Myostatin

Abstract

Cachexia in chronic heart failure (HF) is a major clinical problem that is still underestimated for its impact on morbidity, mortality, and healthcare expenditures. The pathophysiology of cardiac cachexia is characterized by a catabolic/anabolic imbalance. An important player in the development of muscle wasting and cachexia in HF may be myostatin. Article see p 419 Myostatin, also known as growth differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β superfamily and was identified in 1997.1 In humans, myostatin is expressed almost exclusively in skeletal muscle and is essential for normal regulation of muscle mass through its actions as a negative regulator of muscle bulk.2 Gene disruption, either natural or by targeted mutation, leads to a marked increase in muscle mass due to hypertrophy and hyperplasia.1 This was clearly evident in a child with a mutation in the myostatin gene who had the ability to hold two 3-kg dumbbells at the age of 4 years.3 Myostatin has been shown to be upregulated in human immunodeficiency virus– and cancer-associated cachexia,4 with advanced age,5 and in chronic HF.6 In each of these conditions, a loss of skeletal muscle mass occurs that leads to a disproportionate loss of exercise tolerance and an early increase in muscle fatigue. Human cardiovascular studies concerning myostatin are generally lacking. Before the report by Heineke et al7 in this issue of Circulation , 2 animal studies reported increased myostatin expression in the peri-infarct zone in sheep8 and in a rat model of volume overload induced by an aortocaval shunt.9 Importantly, the expression remained increased after 4 weeks in the shunt model. In 2008, Hoenig10 presented a hypothesis that myostatin acts as a mediator of cardiac cachexia, insulin resistance, and osteoporosis in chronic HF. To date, it …