Regulator of Muscle Wasting in Heart Failure and Treatment Target for Cardiac Cachexia

Myostatin, also known as growth differentiation factor-8 (GDF-8), is a member of the transforming growth factorsuperfamily 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 cancerassociated 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 has been unclear how alterations in the myocardium of patients with HF influence gene expression and function of the peripheral skeletal muscle. It has been hypothesized that soluble factors secreted by the heart may be responsible for the observed skeletal muscle alterations. The data to support or refute this hypothesis have been missing thus far. The article by Heineke et al7 in this issue aims to fill this gap by proposing that myostatin released from the failing heart induces skeletal muscle wasting in HF. Furthermore, their results suggest that myostatin inhibition may be a therapeutic option to counteract skeletal muscle wasting in HF. A loss of cardiac mass is reported in their model of HF. This is known to be a late event in human HF; skeletal muscle wasting and general loss of body weight (ie, development of body cachexia) precede the loss of cardiac mass.11 Although no data on actual animal body weight or body weight loss have been reported, the term “muscle cachexia” is used. This term is misleading, because a loss of muscle mass without actual body weight loss is not cachexia but muscle wasting. When muscle wasting occurs in the context of aging, it is termed “sarcopenia.”12 The term “cachexia,” however, describes a “complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass.”13 This statement is taken from a recent consensus definition of cachexia, which continues, “The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders).”13 We believe that when cachexia and muscle wasting are discussed, the use of precise language based on precise definitions is important. Otherwise, this new research area may suffer from misunderstandings and misleading conclusions. Heineke et al7 did not find an increased expression of myostatin in skeletal muscle after transverse aortic banding. Knockout of myostatin expression in the heart but not in the skeletal muscle reduced transverse aortic banding–induced loss of lean body mass. This is somewhat contradictory to an earlier publication that used the left anterior descending coronary artery ligation model to induce HF, in which a robust induction of myostatin messenger RNA expression in skeletal muscle was observed that correlated with the protein level of myostatin.6 In that study, myostatin expression correlated with the expression of tumor necrosis factor, which suggests that tumor necrosis factor is a potent regulator of myostatin expression. Exercise reduced both tumor necrosis factor and myostatin expression in both heart and skeletal muscle.6 These differences could be due to the different models used to induce HF. When one looks at the relevance of the 2 models for human HF, the incidence of chronic HF due to aortic stenosis is rare, whereas development of chronic HF due to coronary artery disease is frequent. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Applied Cachexia Research, Department of Cardiology (J.S., S.D.A.) and Center for Cardiovascular Research (J.S.), Charité Medical School, Berlin, Germany; University Leipzig–Heart Center Leipzig (V.A.), Department of Cardiology, Leipzig, Germany; and Centre for Clinical and Basic Research (S.D.A.), IRCCS San Raffaele, Rome, Italy. Correspondence to Jochen Springer, PhD, Center for Cardiovascular Research, Charité, Campus Mitte, Hessische Straße 3-4, D-10115 Berlin, Germany. E-mail [email protected] (Circulation. 2010;121:354-356.) © 2010 American Heart Association, Inc.