Myostatin and beyond in cirrhosis: all roads lead to sarcopenia

Sarcopenia or loss of skeletal muscle mass is a major complication of cirrhosis and liver disease. A large body of literature exists to support the prognostic significance of sarcopenia in cirrhosis. Independent clinical consequences of sarcopenia in cirrhosis include lower survival and quality of life, increases risk of complications including infections and encephalopathy, and lower post liver transplant survival. Interestingly, unlike other complications of cirrhosis, sarcopenia does not reverse and usually worsens after liver transplantation that raises an important question of the utility of targeting sarcopenia for therapy before transplantation. Because the majority of patients with cirrhosis do not undergo transplantation and the window of opportunity is widest prior to transplantation, the focus should be in trying to reduce the severity and frequency of sarcopenia in cirrhosis prior to transplantation. Even though clinicians nearly universally recognize the high clinical significance of sarcopenia in cirrhosis, there are no effective treatment options. The major reason for lack of effective therapies has generally been attributed to a limited understanding of the underlying mechanisms of sarcopenia in cirrhosis. However, other factors include the lack of precise measures of sarcopenia, absence of sensitive and specific biomarkers, and therapies that are based on deficiency replacement rather than mechanistic targets. The work by Nishikawa et al. in this issue goes towards addressing a number of these issues. In a very elegant study, the investigators quantified serum myostatin in a large cohort of patients with cirrhosis. Subjects were stratified by gender and median concentration of serum myostatin. Serum myostatin was significantly higher in males than females. Myostatin concentrations were higher with worsening severity of liver disease measured by Child Pugh score, a standard clinical method to predict outcomes in cirrhosis. Higher myostatin concentration was an independent predictor of worse survival in both male and female patients with cirrhosis. Finally, serum myostatin concentrations were associated with lower muscle mass measured as psoas muscle index on computed tomography, serum ammonia concentration, serum albumin, and branched chain to tyrosine ratios. These studies complement an earlier brief report that serum myostatin was elevated in cirrhosis, but one must note that circulating myostatin concentrations are elevated in heart failure and COPD also. These studies are therefore of broad interest to investigators and physicians taking care of patients with other chronic diseases with sarcopenia. The present study also reiterates their data that circulating myostatin is inversely related to skeletal muscle mass but extends these data by demonstrating the prognostic significance and relate it to underlying pathophysiological perturbations. These investigators also report the use of psoas muscle index as a measure of muscle mass. This requires the use of imaging techniques while myostatin measurement is done in blood samples with lower costs and no risk of radiation exposure. Whether serial myostatin measurements will correlate with serial changes in muscle area or provide a better predictor of progressive muscle loss is an intriguing possibility because more rapid muscle loss worsens outcome in cirrhosis. Since the discovery of myostatin, the number of publications has increased exponentially with a detailed characterization of its biological properties. Even though myostatin is consistently expressed in skeletal muscle, other tissues also express and possibly secrete myostatin. Signalling and functional responses to myostatin have focused on a paracrine effect even though there is increasing interest in ED ITOR IAL