Copyright © 2005, European Society of Cardiology
Myostatin, the cardiac chalone of insulin-like growth factor-1
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry New Jersey, New Jersey Medical School, 185 South Orange Street, MSB G-609, Newark, NJ 07103, United States
* Corresponding author. Tel.: +1 973 972 3926; fax: +1 973 972 7489. Email address: deprech{at}umdnj.edu
Received 4 August 2005; accepted 16 September 2005
See article by Shyu et al. [2] (pages 405–414) in this issue.
In the 1960s, Bullough introduced the concept of chalones, inhibitors of cell growth that provide a negative feedback mechanism to control the size of a specific tissue [1]. In a very elegant study in this issue, Shu et al. [2] demonstrate that myostatin represents a chalone of the insulin-like growth factor-1 (IGF-1) pathway in the heart.
The IGF-1 signaling pathway, as summarized in Fig. 1A, represents an important physiological mechanism of cardiac cell growth that is initiated upon binding of IGF-1 to a tyrosine–kinase receptor (IGFR) very similar to the insulin receptor. When activated, the IGFR phosphorylates the insulin receptor substrate-1 (IRS-1). Tyrosine phosphorylated IRS-1 is a docking protein for the phosphatidylinositol 3-kinase (PI3K), which in turn activates the protein kinase Akt. IGFR can also bind adapter proteins such as Sos-2, which activates the proto-oncogene Ras and thereby the MAP kinases ERK1 and ERK2 (or p42/p44 MAP kinases). As illustrated in Fig. 1A, these two signaling pathways mediate most of the effects of IGF-1 in the heart, which are very reminiscent of the effects of insulin. ERK1/2 stimulates cell growth through activation of specific transcription factors (such as Elk-1 or GATA), whereas Akt stimulates glucose metabolism and cell growth [3] and prevents apoptosis [4].
|
Due to these multiple effects on cardiac cell growth, the IGF-1 pathway must respond to negative feedback mechanisms. For instance, IRS-1 is a substrate for S6K, a protein kinase downstream PI3K and Akt that stimulates cardiac cell growth (Fig. 1A). Upon chronic activation of the PI3K pathway, S6K phosphorylates IRS-1 on specific serine residues, tagging the protein for ubiquitination and subsequent degradation by the proteasome [5]. More recently, it was shown that chronic activation of Akt also decreases the expression of IRS-1 through a stimulation of proteasome degradation and by transcriptional repression [6]. IGFR can also be a target for proteasome-mediated degradation, a process that is limited by the heat shock protein Hsp 60 [7].
These negative feedback mechanisms will inhibit components of the IGF-1 pathway, but one may wonder if this is sufficient to slow down cell growth or if a separate signaling pathway that specifically inhibits cell growth would also need to be activated. Shyu et al. demonstrate that the IGF-1 signaling pathway directly activates the expression of myostatin, an inhibitor of cell growth [2]. The authors show that stimulation of cardiac myocytes with IGF-1 activates the stress kinase p38 MAPK, which in turn increases the activity of the transcription factor MEF-2, leading to the transactivation of the myostatin gene. In this study, which unravels the entire signaling cascade (stimulus–transducer–effector–target), the novelties are twofold. First, myostatin acts as a cardiac chalone for IGF-1. Second, the induction of myostatin expression by IGF-1 is mediated by p38 MAPK. A chalone is secreted by specific tissues and provides a negative feedback mechanism to control the size of the tissue producing it [1]. In the present model, IGF-1 mediates cardiac myocyte growth, myostatin is secreted by cardiac myocytes and accumulates until it reaches a threshold causing inhibition of cardiac growth.
Myostatin is a member of the transforming growth factor-beta superfamily of secreted regulatory factors [8] that is found predominantly in skeletal muscle, but also in the heart [9]. Germline deletion of myostatin in mice resulted in a dramatic increase in skeletal muscle mass due to hyperplasia and hypertrophy, showing that myostatin acts as a negative regulator of skeletal muscle growth [8]. Myostatin is present in the extracellular milieu as a latent complex, bound to inhibitory proteins such as the inhibitory propeptide, follistatin and follistatin-related gene (Fig. 1B). Proteolytic cleavage by members of the bone morphogenetic protein (BMP)-1/tolloid family of metalloproteinases releases the active form of myostatin, which binds two types of receptors. Upon ligand binding, the type II receptor phosphorylates and activates the type I receptor, which in turn phosphorylates the receptor-regulated Smads (R-Smads), Smad2 and Smad3. Upon binding to Smad4, the Smad complex translocates to the nucleus where it recruits co-activators and co-repressors to regulate the expression of target genes. In adult muscle, myostatin maintains the regenerative satellite cells in a quiescent state by upregulating p21, a cyclin-dependent kinase inhibitor, and decreasing the levels of Cdk2 and phosphorylated Rb [10]. Myostatin also negatively regulates myoblast differentiation to myotubes by downregulating the myogenic bHLH transcription factors MyoD, myf5, and myogenin.
Whereas IGF-1 is known to mediate its effects through ERKs and Akt, the current study shows that the transactivation of myostatin is mediated by the stress-activated p38 MAPK. Although it remains unclear by which mechanism IGFR activates p38 MAPK, this protein kinase is a well-known mediator of "pathological" hypertrophy, i.e., the pattern of hypertrophy that follows pressure or volume overload. Reciprocally, activation of the ERK and Akt pathways are regarded more as the mechanisms mediating "physiological" hypertrophy, such as the increase in heart mass induced by exercise [11]. The "pathological" form of hypertrophy is maladaptive because it increases cardiac stress, leads to progressive cell loss and eventually precipitates heart failure if the cause is not treated. The clinical conditions corresponding to these models are systemic hypertension (pressure overload) and post-ischemic cardiomyopathy (volume overload). Reciprocally, the physiological hypertrophy induced by aerobic (isotonic) exercise is a pure adaptation to increased cardiac output and does not increase cardiac stress. IGF-1 mediates the latter form of hypertrophy, yet an excess of IGF-1 can lead to cardiac dysfunction and failure. A typical example is the hypertrophic cardiomyopathy that accompanies acromegaly, a disease characterized by an excessive production of growth hormone, which stimulates the massive release of its effector IGF-1 [12]. Therefore, moderate concentrations of IGF-1 induce an adaptive hypertrophy, whereas excessive levels will stimulate p38 MAPK and thereby limit hypertrophy through the production of its chalone myostatin.
This dose-dependent effect of IGF-1 leads to the unanswered question whether myostatin expression is good or bad for the hypertrophied heart. For example, Shyu et al. show that myostatin expression increases in a model of volume overload, which is in agreement with reports showing that IGF-1 production increases after myocardial infarction [9,13]. Although IGF-1 is a positive effector of post-infarction remodeling, myostatin production in that setting could limit the increase in heart mass, thereby inducing an imbalance between the increase in contractile demand due to the overload and the contractile capacity of the heart. Such imbalance would lead to further cellular damage and to heart failure if the cause of overload is not removed. Therefore, more work is required to elucidate the physiological relevance of this interesting feedback mechanism. It is likely that a genetic manipulation of myostatin expression in the heart will shed further light about its potential role in the transition to heart failure.
 |
References |
|---|
 Top References |
|---|
- Bullough W. Mitotic and functional homeostasis. Cancer Res (1965) 25:1683–1727.
[Free Full Text] - Shyu K.G., Ko W.H., Yang W.S., Wang B.W., Kuan P. Insulin-like growth factor-1 mediates stretch-induced upregulation of myostatin expression in neonatal rat cardiomyocytes. Cardiovasc Res (2005) 68:405–414.
[Abstract/Free Full Text] - Cantley L. The phosphoinositide 3-kinase pathway. Science (2002) 296:1655–1667.
[Abstract/Free Full Text] - Skurk C., Izumiya Y., Maatz H., Razeghi P., Shiojima I., Sandri M., et al. The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem (2005) 280:20814–20823.
[Abstract/Free Full Text] - Haruta T., Uno T., Kawahara J., Takano A., Egawa K., Sharma P.M., et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol (2000) 14:783–794.
[Abstract/Free Full Text] - Nagoshi T., Matsui T., Aoyama T., Leri A., Anversa P., Li L., et al. PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. J Clin Invest (2005) 115:2128–2138.[CrossRef][Web of Science][Medline]
- Shan Y., Yang T., Mestril R., Wang P. HSP10 and HSP60 suppress ubiquitination of IGF I receptor and augments IGF I receptor signaling in cardiac muscle. J Biol Chem (2003) 278:45492–45498.
[Abstract/Free Full Text] - McPherron A.C., Lawler A.M., Lee S.J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature (1997) 387:83–90.[CrossRef][Medline]
- Sharma M., Kambadur R., Matthews K., Somers W., Devlin G., Conaglen J., et al. Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct. J Cell Physiol (1999) 180:1–9.[CrossRef][Web of Science][Medline]
- McCroskery S., Thomas M., Maxwell L., Sharma M., Kambadur R. Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol (2003) 162:1135–1147.
[Abstract/Free Full Text] - Dorn G.W. II, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest (2005) 115:527–537.[CrossRef][Web of Science][Medline]
- Sacca L., Cittadini A., Fazio S. Growth hormone and the heart. Endocr Rev (1994) 15:555–573.
[Abstract/Free Full Text] - Reiss K., Meggs L., Li P., Olivetti G., Capasso J., Anversa P. Upregulation of IGF-1, IGF-1 receptor, and late growth related genes in ventricular myocytes acutely after myocardial infarction in rats. J Cell Physiol (1994) 158:160–168.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. D. Rodgers, J. P. Interlichia, D. K. Garikipati, R. Mamidi, M. Chandra, O. L. Nelson, C. E. Murry, and L. F. Santana Myostatin represses physiological hypertrophy of the heart and excitation\#8211;contraction coupling J. Physiol., October 15, 2009; 587(20): 4873 - 4886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Rodgers and D. K. Garikipati Clinical, Agricultural, and Evolutionary Biology of Myostatin: A Comparative Review Endocr. Rev., August 1, 2008; 29(5): 513 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-W. Wang, H. Chang, P. Kuan, and K.-G. Shyu Angiotensin II activates myostatin expression in cultured rat neonatal cardiomyocytes via p38 MAP kinase and myocyte enhance factor 2 pathway J. Endocrinol., April 1, 2008; 197(1): 85 - 93. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||