Impact of Terminology and Definitions in Identifying Pathophysiology of Sarcopenia

The term malnutrition in cirrhosis has been used in the past to refer to a constellation of nutritional deficiencies in patients with liver disease that adversely affected clinical outcomes [1, 8, 18]. However, a careful evaluation of these studies has shown that the principal component of malnutrition that affects clinical outcomes is the phenotype of skeletal muscle loss with or without fat loss and bioenergetic dysfunction [1, 19–23]. In contrast to the past when the phenotype of malnutrition consisted primarily of muscle loss with varying degrees of fat loss, the epidemic of obesity has made it difficult to clinically recognize malnutrition or sarcopenia in these patients [24–26]. Therefore, with the increasing availability of imaging techniques, muscle mass can be quantified with increasing precision and reiterates the previous studies that muscle loss is a critical predictor of clinical outcomes in patients with liver disease [8]. Multiple groups have reported criteria to define sarcopenia based on local population-based normative values [27–30]. This is critical because physiological studies have shown that major predictors of skeletal muscle mass depend on age, gender, and ethnicity, and normative values need to be defined based on these characteristics [26, 31, 32]. Since muscle loss occurs physiologically with aging after about 50 years of age, females have lower muscle mass, and age- and gender-specific values should be used to define sarcopenia [28, 31]. This is critical because identifying the mechanisms of sarcopenia and developing therapies and measures of response to interventions require appropriate measures of muscle mass. Currently, CT-based measures of the skeletal muscle index at the level of the 3rd lumbar vertebra are used to define sarcopenia in liver disease at most centers using published cutoff values [8, 29]. Even though loss of muscle mass is generally accompanied by impaired muscle contractile function, the term sarcopenia specifically refers to loss of muscle mass, while the term contractile dysfunction and frailty are used to define the disordered functional consequences in these patients [33, 34]. There is increasing recognition of the interplay between loss of muscle mass and impaired contractile function [35], and there may be shared and independent underlying mechanisms that cause sarcopenia and frailty. Unlike sarcopenia that has a defined phenotype, frailty is a constellation of functional abnormalities making it difficult to identify the pathogenesis [6, 34, 36, 37]. Therefore, the mechanisms of sarcopenia and contractile dysfunction are most likely to provide insights into the underlying pathogenesis of frailty.

Models of Sarcopenia in Liver Disease and Relevance to Mechanistic Studies

Skeletal Muscle Proteostasis in Cirrhosis

Since skeletal muscle mass is regulated by a dynamic balance between protein synthesis and proteolysis, both metabolic and molecular alterations contribute to protein loss and ultimately sarcopenia. The metabolic regulation of protein synthesis and proteolysis depends on the underlying molecular regulatory pathways, and there is now increasing interest in identifying how metabolic perturbations are sensed by and alter the cellular molecular signaling pathways.

Whole-Body and Muscle Metabolism in Physiology and Disease

The skeletal muscle is the major protein store in the body and serves as a source for amino acids during times of stress or fasting. Protein synthesis and breakdown occur physiologically in the skeletal muscle depending on the metabolic state that includes the postprandial or the fed state and the postabsorptive or the fasted state [49]. Physiologically, during the postprandial state that generally lasts about 4–6 h after a meal, muscle protein synthesis is stimulated by diet-derived substrates including carbon sources for energy (glucose, fatty acid) and nitrogen for protein synthesis (amino acids) [50]. The skeletal muscle is a net importer of amino acids, and proteolysis is suppressed in the postprandial state [51, 52]. Dietary substrates, specifically glucose, are the major source of energy, and amino acids are primarily used for protein synthesis in the skeletal muscle [53–55]. In the postabsorptive or fasted phase, nonessential protein synthesis is inhibited with a basal protein balance maintained by influx and efflux of substrates from and into circulation. During fasting, proteolysis is activated, and the skeletal muscle becomes a net exporter of amino acids [56]. The physiological response with amino acid release during fasting is required for both synthesis of essential proteins like cytokines, immunoglobulins, and enzymes that are necessary even in the fasted state and as gluconeogenic substrates. During fasting there is a switch in substrate utilization for energy from glucose to fatty acids generated by lipolysis [50]. However, since glucose is still the preferred substrate for certain organs, gluconeogenesis is activated during fasting, and amino acids (from muscle proteolysis) serve as the primary gluconeogenic substrates [50, 57, 58]. When the next meal is ingested, proteolysis is suppressed, and protein synthesis is stimulated to restore the protein content lost during the fasting state. In healthy subjects, the alternating fed and fasting cycle of substrate utilization regulates the muscle protein content and mass with the protein lost during fasting being restored during feeding to maintain a stable muscle mass (Fig. 4.1) [49, 50].

Unlike the physiological postprandial (fed) state that lasts about 4–6 h after each meal, cirrhosis is a state of accelerated starvation [8, 50, 59]. Indirect calorimetry studies demonstrate a more rapid switch from a carbohydrate/glucose preference for energy (high respiratory quotient) to fatty acids as the major energy substrate with amino acid catabolism serving as gluconeogenic substrates (low respiratory quotient) [50, 57, 60]. In addition to the accelerated starvation physiology with proteolysis that occurs much earlier in cirrhosis after a meal than in controls, a significant proportion of patients with cirrhosis are hypermetabolic [61–63]. The underlying pathophysiology of hypermetabolism in cirrhosis is not clear but is associated with worse clinical outcomes [64, 65]. These data suggest that the duration of fasting, when proteolysis and muscle loss occur, lasts longer and the postprandial protein synthesis period is shorter in cirrhosis. In addition to the shorter duration of the postprandial phase and longer postabsorptive or fasting phase, cirrhosis is believed to be a state of anabolic resistance characterized by impaired responses to anabolic stimuli [7, 66, 67]. Therefore, the restoration of the muscle protein loss during the postprandial or fed state may not completely reverse the losses of the postabsorptive or fasting state resulting in a gradual but progressive muscle loss. Targeting the accelerated fasting in cirrhosis by frequent feeding and shortening the duration of the postabsorptive phase is a potential mechanistic therapeutic option to reverse and prevent worsening sarcopenia. The underlying mechanisms of these are currently under investigation, but cytokine and hormonal perturbations, including insulin resistance and endotoxemia, may contribute to these alterations.

Molecular Perturbations in the Skeletal Muscle in Cirrhosis

In addition to direct studies in the skeletal muscle signaling pathways that regulate protein homeostasis, there is increasing interest in the regulation of these signaling perturbations in sarcopenia of liver disease [14, 59, 85]. Protein synthesis is regulated by two principal regulatory factors: myostatin, a transforming growth factor β superfamily member that inhibits protein synthesis, and locally generated insulin-like growth factor 1 (also known as mechanogrowth factor) that stimulates protein synthesis [2, 8, 40]. Canonical regulation of protein synthesis occurs via the Akt/mTORC1 that increases and the eukaryotic initiation factor 2α dependent regulatory pathway that inhibits protein synthesis [86]. A number of proteolytic pathways have been identified in the skeletal muscle and include the ubiquitin proteasome pathway, the lysosomal autophagy pathway, and the calcium-dependent calpain pathway of which there is robust literature in the former two proteolytic pathways in the muscle from models of liver disease [41, 45]. Perturbations in a number of upstream mediators including hyperammonemia, endotoxin, hormones, and nutrients cause dysregulation of these signaling pathways with impaired proteostasis and consequent sarcopenia [8, 14, 87, 88]. Understanding these perturbations is gaining increasing clinical interest because of the increasing availability of therapeutic options to restore proteostasis as a targeted approach to treat sarcopenia in liver disease.

Mediators of the Liver-Muscle Axis

Cirrhosis and other forms of liver disease with loss of muscle mass result in a number of biochemical, hormonal, cytokine, and metabolic perturbations that alter molecular signaling responses in the muscle culminating in dysregulated proteostasis and loss of muscle mass [7, 8]. Some of these have been studied directly in patients and models of cirrhosis, while others have been studied in non-hepatic disorders but are expected to result in activation of similar molecular perturbations. Of these, hyperammonemia is one of the best characterized mediators of the liver-muscle axis [89].

Physiologically, ammonia is a cytotoxic molecule generated mainly by gut bacterial metabolism as well as endogenous amino acid catabolism and purine breakdown during exercise in the skeletal muscle [90, 91]. Hepatocytes are the primary mechanism of ammonia disposal by the formation of urea, an energy requiring reaction [92]. In cirrhosis, ureagenesis is decreased due to hepatocellular dysfunction and portosystemic shunting with resultant hyperammonemia [93–95]. Even though hepatic encephalopathy is the best recognized adverse consequence of hyperammonemia [85], more recently the role of skeletal muscle in ammonia disposal and its consequences have been identified [96]. In a healthy subject, muscle is a net exporter of ammonia during fasting and exercise due to amino acid and purine catabolism with little clinical consequences because of normally functioning hepatocytes. In cirrhosis, multiple groups have reported an increased muscle uptake of ammonia [97, 98]; muscle ammonia uptake was generally believed to be a benign process. However, in the past decade, it is increasingly recognized that the skeletal muscle accumulates ammonia and functions as a metabolic partner to the liver [40, 41, 82]. Accumulation of ammonia in the skeletal muscle is not benign and initiates a series of metabolic, molecular, and organelle dysfunction with dysregulated protein homeostasis and potentially contributing to anabolic resistance [14, 40, 41]. Emerging data suggests that ammonia uptake by the transporter, RhBG, is increased by ammonia itself as well as causes of liver disease including ethanol [99].

Other potential mediators of the liver-muscle axis include endotoxemia with altered toll-like receptor signaling-mediated dysregulated protein homeostasis and muscle cell regeneration [87, 100], hormonal abnormalities including altered growth hormone secretion or resistance, and hypogonadism with decreased testosterone [101–103] and altered nutrient intake [104] and decreased physical activity [105]. This is however not a comprehensive list of potential mediators of the liver-muscle axis but includes those that have been evaluated in the development of sarcopenia. Other complications of cirrhosis including gastrointestinal bleeding, encephalopathy, ascites, renal dysfunction, and development of hepatocellular malignancy also aggravate the adverse consequences of the liver-muscle axis on skeletal muscle proteostasis, and their interaction with or contribution to the mediator (s) of the liver-muscle axis is not well characterized. Targeting the mediators of the liver-muscle axis is critical to reverse anabolic resistance, restore proteostasis, and improve muscle mass and function in cirrhosis.

Hormonal Perturbations in Cirrhosis

Male patients with cirrhosis and the PCA rat have lower circulating testosterone [106, 107]. Testosterone supplementation increases muscle mass in male patients with cirrhosis [103]. One of the potential mechanisms of testosterone is by a reduction in myostatin expression, but a more rapid aromatization of testosterone can accelerate its conversion to estradiol and impair beneficial responses [108]. Long-term safety of testosterone is also a concern, but given that testosterone or other aromatase resistant androgenic agents can inhibit muscle myostatin and protein synthesis, low androgens may be a potential mediator of decreased muscle protein synthesis in cirrhosis.

Growth hormone resistance or loss of the periodicity of growth hormone secretion has been reported in cirrhosis [102, 109, 110]. Growth hormone activates local insulin-like growth factor 1 and inhibits myostatin, and loss of growth hormone signaling may contribute to muscle loss [111].

Endotoxemia in Cirrhosis

Endotoxin is the lipopolysaccharide molecule in Gram-negative bacteria that is toxic to organisms primarily by the activation of host immune responses [112]. Low-grade sepsis and circulating endotoxemia have been reported in cirrhosis and patients with liver disease that can mediate muscle loss [87, 113, 114]. Endotoxin has been reported to impair protein synthesis by reduction in translational efficiency [12, 115]. The mechanistic basis of LPS-induced muscle loss is suggested to be mediated via a toll-like receptor (TLR)-4-dependent signaling with increased P65NFkB signaling, activation of inflammatory responses, and initiation of a cascade of molecular events that culminate in dysregulated proteostasis and muscle loss [100]. Even though overt sepsis may not be common, the low-grade endotoxemia due to a combination of increased gut permeability and impaired hepatic clearance of lipopolysaccharide has been referred to as metabolic endotoxemia [8]. Metabolic endotoxemia has been shown to impair muscle recovery responses and contribute to atrophy [116]. However, whether metabolic endotoxemia causes sarcopenia of cirrhosis and if the potential benefits of long-term antibiotics outweigh the risks are not known. Novel approaches to modulate TLR4 signaling and approaches to control metabolic endotoxemia are needed.

A schematic of these regulatory mediators is shown in (Fig. 4.2).

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