Metabolic and immune links between sarcopenia and liver disease

Abstract

Skeletal muscles perform important metabolic functions. Muscle mass wasting in sarcopenia is an urgent problem of modern medicine, the interest in which is related to its prognostic significance. The liver has numerous direct and indirect metabolic and immune connections with skeletal muscle and disruptions of these connections in liver disease are of clinical interest. A recent article by Liang et al emphasized potential biomarkers of sarcopenia in liver cirrhosis. Identification of biomarkers of sarcopenia in patients with cirrhosis has important diagnostic value. Common pathophysiologic mechanisms of sarcopenia and liver cirrhosis include disorders of protein and energy metabolism, disturbances in the structure of gut microbiota, inflammation and oxidative stress.

Key Words: Sarcopenia; Skeletal muscle wasting; Liver disease; Liver cirrhosis; Metabolic disorders; Immune mechanisms; Biomarkers

Core Tip: Sarcopenia is characterized by loss of mass, strength, and skeletal muscle function. Skeletal muscle has numerous direct and indirect metabolic and immune links with the liver, which are disrupted in diseases such as metabolic dysfunction-associated steatotic liver disease and cirrhosis. Disruption of these links contributes to the premature development of sarcopenia, which further worsens the course of these diseases and the prognosis.

INTRODUCTION

Sarcopenia, i.e. age-related loss of skeletal muscle mass, strength and function, is of growing interest to clinicians and researchers as it leads to serious health problems including the development of frailty syndrome, increased risk of falls and premature death[1-3]. Skeletal muscles are considered the largest organ in the human body, but their mass depends on various factors and changes with age[4,5]. In the process of natural aging there is a decrease in skeletal muscle mass, but the rate of this decrease is not so significant and allows to maintain physiological muscle functions until deep old age. A number of diseases can cause premature development of sarcopenia up to cachexia[6]. In patients with liver cirrhosis, the prevalence of sarcopenia, for example, ranges from 40% to 68%[7]. The presence of sarcopenia is an unfavorable prognostic factor in chronic diseases[8,9]. It is also associated with a decrease in the level of physical activity of patients with sarcopenia due to weakness and rapid fatigue and due to impaired biological muscle function. In this regard, improving the early diagnosis of sarcopenia is an important research objective. A recent article by Liang et al[10] emphasized potential biomarkers of sarcopenia in liver cirrhosis, which is of clinical interest.

Various biomarkers are known to assess the risk of sarcopenia in patients with cirrhosis. It has been previously shown that serum levels of irisin and myostatin (and myostatin in combination with creatine phosphokinase or albumin) can be used as a potential biomarker to predict sarcopenia in patients with cirrhosis. In addition, hemoglobin and ferritin levels and low testosterone levels also predict sarcopenia in these patients[11-15].

Research in recent decades has greatly increased the understanding of the function of skeletal muscles and their links to other organs. In addition to the mechanical function of maintaining body position in space and locomotion, skeletal muscle plays a key role in thermoregulation and energy metabolism. Skeletal muscles also produce a large number of different bioactive substances such as myokines, as well as vesicles containing micro ribonucleic acids (microRNAs) and other regulatory molecules that link muscles and other organs[16-19].

Skeletal muscles are predominantly represented by type I and type II fibers (subtypes IIa and IIx), which have biochemical and physiological differences[20-22]. Type I muscle fibers are known as “slow-twitch” fibers because they are characterized by a slower contraction speed but greater resistance to fatigue due to a greater number of mitochondria. Type II muscle fibers are known as “fast-twitch” fibers. Type 2A muscle fibers primarily use oxidative metabolism, and type IIx fibers rely predominantly on glycolysis[23,24]. However, type I fibers express higher levels of the insulin-dependent glucose transporter 4 and glycolytic enzymes as a consequence of which they are highly sensitive to insulin[25-27].

Given the total mass of skeletal muscle, they are a key insulin-dependent consumer of glucose. They account for the utilization of more than 70% of all glucose in the postprandial period[28,29]. In doing so, insulin regulates muscle glucose uptake both by enhancing glucose entry into the cell and by improving delivery to glucose to muscle fibers through improved muscle microcirculation[30,31]. In addition, insulin has an anabolic effect on skeletal muscle by stimulating protein synthesis[32]. In this regard, insulin resistance has a major impact on skeletal muscle structure and function[33,34].

In addition to glucose, skeletal muscles can utilize fatty acids for energy. Fatty acids enter skeletal muscle cells by both passive diffusion and via transfer proteins. Key transfer proteins include fatty acid translocase/CD36, plasma membrane associated fatty acid binding protein, and fatty acid transfer proteins (FATP1-FATP6). Exercise enhances the expression and movement of these transfer proteins, thereby increasing fatty acid uptake and oxidation[35-37]. But excessive dietary fat intake promotes the accumulation of intramyocellular lipids (IMCL) in muscle[38]. IMCL serves as an intracellular energy source during prolonged submaximal exercise. Excessive amounts of IMCL can lead to lipotoxic phenomena by impairing signaling and insulin action, contributing to metabolic disorders. In addition, accumulation of lipids such as diacylglycerol and ceramide play a role in the development of lipid-induced insulin resistance[38-42]. The presence of ceramides in muscle cells activates inflammatory processes, such as nuclear factor kappa B (NF-κB) signaling, and suppresses anabolic processes, including protein kinase B (AKT) and mammalian target of rapamycin (mTOR) signaling. This dual action results in decreased muscle protein synthesis and increased muscle protein breakdown, accelerating sarcopenia[43,44].

Thus, skeletal muscle is an important metabolic and energy regulator in the body. At the same time, skeletal muscle has numerous metabolic connections with the liver, another important metabolic regulator in the body (Figure 1)[45,46].

Figure 1 Metabolic and immune connections between skeletal muscle and liver and disruptions of these connections in liver diseases leading to sarcopenia. IGF-1: Insulin-like growth factor 1.

Identification and better study of these relationships may improve the understanding of the pathogenesis of sarcopenia in liver disease and enhance its early diagnosis and treatment.

MECHANISMS OF SARCOPENIA DEVELOPMENT

There are two major regulatory mechanisms of skeletal muscle growth. First, the insulin-like growth factor 1 (IGF-1) pathway, which regulates muscle growth through the AKT and mTOR pathways. IGF-1 also stimulates muscle cell proliferation via MAPK and ERK. The second pathway in the regulation of skeletal muscle growth is the myostatin/Smad pathway. Myostatin belongs to the transforming growth factor (TGF)-β superfamily and negatively regulates muscle growth through activation of the myostatin/Smad pathway by inhibiting transcription of muscle regulatory factors that regulate muscle cell differentiation and proliferation. Myostatin also negatively affects muscle growth by inhibiting the AKT/mTOR pathway and thereby inhibiting protein synthesis[47-51].

The imbalance of protein synthesis and degradation is one of the most important mechanisms of sarcopenia. This imbalance is influenced by factors such as endoplasmic reticulum stress and unfolded protein response, which play an important role in muscle atrophy[52-54].

Insulin resistance is an important mechanism associated with the development of sarcopenia. Given the extensive role of skeletal muscles in glucose utilization, insulin resistance leads to impaired glucose uptake and utilization by muscles, impairing the maintenance of their energy balance on the one hand, and on the other hand increasing hyperglycemia and liver burden[55,56]. The importance of impaired carbohydrate metabolism is evidenced by the high prevalence of sarcopenia in patients with diabetes mellitus, which according to various studies is more than 18%[57-59].

Systemic inflammation is another important factor contributing to the development of sarcopenia. Tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and other pro-inflammatory molecules, activate NF-κB in muscle by stimulating proteolysis via the ubiquitin-proteasome system (UPS). On the other hand, muscles are active participants in immune processes through the production of myokines[60-63].

Mitochondrial dysfunction is considered another important mechanism of sarcopenia. Mitochondrial dysfunction leads to impaired oxidative phosphorylation and adenosine triphosphate (ATP) production, which are critical for muscle function and maintenance[64]. Oxidative stress may contribute to the development of mitochondrial dysfunction. Accumulation of reactive oxygen species (ROS) damages mitochondria in muscle and liver, impairing β-oxidation of fatty acids and energy metabolism. Another factor in mitochondrial dysfunction is decreased mitochondrial biogenesis[65-69].

The links between mitochondrial dysfunction and inflammation are of interest. Damaged mitochondria release mitochondrial DNA and other signals that activate inflammatory pathways such as NF-κB, leading to chronic inflammation[70,71]. On the other hand, chronic inflammation can impair mitochondrial function by disrupting mitochondrial biogenesis, leading to further mitochondrial damage and dysfunction. In conditions such as insulin resistance, a vicious cycle occurs in which mitochondrial dysfunction leads to increased lipid accumulation and oxidative stress, which in turn promotes inflammation and exacerbates mitochondrial damage[72-74]. One pathway by which inflammation may affect mitochondrial function in muscle is through nitric oxide (NO) signaling. TNF-α is a potent inducer of inducible NO synthase, which promotes excess NO production, resulting in extensive inhibition of the mitochondrial electron transport chain[75]. TNF-α can also reduce mitochondrial respiration via NF-κB. TNF-α-induced activation of NF-κB decreased promoter transactivation and transcriptional activity of regulators of mitochondrial biogenesis and muscle oxidative phenotype (oxphen)[76]. In this regard, the role of chronic systemic inflammation and its links with sarcopenia is of considerable clinical interest, which is particularly relevant to older individuals. Thus, sarcopenia is the result of a complex chain of events involving metabolic and immune mechanisms.

METABOLIC AND IMMUNE LINKS BETWEEN SKELETAL MUSCLE AND LIVER

Skeletal muscle and liver are important metabolic and energy regulators. There are direct and indirect functional connections between these organs. Examples of this linkage include creatine, which is synthesized endogenously in the liver, kidney, and pancreas by a two-step process involving the enzymes (1) L-Arginine: Glycine amidinotransferase; and (2) Guanidinoacetate methyltransferase[77,78]. After synthesis, creatine is transported to target cells, including muscle cells, by a specific creatine transporter 1[79]. Creatine and its phosphorylated form, phosphocreatine (PCr), act as an energy buffer. The enzyme creatine kinase catalyzes the reversible phosphorylation of creatine to PCr, which can rapidly recover ATP from ADP during periods of high energy demand. Creatine increases muscle strength and bulk, allowing for faster muscle mass gain and improved muscle performance[80]. Creatine supplementation is being considered as a way to correct sarcopenia in liver cirrhosis[81].

During intense anaerobic exercise, muscles produce lactate as a byproduct of glycolysis because of the high demand for ATP and limited oxygen availability. This lactate accumulates in the muscle and enters the bloodstream[82]. Lactate can be used as an energy substrate by both type I and type II muscle fibers, providing adequate energy levels during exercise. During the Cori cycle, lactate produced by anaerobic glycolysis in muscle is transported to the liver. In the liver, lactate is converted back to glucose via gluconeogenesis[83-85]. This glucose is then released back into the bloodstream and can be taken up by the muscles to be used as an energy source, allowing sustained physical activity[83-85]. The Cori cycle is critical for endurance performance because it helps maintain blood glucose levels during prolonged exercise, preventing hypoglycemia and allowing continuous muscle activity[83-85]. Efficient excretion of lactate and its conversion to glucose in the liver supports sustained aerobic metabolism and slows the onset of fatigue.

Skeletal muscle is an important regulatory organ. Muscles secrete myokines (e.g., irisin, IL-6) that affect liver metabolism by stimulating gluconeogenesis or fat oxidation[86-89]. Skeletal muscle production of IL-6 is stimulated by exercise and muscle loading[90,91]. Short-term exposure to IL-6 is known to enhance insulin-stimulated glucose utilization and fatty acid oxidation in skeletal muscle via AMP-activated protein kinase (AMPK)[92]. In addition, muscle-produced IL-6 can have systemic effects on the liver, adipose tissue, and immune system, as well as provide interactions between intestinal L-cells and pancreatic islets of Langerhans[93].

It is important to note that the role of IL-6 in skeletal muscle is more multifaceted, including those related to negative effects on skeletal muscle, as IL-6 can act in both anti-inflammatory and pro-inflammatory ways. Through its pro-inflammatory action, IL-6 causes muscle atrophy. Continuous administration of IL-6 to muscle tissue has been shown to cause significant muscle atrophy by activating immune receptors and decreasing energy metabolism[94]. Elevated IL-6 Levels are also associated with increased protein ubiquitination and decreased markers of muscle regeneration. This suggests that IL-6 promotes muscle atrophy by enhancing protein degradation pathways, particularly the UPS[95]. In this regard, IL-6 is a promising target for further research.

Irisin has been shown to attenuate liver fibrosis by inhibiting hepatic stellate cell activation and improving mitochondrial function. This is achieved through modulation of TGF-β1/Smad signaling pathway and mitochondrial biogenesis. In models of liver fibrosis, irisin treatment reduced collagen deposition and improved liver performance, indicating its potential as a therapeutic agent for liver fibrosis[96-98]. Irisin improves the regulation of glucose and lipid metabolism in the liver by activating AMPK, which is a key regulator in the liver. This leads to a decrease in liver triglyceride levels, increased glycogen levels and improved insulin resistance[99]. Administration of irisin in experimental models of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic syndrome significantly decreased fasting blood sugar, improved lipid profile and increased insulin levels. This suggests that irisin may be a potential therapeutic agent for the treatment of liver-related metabolic disorders[100]. Irisin also reduces lipid accumulation in the liver by enhancing autophagy and modulating the sirtuin-3 pathway, which is critical for lipid metabolism and preventing hepatic steatosis[101]. Given that muscle production of irisin depends on the level of physical activity, hypodynamia and sarcopenia disrupt this communication pathway between skeletal muscle and liver.

The liver in turn produces hepatokines [e.g., fibroblast growth factor 21 (FGF21), angiopoietin-like protein 4 (ANGPTL4)] that regulate energy metabolism in muscle. Regular physical activity increases the secretion of some hepatokines such as FGF21, follistatin, ANGPTL4 and IGF binding protein 1. These hepatokines help exert the positive effects of exercise on whole body metabolism, including increasing insulin sensitivity and reducing the risk of metabolic diseases such as type 2 diabetes and cardiovascular disease[102,103]. In addition, liver-produced apolipoprotein J improves muscle glucose metabolism and insulin sensitivity through mechanisms involving low-density lipoprotein receptor-related protein-2 and the insulin receptor signaling cascade. This interaction is critical for maintaining normal glucose homeostasis and preventing insulin resistance[104]. The altered profile of hepatokine secretion in hepatic steatosis, may cause skeletal muscle insulin resistance and muscle atrophy. This occurs due to increased protein breakdown and impaired glucose uptake by muscle cells caused by the secretion of specific hepatokines from the liver[105,106]. Cytokines such as TNF-α produced by liver injury can also cause muscle atrophy by promoting protein breakdown and inhibiting protein synthesis[107]. Damaged liver also produces growth differentiation factor 8 and possibly other activin type IIB receptor ligands, contributing to the progression of liver injury while causing systemic disruption of TGF-β signaling in skeletal muscle, leading to degeneration and impaired muscle regeneration[108].

Thus, the liver and skeletal muscle have numerous reciprocal relationships based on different metabolic and immune mechanisms. These mechanisms may be impaired in various liver diseases, which is of clinical interest.

METABOLIC AND IMMUNE LINKS BETWEEN SARCOPENIA AND LIVER DISEASE

Sarcopenia, characterized by loss of muscle mass and strength, is closely related to MASLD, a common liver disease. The relationship between these two conditions is bidirectional and involves several common pathophysiologic mechanisms. Insulin resistance is a major mechanism of both sarcopenia and MASLD. Skeletal muscle plays a key role in glucose utilization, and loss of muscle mass in sarcopenia exacerbates insulin resistance, which in turn contributes to the development of MASLD[109-111]. A sedentary lifestyle contributes to both sarcopenia and MASLD. Lack of physical activity leads to muscle atrophy and impairs insulin resistance, which further promotes fat accumulation in the liver[109,110]. Eating disorders play an important role in both diseases. Excessive dietary fat intake leads to fat accumulation in both skeletal muscle and liver.

Chronic low-intensity inflammation is another common feature of both diseases[109,112]. Inflammatory cytokines contribute to muscle atrophy and liver fibrosis, linking systemic inflammation to the progression of both sarcopenia and MASLD. Oxidative stress is another common mechanism. It causes damage to muscle cells and hepatocytes, leading to muscle atrophy and liver fibrosis[109,113]. Dysregulation of hormones such as myostatin and adiponectin plays an important role in the pathogenesis of sarcopenia and MASLD. Myostatin suppresses muscle growth and adiponectin has anti-inflammatory properties. An imbalance of these hormones can lead to muscle atrophy and fat accumulation in the liver[109].

Disturbances in the composition of the gut microbiota are of growing interest due to its multifaceted role in many immune and metabolic processes not only in the gut but also in other organs through a number of bioactive substances such as short-chain fatty acids (SCFAs). SCFAs, including acetate, propionate and butyrate, are produced by the intestinal microbiota as a result of fermentation of dietary fiber in the colon. SCFAs serve as a direct source of energy for muscle cells and influence glucose metabolism. SCFAs enhance insulin sensitivity in skeletal muscle by increasing histone acetylation, which promotes glucose uptake. Acetate improves mitochondrial function, which is critical for energy production and muscle function[114]. Butyrate reduces inflammation in skeletal muscle by decreasing the expression of inflammatory mediators such as IL-6, monocyte chemoattractant protein-1, and C-C motif chemokine ligand 5. This effect is mediated by inhibition of NF-κB and signal transducer and activator of transcription 3 signaling pathways[115,116]. SCFAs activate AMPK, promoting fatty acid uptake, lipid catabolism, and mitochondrial biogenesis, thereby inhibiting lipid anabolism in skeletal muscle[117-119]. SCFAs also act in an anti-inflammatory manner[114]. Transplantation of gut microbiota from healthy mice to mice reared without microbes has been shown to improve muscle mass and muscle function, indicating a critical role for gut microbiota in muscle health[120]. The connection between the gut and liver, involving the gut microbiota and their metabolites, affects both muscle and liver health. Dysbiosis can lead to increased gut permeability, systemic inflammation and subsequent muscle and liver damage. Disturbances in the gut microbiota are considered an important contributor to the development of MASLD, for example through increased bacterial lipopolysaccharide (LPS) entry into the liver and stimulation of inflammation[121-123].

The bacterium Akkermansia muciniphila (A. muciniphila) has been shown to play an important role in intestinal and liver function. In patients with cirrhosis, lower levels of A. muciniphila are associated with sarcopenia, a condition characterized by decreased muscle mass and function. This bacterium is part of the gut microbiota that supports physical activity and muscle health[124,125]. Supplementation of A. muciniphila in mice has been shown to reduce metabolic inflammation and improve muscle function by reducing endoplasmic reticulum stress and inflammation in muscle tissues[126].

The pathogenesis of sarcopenia in cirrhosis is also multifactorial and involves several interrelated mechanisms. Altered metabolism, decreased protein synthesis, and increased protein degradation are important contributors to sarcopenia in cirrhosis. Cirrhosis leads to a catabolic state in which muscle protein synthesis is decreased and protein degradation is increased[127,128]. This imbalance is caused by metabolic changes including hyperammonemia and chronic inflammation[127]. As previously mentioned, IGF-1, is a peptide hormone that is mainly produced in the liver and plays a critical role in growth, metabolism and cellular functions such as proliferation, differentiation and apoptosis. In liver cirrhosis, IGF-1 Levels are significantly decreased, which affects disease progression and patient prognosis[129-131].

A key factor contributing to sarcopenia in patients with chronic liver disease may be the hyperammonemia-induced increased production of myostatin, which causes muscle atrophy through the expression of atrophy-related genes[132]. Ammonia, which is produced during protein catabolism and is an important component of nucleic acid and protein biosynthesis, is mainly neutralized in the liver. In patients with liver disease, especially cirrhosis, insufficient detoxification of ammonia leads to an increase in its concentration in the blood, resulting in severe skeletal muscle atrophy, increased apoptosis and decreased protein synthesis. Ammonia induces the expression of myostatin, a negative regulator of muscle growth, and promotes autophagy, leading to muscle atrophy[132-134]. In liver cirrhosis, skeletal muscle replaces the liver as the primary ammonia excreting organ. Thus, a vicious cycle occurs in which hyperammonemia causes severe muscle damage and sarcopenia, which in turn limits the muscle's ability to excrete excess ammonia from the blood[134]. The use of the hypoammonemic agent L-ornithine-L-aspartate in the treatment of sarcopenia in cirrhosis has the potential for positive effects on muscle mass, strength, and function, given the pathogenetic basis of sarcopenia in cirrhosis[134,135].

Liver cirrhosis is also associated with decreased levels of testosterone and growth factors, which are essential for the maintenance and growth of muscle mass[7,136]. Cirrhosis suppresses the hypothalamic-pituitary-gonadal axis, resulting in hypogonadism, high estrogen levels, and decreased testosterone levels[137]. Testosterone, a key anabolic hormone, plays a critical role in the maintenance of muscle mass, and its decline with age is associated with the development and progression of sarcopenia. Testosterone interacts with androgen receptors in muscle cells, affecting muscle metabolism and promoting muscle growth. Its deficiency can lead to muscle atrophy and weakness, characteristic features of sarcopenia[138-140]. In a recent review, decreased testosterone levels have been shown to be an important factor in the development of sarcopenia in cirrhosis[141].

Dietary restrictions, loss of appetite, absorption disorders, and metabolic alterations in patients with cirrhosis result in inadequate intake of calories and protein needed to maintain muscle mass[128,142].

Persistent inflammation in cirrhosis also contributes to muscle breakdown through activation of proteolytic pathways[127,132]. Increased ROS in cirrhosis leads to mitochondrial dysfunction and further muscle protein degradation[133].

Alterations in the gut microbiota of patients with cirrhosis may exacerbate inflammation and metabolic disorders, contributing to sarcopenia[143]. Patients with cirrhosis have a significant decrease in the alpha diversity of the gut microbiota, which means a decrease in the number of different bacterial species. SCFA-producing bacteria are decreased and pathogenic bacteria are increased[144-146]. Due to the damaged intestinal barrier and increased permeability, bacterial products or viable bacteria are transported from the intestinal lumen to the liver, leading to increased LPS levels and increasing inflammation. Recently, Bacteroides fragilis, Blautia marseille, Sutterella spp. and Veillonella parvula have been shown to be associated with patients with cirrhosis and sarcopenia. In contrast, Bacteroides ovatus was found in patients with cirrhosis without sarcopenia. These changes corresponded to abnormalities in bile acid and amino acid metabolism[147]. Another study showed that gut microbial functions related to amino acid biosynthesis were significantly reduced in patients with sarcopenia and cirrhosis. Dialister, Ruminococcus 2 and Anaerostipes deficiency was associated with cirrhotic sarcopenia and significantly correlated with serum amino acid levels[148].

Thus, the metabolic and immune connections between the liver and skeletal muscles are impaired in liver diseases such as MASLD and cirrhosis, entailing the development and progression of sarcopenia. The severity of sarcopenia may indicate the severity of liver disease.

CONCLUSION

Thus, sarcopenia, characterized by progressive loss of muscle mass and function, is a serious clinical problem. The presence of sarcopenia in liver disease is a natural outcome of impaired multiple bilateral metabolic and immune connections between skeletal muscle and liver. The identification of these links and the search for their clinical biomarkers is an urgent research task that will improve early diagnosis and increase the effectiveness of treatment and prevention. It should be noted that, given the complexity and complexity of the links between the liver and skeletal muscles, the search for a universal biomarker characterizing the presence and severity of sarcopenia is a difficult task.