Myostatin and the Heart

Abstract

Myostatin (growth differentiation factor 8) is a member of the transforming growth factor-β superfamily. It is secreted mostly by skeletal muscles, although small amounts of myostatin are produced by the myocardium and the adipose tissue as well. Myostatin binds to activin IIB membrane receptors to activate the downstream intracellular canonical Smad2/Smad3 pathway, and additionally acts on non-Smad (non-canonical) pathways. Studies on transgenic animals have shown that overexpression of myostatin reduces the heart mass, whereas removal of myostatin has an opposite effect. In this review, we summarize the potential diagnostic and prognostic value of this protein in heart-related conditions. First, in myostatin-null mice the left ventricular internal diameters along with the diastolic and systolic volumes are larger than the respective values in wild-type mice. Myostatin is potentially secreted as part of a negative feedback loop that reduces the effects of the release of growth-promoting factors and energy reprogramming in response to hypertrophic stimuli. On the other hand, both human and animal data indicate that myostatin is involved in the development of the cardiac cachexia and heart fibrosis in the course of chronic heart failure. The understanding of the role of myostatin in such conditions might initiate a development of targeted therapies based on myostatin signaling inhibition.

Keywords: cardiac cachexia; cardiac hypertrophy; chronic heart failure; heart physiology; myocardial infarction; myostatin.

Figure 1

The pathway of free myostatin formation. The myostatin gene is located on chromosome 2 in humans and is composed of three exons and two introns. Prepromyostatin exists as a disulfide-linked homodimer composed of a signal peptide (SP), N-terminal prodomain, and C-terminal ligand. It is later processed by signal peptidase, furin protein convertase, and BMP-1/tolloid proteinases. In the blood, myostatin is present in the form of latent complex; thus, only one step is needed to release free myostatin. In skeletal muscles, promyostatin is secreted mostly in the interstitial fluid; thus, two steps are needed to release free myostatin. Blood myostatin is inhibited by follistatin, follistatin-related gene, propeptide, GASP 1 (growth and differentiation factor-associated serum protein 1), and LTBP3 (latent TGF-β binding protein 3). Blue arrows indicate the direction of myostatin synthesis, while red arrows show the place of enzyme action.

Figure 2

The sequence of events in chronic heart failure leading to development of cardiac cachexia on the Smad2/Smad3 (canonical) pathway. Myostatin inhibits Akt, leading to dephosphorylation of FOXO. Dephosphorylated FOXO enters the skeletal muscle nucleus and increases transcription of atrophy genes. Inhibition of Akt downregulates the mTOR pathway of protein synthesis [6,8].