Growth Differentiation Factor 11 and Myostatin: Mechanism and Therapeutic Role in Cardiovascular Diseases

Camparini, Luca (2019). Growth Differentiation Factor 11 and Myostatin: Mechanism and Therapeutic Role in Cardiovascular Diseases. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00010c74

Abstract

During life, cardiac muscle is capable of remodeling in response to an increased hemodynamic demand through cardiac hypertrophy. However, in most cases, if the stress stimuli become chronic the initially compensatory hypertrophic response evolves towards a pathological condition and heart failure. In this scenario, a therapeutic approach capable of reducing pathological cardiac hypertrophy could be beneficial.

Growth differentiation factor 11 (GDF11) is circulating factor able to reduce cardiac hypertrophy in mice. It is a member of TGF-β family, and it shares a high level of homology with myostatin (MSTN) a well-studied protein that regulates skeletal muscle mass and apparently minimal activity on cardiac mass.

Our data showed different protein levels between cardiac and skeletal muscle tissues revealed a higher abundancy of type I TGF-β receptors (ALK4/5/7) in the heart samples. Moreover, ALK7 receptor knockout induced a significant reduction in SMAD3/4 signaling only after GDF11 treatment. These results showed a differential quantity and use of ALKs receptors, possibly explaining the higher GDF11 sensitivity of cardiomyocytes compared to skeletal myocytes.

Using a model of pressure overload-induced cardiac hypertrophy it was possible to further confirm the anti-hypertrophic activity of GDF11. Interestingly, even if with lower potency, this effect was recapitulated also by MSTN, demonstrating that both peptides have overlapping effects on cardiac tissue. Furthermore, aiming to reduce controversies regarding GDF11 and MSTN serum quantifications, we contributed to develop a novel assay based on mass spectrometry that can discriminate and quantify reliably both proteins. Using this method, it was also possible to identify an age-dependent reduction of both GDF11 and MSTN ligand in mice.

In conclusion, GDF11 and MSTN share a common cardiac anti-hypertrophic activity that was not previously expected. Modulation of GDF11/MSTN signaling pathway can be considered for development of novel therapeutic strategies and new biotherapeutics.