18. A Research Wish List to Understand, Diagnose, and Manage Frailty and Sarcopenia

Michael A. Dunn^{1, 2}

(1)

Center for Liver Diseases, Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, USA

(2)

Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA

Michael A. Dunn

Email: dunnma@upmc.edu

Keywords

SarcopeniaCirrhosisFrailtyProteostasisAmmonia

Muscle and the Liver-Brain-Gut Axis

There has been a rapid progress in our understanding of the key connections mediated by substrates, cytokines, and other signaling messengers among the liver, the brain, and the gut, a constellation described as the gut-liver-brain axis [1]. Appreciation of the functions of this axis in response to impaired ammonia metabolism in advanced liver disease, for example, illustrates the impact of interorgan shifts in handling this key substrate on the development of hepatic encephalopathy.

Muscle, as the obligate location where extrahepatic ammonia disposition takes place in advanced cirrhosis, is best understood as the fourth member of this axis. Until now, however, we have mainly thought more about muscle as an end target in these pathologic relationships rather than as a key culprit promoting injury and pathologic signaling.

Are muscle disturbances an independent driver of liver injury in addition to being a consequence? Bhanji et al. reviewed evidence supporting the proposal that sarcopenia could be a contributing cause of nonalcoholic fatty liver disease [2]. They noted that sarcopenia promotes insulin resistance independent of obesity because muscle is the primary tissue responsible for insulin-mediated glucose disposal. In addition, sarcopenia is associated with nonalcoholic fatty liver disease independent of obesity, insulin resistance, or the metabolic syndrome.

As an endocrine organ, muscle produces cytokines such as myostatin, interleukin-6, and irisin. Myostatin impairs muscle protein synthesis and promotes proteolysis. Myostatin also increases adipose tissue mass and leads to decreased adiponectin.

Both interleukin-6 and irisin are thought to be protective in fatty liver disease. Could muscle loss result in their deficient production and consequently promote disease progression?

Alcohol, the premier multi-organ toxin, regularly injures both the liver and muscle. The mechanisms involved in alcoholic muscle injury have been recently reviewed [3]. However, whether alcohol-induced muscle loss can potentiate alcoholic liver injury in a similar manner to that proposed above for the impact of sarcopenia on nonalcoholic fatty liver disease is an open question that merits study.

Our understanding of the relationships between perturbations of the gut microbiome, known as dysbiosis, and the progression of cirrhosis complications is rapidly expanding [4]. Microbial products entering the circulation through a permeable gut barrier have cytokine-like deleterious effects. In parallel with these advances, there has also been robust progress in defining the impacts of gut microbial dysbiosis on sarcopenia [5]. Both gut-liver and gut-muscle communications involve similar messengers, so that it now seems opportune to consider effects of common gut-derived signals on the liver and muscle. Defining the components of gut-liver-muscle cross talk could provide new insight for their significance in liver disease.

Adrenergic Signaling and Muscle in Liver Disease

The adrenergic nervous system is highly complex and involves a multitude of important effects on circulation and metabolic processes. In advanced liver disease, we have learned, often by trial and error, how to protect patients from variceal bleeding with nonselective beta blocker treatment while limiting its adverse impacts on patients with impaired cardiac function, ascites, abnormal renal circulation, and increased gut permeability [6]. Evidence that we are only beginning to appreciate the full scope of adrenergic effects in hepatology is emerging from data on the impact of adrenergic signaling in muscle.

Agricultural use of beta agonists in meat production is widespread because of their ability to increase lean muscle mass in cattle, swine, and poultry. Concerning muscle performance, competition athletes frequently engaged in doping with beta agonists for performance enhancement before their prohibition and mandated testing was enforced by the World Anti-Doping Agency. Interestingly, an exception allowing their use by Olympic athletes with exercise-induced asthma had the result that competitors with permission to use the beta agonist salmeterol won twice the expected number of Olympic medals as those who did not [7]. If beta adrenergic stimulation is a trophic requirement for muscle performance and health, could we learn whether nonselective beta blockade in sarcopenic cirrhotic patients affects muscle mass or performance?

The liver is richly innervated with adrenergic and cholinergic afferent and efferent fibers that generate traffic with the brainstem and cerebral cortex. The signaling exerts important known effects on energy intake, glucose utilization, and lipid metabolism [8]. Virtually nothing is known about how structural or inflammatory liver diseases might affect these pathways and consequently impact key substrate flows to muscle. Subjective severe fatigue is commonplace in cirrhosis, and as noted below, cirrhotic patients often grossly overestimate their levels of physical activity. Could aberrant autonomic central nervous system inputs from a cirrhotic organ be part of the explanation for these highly prevalent brain and volitional drivers of cirrhotic frailty and sarcopenia?

Metabolic Priorities

Excess ammonia delivered to muscle is the key multipotent metabolic driver of frailty and sarcopenia in cirrhotic patients. As shown in Fig. 18.1, the obligate need for muscle to process and export excess ammonia as glutamine depletes critical substrates for muscle protein synthesis and mitochondrial function. Ammonia-mediated myostatin release also impairs protein synthesis, and ammonia independently stimulates autophagy and impairs muscle contractility.