Myostatin represses physiological hypertrophy of the heart and excitation–contraction coupling

Abstract

Although myostatin negatively regulates skeletal muscle growth, its function in heart is virtually unknown. Herein we demonstrate that it inhibits basal and IGF-stimulated proliferation and differentiation and also modulates cardiac excitation-contraction (EC) coupling. Loss of myostatin induced eccentric hypertrophy and enhanced cardiac responsiveness to β-adrenergic stimulation in vivo. This was due to myostatin null ventricular myocytes having larger [Ca 2+ ] i transients and contractions and responding more strongly to β-adrenergic stimulation than wild-type cells. Enhanced cardiac output and β-adrenergic responsiveness of myostatin null mice was therefore due to increased SR Ca 2+ release during EC coupling and to physiological hypertrophy, but not to enhanced myofilament function as determined by simultaneous measurement of force and ATPase activity. Our studies support the novel concept that myostatin is a repressor of physiological cardiac muscle growth and function. Thus, the controlled inhibition of myostatin action could potentially help repair damaged cardiac muscle by inducing physiological hypertrophy.

The aging myostatin null phenotype: reduced adiposity, cardiac hypertrophy, enhanced cardiac stress response, and sexual dimorphism

“…More recent studies have further demonstrated myostatin inhibition of different cardiac muscle growth processes in vitro and in vivo (Shyu et al 2005, Morissette et al 2006, Artaza et al 2007, McKoy et al 2007, Rodgers et al 2009, Zhou et al 2010. It is surprising, therefore, that some studies have failed to identify cardiac hypertrophy in Mstn K/K mice (Morissette et al 2006, Cohn et al 2007, Heineke et al 2010 especially as overexpressing myostatin stimulates cardiac atrophy (Artaza et al 2007.…”

“…We therefore performed DXA scans to assess body and bone composition and weighed individual muscles and organs from WT and Mstn K/K mice. We have previously reported that body and heart weights do not diverge until after w100 days (Rodgers et al 2009). It was therefore surprising to see that body weights were similar in aged WT and Mstn K/K mice ( Fig.…”

“…In addition, we recently identified cardiac hypertrophy in young Mstn K/K mice that more closely resembles physiological, not pathological, hypertrophy especially as excitation-contraction coupling and responses to ISO stress tests were enhanced in Mstn K/K cardiomyocytes and mice respectively (Rodgers et al 2009). We therefore sought to determine whether aged Mstn K/K mice possess a similar phenotype.…”

“…Conversely, we have recently reported that myostatin negatively regulates physiological cardiac hypertrophy (Rodgers et al 2009, Valdivia 2009) as myostatin null (Mstn K/K ) mice had larger hearts, due to eccentric hypertrophy, and an enhanced stress response, due in part to enhanced Ca 2C handling. Analysis of primary ventricular myocytes indicated that [Ca 2C ] i transients and total cellular loads were greater in Mstn K/K mice and this corresponded to enhanced cellular contractility.…”

“…Several recent studies have also indicated that myostatin is not only expressed in skeletal muscle but also in cardiac muscle (Sharma et al 1999, Shyu et al 2005, Artaza et al 2007, Rodgers et al 2009), where it inhibits several growth processes including basal and insulin-like growth factor (IGF)-stimulated proliferation of cardiomyocytes, protein synthesis, and cellular hypertrophy (Morissette et al 2006, McKoy et al 2007, Rodgers et al 2009. Myostatin also circulates and has recently been suggested to regulate hepatic production of IGF1 and several IGF-binding proteins (Williams et al 2011).…”