (45). These alterations in muscle protein turnover contribute to changes in net protein balance (NPB), whereby muscle loss may occur when MPB is greater than MPS, and muscle growth may occur when MPS is greater than MPB (43). Although protein ingestion alone can be sufficient to maintain muscle mass within young, healthy individuals (43), the combination of exercise and protein ingestion can synergistically augment MPS (46) (Fig. 1).

Figure 1.

Schematic representation of muscle protein turnover in response to anabolic stimuli (protein feeding with/without exercise) in healthy and chronic liver disease (CLD). A: we hypothesize that the primary reason for muscle loss in patients with CLD is blunted muscle protein synthesis (MPS) in response to protein ingestion that coincides with an increase in muscle protein breakdown (MPB). This likely equates to a reduction in net protein balance (NPB) within patients with CLD, in response to proposed alterations in muscle protein turnover. B: exercise in combination with protein ingestion may however partially restore the MPS response within patients with CLD patients.

Muscle protein turnover is regulated by several key molecular pathways, including the mechanistic target of rapamycin complex one (mTORC1) signaling cascade, satellite cell (SC) signaling, and the ubiquitin-proteasome pathway (UPP) (Fig. 2). mTORC1 is a critical serine/threonine protein kinase (47), which is activated by many factors including amino acids, growth factors, e.g., IGF-1, energy status, and mechanical stress (48). This subsequently leads to the phosphorylation of two key effectors eIF4E-binding protein 1 (4EBP1) and protein S6 kinase 1 (p70S6K1) (47). Additionally, SC plays a key role in the growth, repair, and regeneration of muscle fibers and is regulated by several growth factors such as IL-6, IGF-1, and myostatin (49–51). Several factors contribute to MPB including inflammation, inactivity, mitochondrial dysfunction, and myostatin. Myostatin is thought to inhibit MPS through the inhibition of the IGF/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTORC1 pathway and SCs (51–53). Additionally, myostatin has been suggested to activate the UPP, contributing to an increase in MPB, resulting in negative protein balance (52). However, the activation of Akt and inhibition of the transcription factor Forkhead box O (FOXO) can prevent the activation of the ubiquitin ligases, muscle RING finger-1 (MuRF-1), and muscle atrophy box (MAFbx) (54).

Figure 2.

Molecular regulation of muscle protein turnover. Muscle protein synthesis is regulated by several signals including energy status, amino acids, and growth factors, for example, insulin growth factor-1 (IGF-1). This leads to the activation of phosphoinositide 3-kinase (PI3K). Protein kinase B (Akt) regulates muscle protein turnover through the activation of mammalian target of rapamycin complex 1 (mTORC1) and inhibition of Forkhead box O (FOXO). In turn, the activation of mTORC1 leads to the phosphorylation of translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase (p70S6K) that contribute to muscle protein synthesis. Muscle protein breakdown can be activated by inflammatory cytokines, for example, tumor necrosis factor-α (TNF-α), which subsequently leads to the activation of nuclear factor-κB (NF-κB), myostatin, and the ubiquitin ligase Muscle RING finger-1 (MuRF-1). Furthermore, activation of the ubiquitin proteasome pathway through FOXO can increase MuRF-1 and muscle atrophy-box (MAFbx).

It is hypothesized that those suffering from CLD have a dysregulated muscle protein turnover that underpins the progression of sarcopenia (Fig. 1). Indeed, initial studies investigating muscle protein turnover in patients with cirrhosis suggested that protein synthesis may be lower in comparison with healthy controls when using arteriovenous (AV) balance and whole body tracer methodologies (55–57). However, for whole body protein breakdown (WbPB), previous work has yielded conflicting results, with different studies reporting that MPB rates in patients with cirrhosis increased, decreased, or even remained unaltered (57–60). These inconsistent findings are likely due to a range of factors including differences in methodology and patient characteristics such as age, severity of CLD, and disease etiology (15).

However, it is known that in age-related sarcopenia, a phenomenon known as muscle “anabolic resistance” is present, referring to a blunted MPS response to the ingestion of amino acids (61), or exercise (62), in comparison with young individuals. It has been proposed that patients with cirrhosis experience a similar state of muscle anabolic resistance (17), but to the best of our knowledge, no study has investigated the MPS response to the ingestion of protein or exercise stimuli in patients with CLD. The absence of such studies may be due to concerns relating to obtaining muscle biopsy samples from patients with CLD, owing to the perceived elevated risks related to platelet dysfunction, coagulopathy, and thrombocytopenia (63). However, more recently, muscle biopsies have been shown to be safe in patients with Child-Pugh class A cirrhosis (63), which will therefore enable a greater understanding of the dysregulation in muscle protein turnover that underpins muscle wasting in patients with CLD.

Hyperammonemia

Hyperammonemia is a consistent abnormality in patients with cirrhosis caused by hepatocellular dysfunction, portosystemic shunting, and impaired ureagenesis, which in turn results in the increased concentration of ammonia within skeletal muscle (64, 65). The increased uptake of ammonia by skeletal muscle has been proposed as a protective mechanism in CLD, with the aim of preventing ammonia neurotoxicity (13, 64). The specific mechanism driving the increased uptake of ammonia is currently unknown, although it has been suggested that the expression of the ammonia transporters, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg) may both play a role (66). However, the resultant accumulation of ammonia is not without consequence and may contribute to the development of sarcopenia (13, 67, 68) (Fig. 2) thus reducing the muscle mass available to remove excess ammonia.

Mechanistically, in vitro experiments have shown that hyperammonemia-induced activation of NF-κB is associated with an increase in myostatin expression, an inhibitor of myogenesis, and a reduction in myotube diameter (13). In patients with cirrhosis, skeletal muscle hyperammonemia was also associated with an increase in myostatin expression and activation of NF-κB, resulting in impaired MPS, increased autophagy, and a reduction in skeletal muscle mass (13, 68–70). Therefore, hyperammonemia is considered a key regulator in the liver-muscle axis (13).

The elevated myostatin expression in patients with cirrhosis is thought to be one of the key drivers of muscle anabolic resistance (70), as it is associated with a reduction in p70S6K, s6 protein, and 4EBP1 protein content, indicating an impaired activation of the mTORC1 pathway that is critical in the regulation of MPS (63). This result is consistent with in vivo data, suggesting that myostatin inhibits MPS via impaired Akt signaling and subsequently reduces MPS via the Akt/mTOR/p70S6K pathway (53). Myostatin may also influence MPS through the impairment of SC function. In a portacaval anastomosis (PCA) rat model, myostatin expression was threefold higher than in control rats and was associated with a decline in SC function mediated via a reduction in myogenic transcription factors myoD, myf5, and myogenin (67, 71). In addition, hyperammonemia-induced upregulation of myostatin may contribute to a reduction in skeletal muscle mass through an increase in MPB. Patients with cirrhosis have been shown to exhibit increased WbPB, alongside an increase in the expression of myostatin, Beclin1, P62 degradation, and LC3 lipidation, representing an increase in autophagy compared with healthy adults (63). However, this increase in WbPB and autophagy occurred with no change in ubiquitinated proteins or MuRF1 mRNA at baseline, or after BCAA/leucine ingestion in healthy control and patients with cirrhosis (63, 68, 71). Collectively, this suggests that hyperammonemia-induced increases in MPB may largely occur through changes in autophagy rather than the UPP.

Hyperammonemia may also contribute to a decrease in MPS through mitochondrial dysfunction. Anaplerosis is the first reaction in the tricarboxylic acid (TCA) cycle, whereby glutamine and glutamate are converted to α-ketoglutarate (α-KG) and ammonia (72). This reaction is catalyzed by the enzyme glutamate dehydrogenase (GDH) (72), and under physiological conditions, this reaction is favored as GDH has a low affinity for ammonia, resulting in the conversion of glutamate to α-KG (73). However, owing to the high concentrations of ammonia present in the skeletal muscle of patients with cirrhosis; it is likely that cataplerosis, that is, the removal of TCA intermediates (72), may be favored and in turn cause a reduction in α-KG availability and impaired mitochondrial function (13, 15). The consequence of reduced TCA cycle intermediates is a reduction in ATP synthesis (74), which may contribute to a reduction in MPS, as translation initiation is an energy-intensive process (15). However, hyperammonemia has also been found to increase reactive oxygen species (ROS) and oxidative damage in both rats and humans (74). These data suggest that ROS may overwhelm the adaptive antioxidant defense systems and in turn lead to muscle loss and tissue injury (74). Thus, hyperammonemia may influence mitochondrial functioning through impairments in TCA cycle metabolism, oxidative damage, and, consequently, a decrease in cellular energy status and subsequently MPS. However, this remains to be clearly demonstrated.

Energy Expenditure and Amino Acid Availability in Chronic Liver Disease

Cirrhosis is associated with an accelerated state of starvation (12). An overnight fast has been shown to accelerate fat oxidation, gluconeogenesis, ketogenesis, and a catabolic state in patients with cirrhosis compared with healthy individuals (12, 75). Because of the increased gluconeogenesis, amino acids are often utilized as an energy source (12, 76), resulting in a low concentration of skeletal muscle BCAA in patients with cirrhosis (77). In response to a state of cellular stress, such as amino acid deprivation, an integrated stress response (ISR) is activated to promote the restoration of cellular homeostasis (78) (Fig. 3). In a state of amino acid deficiency, the ISR is mediated through the activation of general control nondepressed 2 (GCN2), an amino acid deficiency sensor (79). This leads to the phosphorylation of eukaryotic initiation factor 2 (eIF2α), which subsequently, causes a reduction in global protein synthesis and an increase in activating transcription factor 4 (ATF4) mRNA, thus reducing the requirement for amino acids (79, 80). The activation of ATF4 leads to the inhibition of mTORC1 signaling and promotes autophagy in an attempt to restore and preserve levels of amino acids (78). Once this balance has been restored, ATF4 signaling contributes to the dephosphorylation of eIF2α, restoring normal levels of protein synthesis (81).

Figure 3.

The proposed molecular alterations that contribute to ammonia-induced changes in muscle protein turnover. Ammonia enters the skeletal muscle through the Rhcg/Rhbg receptors. Subsequently, ammonia contributes to mitochondrial dysfunction, an impaired integrated stress response, and activation of myostatin. These contribute to an impairment in protein turnover and sarcopenia. 4EBP1, translation initiation factor 4E-binding protein 1; eIF2α, eukaryotic initiation factor 2α; IGF-1, insulin growth factor 1; MAFbx, muscle atrophy-box; mTORC1, mammalian target of rapamycin complex 1; MuRF1, muscle RING finger-1; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; p70S6K, ribosomal protein S6 kinase; Rhbg, Rh B glycoprotein; Rhcg, Rh C glycoprotein; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; TCA cycle, tricarboxylic acid cycle; α-KG, α ketoglutarate.

Patients with cirrhosis display increased GCN2 activation and eIF2α phosphorylation alongside a reduction in mTORC1 signaling, similar to the ISR seen in response to intracellular amino acid deficiency (63, 69). However, hyperammonemia induces a state of cellular stress, which impairs the ISR by preventing an increase in ATF4 mRNA (69). This failure to induce an increase in ATF4 mRNA may contribute to a further decline in MPS and an increase in autophagy, owing to the inability to terminate the ISR and return to normal levels of protein synthesis (69, 78). Therefore, patients with cirrhosis have been suggested to experience an adaptive ISR, in which a second pathway is activated in response to increased ammonia concentrations (69) (Fig. 3). This second signaling pathway appears to be mediated by SLC7A5/LAT1, an amino acid transporter, which is increased in patients with cirrhosis (63, 69). SLC7A5/LAT1 appears to act as an amino acid exchanger, resulting in an increase in l-leucine uptake (63, 69). This increase in l-leucine concentration is thought to occur to utilize this amino acid to generate acetyl-CoA within the mitochondria, to generate an increase in energy output (82). Under normal conditions, the transport of leucine relies on glutamine transport via the glutamine exchanger SLC38A2 (83), but under a state of hyperammonemia, glutamine is primarily utilized for the detoxification of ammonia (69, 82). Taken collectively, the activation of the ISR in patients with cirrhosis results in an impairment in mTORC1 signaling and an increase in autophagy (63, 69), which may contribute to the development of sarcopenia.

Alcohol and Chronic Liver Disease

Both alcohol intake and CLD are believed to contribute to sarcopenia in alcohol-related liver disease (ArLD) (84). Therefore, it is often challenging to distinguish between the specific effects of CLD and that of alcohol. Although ethanol is primarily metabolized within the liver and the brain, it can also be metabolized within skeletal muscle (85, 86). ArLD is frequently associated with a reduction in skeletal muscle mass, alongside alterations in muscle protein turnover (86) and ethanol can inhibit mTORC1 stimulation (87). Furthermore, excessive alcohol intake has been linked to increased myostatin, which is assumed to mediate impairments in MPS (86, 88). Nonetheless, markers of the UPP remain unaltered in animal models of ArLD and are decreased in human ArLD patients, suggesting that autophagy is likely responsible for an increase in MPB (86). Similar to in hyperammonemia, ethanol may also contribute to reductions in MPS through impairment of mitochondrial function, resulting in the generation of ROS and activation of autophagy (89). In turn, the above may impair MPS through a reduction in ATP generation and mRNA translation (84).

Abnormalities in Endocrine Function

CLD is associated with several endocrine abnormalities that could contribute to sarcopenia, including low serum testosterone (90). In male patients with cirrhosis, low levels of testosterone may arise because of changes in the hypothalamic-pituitary-gonadal axis (91). This can lead to a decrease in testosterone production and an increase in aromatase activity, an enzyme responsible for the conversion of testosterone to estradiol, similar to that seen in aging males (92) and PCA rats (93). PCA rats exhibit lower levels of testosterone alongside a reduced growth rate, attributed to a reduction in food intake and efficiency, calculated as the increase in body weight per gram of food eaten (93). Inhibition of aromatase in this model led to an increase in testosterone and improved body weight, alongside improvements in food intake and efficiency (93). However, further research is required in patients with cirrhosis to confirm this relationship.

CLD is also associated with an increase in the secretion of growth hormone (GH) and a reduction in serum IGF-1 concentration (94), a change also seen in human aging. IGF-1 can promote muscle growth through the activation of the Akt/PI3K/mTORC1 signaling cascade, which leads to an increase in MPS (95, 96). Furthermore, IGF-1 also contributes to a reduction in muscle atrophy through the activation of Akt and inhibition of the transcription factor FOXO, in turn preventing the activation of the ubiquitin ligases MuRF-1 and MAFbx (54). GH has been associated with an increase in myostatin expression and impairments in IGF-1 signaling and therefore may further contribute to impairments in MPS (94, 97). Again, the relative contribution of changes in the GH/IGF-1 axis to sarcopenia in CLD remains poorly understood (15).

Nonalcoholic Fatty Liver Disease and Obesity

NAFLD is currently predicted to be the most common cause of CLD, with an estimated global prevalence of ∼25% (98). NAFLD is an umbrella term used to describe the spectrum of disease from nonalcoholic fatty liver (NAFL), identified through the presence of ≥5% steatosis, to nonalcoholic steatohepatitis (NASH) and cirrhosis (99, 100). In contrast, progression to NASH is characterized by the presence of hepatic steatosis alongside inflammation and hepatocellular injury with or without the presence of fibrosis, this, in turn, may lead to the development of cirrhosis and hepatocellular carcinoma (HCC) (99, 100). NAFLD is a growing cause of CLD, largely attributed to the increase in the incidence of obesity (101). However, obesity within this cohort may occur alongside the development of sarcopenia (sarcopenic obesity) (102). There are several risk factors associated with the development of both NAFLD and sarcopenia, with physical inactivity, insulin resistance, and chronic inflammation believed to play key roles (103). It is therefore unsurprising that NAFLD and sarcopenia are typically associated with increased sedentary behavior, alongside a reduction in physical activity (104, 105). Unfortunately, this physical inactivity likely contributes to an increased risk of metabolic syndrome due to an increase in visceral fat accumulation and insulin resistance (106).

A state of insulin resistance may directly lead to the development of sarcopenia through an increase in MPB and a decrease in MPS. Insulin resistance in adipose tissue stimulates lipolysis and the release of free fatty acids (FFAs) to the liver (107, 108). In turn, FFA inhibits IGF-1 signaling, which subsequently impairs PI3K/Akt signaling (109) and reduces MPS (110) (Fig. 4). Impairments in Akt signaling increase FOXO1 phosphorylation, which activates the UPP, leading to an increase in MAFbx and MuRF1 expression (109, 110). Combined, these alterations in protein turnover are thought to contribute to the muscle loss identified in type 2 diabetes (110). Therefore, increased insulin resistance may cause similar effects in patients with CLD with a NAFLD etiology. Insulin resistance also leads to the development of hyperinsulinemia within hepatocytes, which can contribute to a decrease in gluconeogenesis, an increase in lipogenesis, and inhibition of β-oxidation (107, 108). This leads to the accumulation of lipids within liver and muscle, termed myosteatosis (108, 110). Obesity and a reduction in muscle quality, calculated as the ratio of muscle strength to muscle mass, are often associated with the development of insulin resistance and a reduction in muscle mass and strength (111, 112). Furthermore, sarcopenia likely contributes to the development of insulin resistance, independent of obesity, as skeletal muscle is the primary tissue facilitating the uptake of glucose mediated by insulin (113). This suggests that the pathology of NAFLD and that of sarcopenia are closely intertwined (107).

Figure 4.

The molecular regulation of muscle protein synthesis and muscle protein breakdown in chronic liver disease (CLD). The mammalian target of rapamycin complex 1 (mTORC1) can be activated in response to the activation of insulin growth factor-1 (IGF-1), which leads to the activation of protein kinase B (Akt), and inhibited through general control nondepressed 2 (GCN2), activated by a reduction in amino acids (AAs) and ammonia. mTORC1 activation leads to the activation of translation initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase (p70S6K). Akt regulates FOXO, and the subsequent activation of muscle atrophy-box (MAFbx) and Muscle Ring Finger-1 (MuRF-1). Inflammatory cytokines, for example, tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) activate, leading to the activation of myostatin. Myostatin results in an increase in autophagy and inhibition of satellite cells. FOXO, Forkhead box O.

Chronic inflammation and oxidative damage are also important factors associated with the development of CLD (114) and sarcopenia (115). NAFLD is associated with an accumulation of FFAs and increased adiposity, which contribute to an increase in proinflammatory cytokines (116–118). Adipose tissue contains immune cells such as macrophages and also senescent cells, which are highly proinflammatory (119). In addition, adipose tissue produces its own cytokines, termed adipokines, which can also contribute to an increased inflammatory status (120). One key cytokine, TNF-α, appears to have a significant role in the impairment of muscle protein turnover within CLD (121, 122). In rats, TNF-α impairs MPS through a reduction in the phosphorylation of key signaling proteins involved in the mTORC1 pathway, such as eIF-4E (121). In addition, in vitro work has shown that TNF-α may increase MPB through an increase in UPP activity, as shown by an increase in atrogin-1 expression (122, 123). Further in vitro work has shown that TNF-α-induced MPB is thought to arise through an increase in type 1 TNF-$\mathrm{\alpha }$ receptor (TNFR-1) binding and consequently an increase in ROS, which leads to the subsequent activation of NF-κB (122, 124). An increase in NF-κB signaling enhances protein degradation through the activation of the UPP, reduction of myogenesis, and a further increase in inflammation (122, 125). This increase in proinflammatory cytokines may further contribute to the development of NAFLD and muscle loss (115, 126). Together, this suggests that an increase in circulating proinflammatory cytokines, in particular TNF-α, may contribute to a reduction in MPS and an increase in MPB.

Adiponectin

Adiponectin is an adipokine that plays an integral role in the regulation of glucose metabolism and oxidation of fatty acids in an insulin-dependent manner (127). In skeletal muscle, adiponectin binds to adiponectin receptor I (AdipoR1), which is responsible for the regulation of insulin sensitivity and fatty acid oxidation (128, 129). Therefore, a reduction in circulating levels of adiponectin as seen in obesity (130) may contribute to impairments in muscle protein turnover because of insulin resistance (131). In obese individuals, myostatin expression is positively associated with a state of insulin resistance (132). Therefore, this increase in myostatin is believed to contribute to muscle wasting through impairments in mTORC1 signaling and increased autophagy, as discussed previously (13, 53, 68). Therefore, it is plausible to suggest that cross talk between myostatin and adiponectin exists and warrants further investigation in CLD and NAFLD (107, 131).

Vitamin D

Vitamin D deficiency has been shown to contribute to insulin resistance, metabolic syndrome, and NAFLD (133, 134). Evidence from animal models of NAFLD suggests that rats fed a vitamin D-deficient Western diet experienced an increase in NAFLD activity, inflammation, and oxidative stress in comparison with those fed a vitamin D-replete Western diet (135). Thus, vitamin D deficiency may exacerbate NAFLD severity partly through an inflammatory-mediated mechanism (134). Vitamin D has also been suggested to contribute to an increased risk of age-related sarcopenia (136). In older individuals, low levels of vitamin D are independently associated with a greater risk of sarcopenia (136) and is thought to contribute to muscle loss through several mechanisms including a reduction in MPS, an increase in muscle atrophy, and mitochondrial dysfunction (137). However, it is currently unclear whether low 25-hydroxyvitamin D (25(OH)D) levels are a cause or a consequence of age-related sarcopenia (138). As patients with CLD experience vitamin D deficiency, similar to that identified within older sarcopenic individuals, it is possible that low levels of vitamin D contribute to the pathology of sarcopenia within these patients. However, patients with CLD often experience several fat-soluble vitamin deficiencies, including vitamin A, D, E, and K deficiencies, which are affected by malabsorption, impaired synthesis, and storage (139).

MANAGEMENT OF SARCOPENIA IN CLD: CURRENT AND EMERGING INTERVENTIONS

Although many complications associated with CLD such as ascites and encephalopathy can be treated by undergoing an LT, sarcopenia may develop, or be sustained, in patients post-LT (39, 40). Sarcopenia is commonly associated with adverse complications, but there are currently limited data, showing that improvements in muscle mass and strength improve survival both, before and after LT (15). Therefore, the management of sarcopenia in CLD and the treatment thereof is an urgent clinical priority. Inevitably, sarcopenia management in CLD requires a multifaceted approach including nutrition, exercise, and psychological and pharmacological interventions (25).

Nutrition

Patients with cirrhosis experience a persistent state of accelerated starvation, enhancing catabolism, in addition to a state of muscle anabolic resistance, resulting in blunted metabolic responses to anabolic stimuli such as nutritional intake (17). Furthermore, the daily intake of total calories, protein, and carbohydrates is consistently reported to be inadequate in ∼85%–95% of those undergoing assessment for LT, exacerbating malnutrition and more specifically, sarcopenia (140). International guidelines from the EASL and ESPEN suggest that nutritional interventions should include the optimal energy intake of 25–35 kcal/kg of dry body weight per day in well-compensated patients with cirrhosis, with a target protein intake of 1.2–1.5 g/kg of body weight per day (25, 26). However, stable patients with obesity should consider adopting a hypocaloric diet consisting of a 500–800 kcal/day caloric deficit while maintaining an optimal consumption of protein to promote the simultaneous reduction in adipose and maintenance of muscle mass, in conjunction with an exercise regime (25). In contrast, patients with decompensated cirrhosis require both an increased energy and protein intake, with an energy target of 35–40 kcal/kg and a protein target of 1.5–2 g/kg, respectively (25, 26).

To achieve the recommended energy intake, the consumption of more frequent meals and a late-evening snack (LES), consisting of 50 g of carbohydrate, are often recommended in patients with CLD owing to their accelerated state of starvation (25, 75). This accelerated catabolism may in turn contribute to the development of sarcopenia (17). Therefore, patients are advised to avoid prolonged periods of fasting through the ingestion of three main meals and three snacks (25). Because the most prolonged period of fasting occurs at night, an increased importance has been placed on the consumption of an LES and breakfast. The ingestion of a high-protein (21 g), high-calorie (500 kcal, 30% of daily calorie intake) breakfast has been shown to have beneficial effects on cognitive function (141).

Additionally, the consumption of BCAA as an LES has been shown to have several benefits, including improvements in QoL, nitrogen balance, respiratory quotient, carbohydrate utilization, and lean body mass (17, 142, 143). Recently, the use of BCAA supplementation as an LES in patients with cirrhosis has also been shown to improve HGS over a 24-wk intervention period (144). However, no change in body mass index (BMI) or lean body mass was identified, contradicting previous findings. The positive outcomes identified in response to short-term BCAA LES ingestion may be due to an increase in lipid utilization, amino acid availability, and reduction in gluconeogenesis, derived from the breakdown of protein in skeletal muscle (2, 17). This is consistent with indirect measures of MPS and MPB, which have shown an increase in nitrogen balance, alongside a reduction in urinary 3-methylhistidine (3-MH), a marker of MPB (17). This suggests that the ingestion of an LES and breakfast should be utilized to extend the time patients spend in a postprandial fed state, with implications for muscle mass maintenance. Although the consumption of BCAA as an LES is considered to be a safe and cost-effective intervention, potential adverse effects include esophageal reflux, increased insulin resistance, and disturbances in sleep cycle (17); therefore, the use of BCAA must be conducted with caution. As a result, future research should aim to investigate the ideal composition of LES, as there is little research comparing high carbohydrate foods against BCAA, alongside the effectiveness of LES and breakfast consumption at a molecular level.

It is important to note that malnourished patients with cirrhosis may be unable to achieve an adequate oral dietary intake of protein-rich whole foods often due to sickness and/or nausea. Therefore, to conserve lean body mass, the use of additional protein supplementation offers a practical method to allow individuals to reach the enhanced protein requirements in CLD (1.2 g to 1.5 g/kg of body weight per day) (25, 26). Protein intake can be achieved through the ingestion of whole foods, including both animal- and plant-based sources of protein (26). However, animal proteins are not recommended as a suitable protein source for patients with CLD, as they are rich in aromatic amino acids (AAAs). AAAs are not metabolized by the skeletal muscle and therefore may contribute to an increase in HE severity, due to the increase in associated ammonia (15, 145, 146). In comparison, vegetable proteins are rich in BCAA and may have a beneficial effect by removing one mole of ammonia per mole of BCAA (15). Nonetheless, adequate protein intake can still be difficult to achieve in patients with CLD and thus BCAA supplements can be utilized (63, 147). BCAA, in particular the essential amino acid leucine, is a potent stimulus for MPS, identified within both young (148) and older individuals (149). BCAA contributes to an increase in anabolic signaling through mTORC1 and its downstream targets 4EBP1 and p70S6K (150). Similarly, in patients with cirrhosis, supplementation of a BCAA solution rich in leucine (7.5 g leucine, 3.75 g l-isoleucine, and 3.75 g l-valine) has been shown to inhibit GCN2 activity, improve mTORC1 signaling, and decrease markers of autophagy, in comparison to presupplementation values (63). However, no change in myostatin expression or MPS was identified in response to the ingestion of BCAA (63). The authors later expanded upon these findings and found that the in vitro treatment of l-leucine can reverse the hyperammonemia-induced suppression of mTOR signaling and MPS, through the inhibition of GCN2 activity (69). However, further research investigating the effect of BCAA, in particular leucine, in this cohort is required due to the small sample size utilized in a previous mechanistic work (63).

Although BCAA supplementation appears to have beneficial molecular effects, previous research has shown that this approach did not improve intramuscular adipose tissue, or skeletal muscle mass, in patients with cirrhosis when given in the absence of exercise in patients who exhibited no changes in metabolic parameters (147). However, a decrease in adipose accumulation and maintenance of skeletal muscle mass was identified in patients who experienced improved glucose sensitivity (147). Work by Román et al. (151) demonstrated an increase in lower thigh circumference when 10 g/day of leucine was combined with 12 wk of moderate-intensity aerobic exercise training (AET), whereas no change was identified with the ingestion of leucine alone. This suggests that patients with CLD may experience a blunted MPS response to protein intake. Furthermore, this highlights the potential benefits of a combined nutritional and exercise intervention within patients with CLD. It is possible that resistance exercise training (RET), in combination with protein ingestion, may improve MPS within patients with CLD, as described in Fig. 1B. However, further research, which investigates the molecular adaptation in response to protein ingestion and exercise, is required within this population.

Following the optimization of oral intake and oral nutritional supplementation, the use of enteral or parenteral nutrition should be considered to counteract malnutrition and sarcopenia (25). Enteral feeding has been utilized in malnourished patients with cirrhosis admitted to hospital; however, studies have reported mixed results (152). ESPEN guidance strongly recommends the use of enteral feeding in those unable to meet nutritional requirements, with no increased adverse events identified (26). Previous work has shown improved clinical outcomes and a reduction in mortality, supporting the use of enteral feeding within patients with liver cirrhosis (153). Additionally, enteral feeding has been shown to improve nitrogen balance (154). Data on parental nutrition are less established and are only recommended as a method of nutrition when oral and enteral routes have been exhausted. The data regarding the composition of parental nutrition present conflicting results in patients with cirrhosis; however, it is likely to have a beneficial impact during prolonged periods of poor oral intake and improve the mental state in those with severe HE (155). However, in reality, added complications of total parental nutrition-induced liver damage and line-related complications, such as sepsis, make many clinicians hesitant to advocate parenteral nutrition in patients with CLD (156).

Exercise

Exercise is known to play an integral part in improving muscle mass and function in older patients with sarcopenia (157) and many other chronic diseases [e.g., cardiovascular, metabolic, pulmonary, and cancer (158)]. However, the safety of exercise interventions in treating frailty and sarcopenia in patients with CLD is unclear (16). Specifically, there are many considerations to be made including the potential for acute increases in ammonia, elevation of portal pressure, and potential risk of variceal bleeding during exercise (159, 160).

Nonetheless, to date, 11 studies have investigated the impact of exercise in patients with compensated and decompensated cirrhosis. These interventions reported improvements in QoL and key components of physical frailty demonstrated by improvements in muscle mass and function (161), V̇O₂ peak (162), and 6MWD (163). Exercise is typically divided into two predominant categories: AET that induces improvements in cardiovascular function and RET that is associated with improvements in muscle mass and strength (164). In patients with cirrhosis, two studies aimed to investigate the impact of 8 wk of AET (162, 163). Zenith et al. (162) identified that 8 wk of supervised moderate-intensity AET induced significant improvements in quadriceps muscle thickness, muscle fatigue, and VO₂ peak in patients with cirrhosis. Similarly, Kruger et al. (163) showed that a partially supervised 8-wk moderate-to-high intensity AET program also induced a significant increase in thigh muscle thickness and exercise capacity (identified as an increase in 6MWD) in patients with cirrhosis, in comparison with a control group receiving standard care. Importantly, no adverse events were identified throughout the duration of these interventions, suggesting that AET can be carried out safely in patients with cirrhosis (162, 163).

Despite the known benefits of RET on muscle mass and strength (157, 164), little research has been conducted in patients with CLD. However, Aamann et al. (161) recently conducted a 12-wk RET program consisting of seven whole body exercises that gradually progressed from 15 to 8 repetitions along with increasing load in patients with compensated cirrhosis. Improvements in whole body lean mass and strength of the knee extensors were observed in the RET group (161). However, no significant differences in QoL, assessed by short-form 36 (SF-36), were identified between trained and untrained individuals (161). This may be attributed to the absence of any significant effect of RET on physical function as measured by 6MWD. Additionally, it is currently unclear whether RET reduces the incidence of complications associated with cirrhosis, which could explain the failure to improve QoL (161).

Although only a limited number of studies have investigated the use of RET in patients with CLD, several have combined the use of AET and RET in patients with cirrhosis awaiting transplantation (165, 166). Debette-Gratien et al. (165) conducted a 12-wk adapted physical activity program which consisted of AET and RET twice weekly in 13 patients with cirrhosis awaiting LT. Following training, there was a significant increase in knee extensor strength, maximal power, and 6MWD. This result is in contrast to results of Aamann et al.’s study (161) who identified no such changes in 6MWD in response to the participation of RET alone. Therefore, the improvements in 6MWD identified within this study may be largely attributed to AET within a combined intervention. More recently, work by Williams et al. (166) investigated the effectiveness of a 12-wk home-based intervention consisting of daily step targets and functional body weight resistance exercises in 20 patients awaiting LT. The authors identified an improvement in SPPB scores, which suggests that patients experienced an improvement in overall function, which may be reflected through improvements in mobility. These findings suggest that RET improves skeletal muscle mass and strength. However, in patients with CLD, a concurrent training program, consisting of both AET and RET, should be recommended to improve cardiorespiratory fitness and delay sarcopenia progression, identified through improvements in muscle mass, strength, and function (16, 18).

Pharmaceutical Approaches

Hormone replacement therapy.

As previously discussed, low levels of serum testosterone have been identified in male patients with cirrhosis, which often decline with the progression of CLD (90). Previous research has shown that testosterone treatment in patients with cirrhosis can induce favorable effects on body composition via a reduction in fat mass (167) in addition to increasing HGS (168). It is believed that increasing levels of testosterone can increase androgen receptor expression and in turn may induce an increase in cell growth through the regulation of differentiation and MPS (169). Testosterone treatment also upregulates IGF-1 levels and Akt signaling, which could lead to improvements in muscle growth through SC activation and proliferation (170, 171). Finally, testosterone treatment is known to suppress myostatin levels in skeletal muscle, preventing the activation of JNK, and therefore apoptosis (170). However, the use of testosterone in patients with cirrhosis is not clear cut. Although there appears to be no significant increase in adverse events from testosterone therapy, the long-term outcomes remain largely unclear (90). Therefore, clear evidence to support the safe and efficacious use of adjunct testosterone therapy in patients with cirrhosis remains limited.

In addition, a state of hepatic GH resistance is present in CLD, which may lead to the development of malnutrition (172). A pilot study investigating the effectiveness of 7 days of GH therapy in patients with cirrhosis identified improvements in serum levels of IGF-1 and insulin-like growth factor binding protein 3 (IGFBP-3) in comparison with patients in a placebo group (173). This increase in IGF-1 may contribute to improvements in muscle mass, through an increase in MPS (174) via the activation of the PI3K-mTORC1 pathway (175). However, GH is also associated with several negative side effects, such as the worsening of edema and ascites (172). As a result, the use of GH supplementation should be conducted with caution, and further research into the safety and mechanisms by which GH therapy may contribute to improvements in sarcopenia are required.

Ammonia-lowering therapy.

As previously discussed, hyperammonemia is an abnormality consistently identified in cirrhosis that has been associated with impairments in MPS and increased proteolysis (13, 68, 69). Ammonia-lowering measures have previously been used in both preclinical and clinical settings in the treatment of hepatic endotoxemia, a known complication associated with hyperammonemia (176), but few studies have investigated the benefit of ammonia-lowering strategies in the treatment of sarcopenia in CLD. In vitro, work has shown that although a state of hyperammonemia induces myotube atrophy, ammonia withdrawal can significantly reverse these effects, increasing myotube diameter and anabolic signaling and decreasing catabolic signaling (177). Similarly, in vivo responses to ammonia-lowering therapy in hyperammonemia PCA rats resulted in a significant increase in lean body mass, grip strength, and anabolic signaling, alongside a reduction in markers of autophagy and myostatin expression (177). One of the mechanisms used in this study was administration of rifaxamin, a drug increasingly used in patients with decompensated CLD to manage HE (178). Whether these patients experience reductions in sarcopenia is not known but is an area of considerable interest that could be examined clinically. Although these animal and cellular models suggest that ammonia-lowering therapies may have the potential for clinical implications in the reversal of sarcopenia, human studies are required to confirm these findings (25).

Emerging therapies.

Over recent years, several new potential therapies have been suggested for the treatment of sarcopenia in patients with CLD, including the use of l-carnitine (179), vitamin D, and zinc supplementation (25). In addition, several innovative therapies have also been utilized for the treatment of age-related sarcopenia, and chronic inflammatory disease states such as chronic obstructive pulmonary disease (COPD) including the use of activin receptor II (ActRII) blockers (180, 181) and the nutraceutical Urolithin A (UA) (182). Although this research has not specifically been conducted with patients with CLD, some of the underlying molecular mechanisms that contribute to the development of sarcopenia in these cohorts are likely similar to CLD. As a result, these treatments could provide a novel insight into therapies for the treatment of sarcopenia within CLD.

Cirrhosis is often associated with the development of carnitine deficiency (183). l-Carnitine is a quaternary amine responsible for the transport of long-chain acetylated fatty acids into the mitochondria for fatty acid oxidation, through binding to acetyl groups (184). This leads to the generation of energy, through the production of ATP (184). As previously discussed, a state of hyperammonemia leads to a reduction in ATP synthesis due to a reduction in TCA cycle intermediates (74) and subsequently translation initiation (15). Previous reports suggest that l-carnitine supplementation in patients with cirrhosis results in reductions in ammonia level (185), alongside improvements in muscle cramps (186) and fatigue (187). More recent work has shown that l-carnitine supplementation is associated with a suppression of muscle loss in patients with cirrhosis, particularly when higher dosages were utilized (179).

In addition, vitamin and micronutrient deficiencies in CLD are common and related to hepatic dysfunction, malabsorption, and inadequate dietary intake (25, 26). In particular, CLD is associated with vitamin D (188) and zinc deficiencies (189). Current guidelines set by the EASL recommend that all patients with CLD undergo assessment of plasma vitamin D (25(OH)D) levels, and those who are vitamin D-deficient (below 20 ng/mL) should receive supplementation with oral vitamin D (25). However, vitamin D supplementation in older individuals has shown little benefit for muscle strength, whereas significant improvements in mobility have been identified (190). Zinc supplementation in patients with cirrhosis has been shown to have beneficial effects, improving clinical outcomes such as a decrease in liver enzyme levels and improvements in hyperammonemia and liver function (191). This study, however, did not specifically investigate sarcopenia in CLD. Currently, there is little available evidence on the use of vitamin D and zinc supplementation in patients with sarcopenic CLD and, hence, the effectiveness of these micronutrients is largely unknown.

Previously, this review has discussed the role of increased levels of myostatin in the development of muscle wasting within CLD, which arises because of hyperammonemia (13, 70). Myostatin regulates muscle growth/size by acting on the anti-ActRIIB receptor, consequently inhibiting myoblast differentiation and anabolic mTORC1 signaling (53). Therefore, the inhibition of myostatin has the potential to treat sarcopenia in patients with CLD. Bimagrumab, a human antagonistic anti-ActRIIB receptor antibody, prevents the binding of myostatin and has been shown to promote muscle hypertrophy (192). Indeed, when employed in community-dwelling older adults, 16 wk of bimagrumab treatment resulted in improvements in muscle mass, strength, and gait speed when compared with a placebo (181). Similarly, 24 wk of bimagrumab treatment in patients with COPD led to improvements in lean body mass, thigh muscle volume, and a reduction in intermuscular and subcutaneous fat in comparison to a placebo (180). Despite the improvements in muscle mass, no improvements in physical function measured by 6MWD, Timed Up and Go Test, and HGS were found in this cohort. However, the use of myostatin inhibitors is associated with a number of adverse side effects including muscle spasms, diarrhea, and acne (180, 181). Although this therapy has not yet been investigated in patients with CLD, the available findings imply that this is a promising therapeutic option for the treatment of muscle atrophy.

Mitochondrial dysfunction has been shown to arise because of hyperammonemia (74) and alcohol consumption (89) and is thought to contribute to muscle wasting identified within patients with CLD. Therefore, improvements in mitochondrial functioning may serve as a potential therapeutic target within this cohort. UA is a naturally occurring metabolite, which is formed by the gut microbiota in response to the consumption of ellagitannin-rich food, such as pomegranates, raspberries, strawberries, and walnuts (193). UA has been reported to have several health benefits including the maintenance of mitochondrial biogenesis and respiratory capacity, through the activation of mitophagy in C2C12 skeletal muscle cells and Caenorhabditis elegans (194). In rodent models of aging, induction of mitophagy was identified alongside improvements in muscle function, measured by grip strength and voluntary running activity (194). In addition, UA has been reported to have anti-inflammatory and antioxidant properties (195). In sedentary older individuals, UA induced improvements in mitochondrial and cellular health, with no adverse side effects identified (182). Although no research surrounding the use of UA has been conducted in CLD, the studies to date suggest that UA supplementation may have beneficial effects on mitochondrial health through the activation of mitophagy, which may, in turn, lead to improvements in skeletal muscle function.

CONCLUSIONS

Sarcopenia is common in patients with CLD and is associated with several adverse outcomes including reductions in QoL, increases in mortality, and complications such as infections. Sarcopenia is most commonly defined through the assessment of L3 SMI; however, a lack of sex-specific cutoff values limits the applicability of this modality for the diagnosis of sarcopenia. CLD is characterized by a state of hyperammonemia, an increased catabolism, systemic inflammation, physical inactivity, and poor nutritional status, all of which contribute to the development of sarcopenia through alterations in muscle protein turnover. The therapeutics developed to treat sarcopenia should focus on modifying these potential risk factors and targeting the downstream regulators of muscle mass that they affect. The current literature suggests that patients should ingest 1.6 g/kg/day of protein and reduce the amount of time spent in a period of fasting through the ingestion of more frequent meals, including breakfast and an LES. BCAA supplementation may provide an additional benefit, particularly to those who cannot reach the recommended protein target through the ingestion of whole foods alone. In patients unable to reach the required calorie intake, enteral feeding should be considered. Regular RET and AET are safe and should be encouraged. Emerging pharmaceutical strategies include ammonia-lowering therapy, myostatin inhibition, and anabolic hormone therapy. Future research should aim to identify the molecular and metabolic pathways that contribute to the development of sarcopenia in CLD, which will allow for the creation of targeted therapies to manage and reverse this and also demonstrate improvements in morbidity and mortality within these cohorts.

GRANTS

This work is supported by the National Institute for Health Research Birmingham Biomedical Research Center (BRC-1215-20009) (to S. L. Allen).

DISCLOSURES

The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

S.L.A., J.I.Q., and L.B. conceived and designed research; S.L.A. prepared figures; S.L.A., J.I.Q., and L.B. drafted manuscript; S.L.A., J.I.Q., A.D., M.J.A., A.M.E., C.A.G., J.M.L., G.G.L., and L.B. edited and revised manuscript; S.L.A., J.I.Q., A.D., M.J.A., A.M.E., C.A.G., J.M.L., G.G.L., and L.B. approved final version of manuscript.