A new study reports that growth differentiation factor 11 (GDF11) contributes to muscle wasting in pulmonary arterial hypertension (PAH) and inhibition of its downstream molecule, signal transducer and activator of transcription 3 (STAT3), might represent a therapeutic target for preventing muscle atrophy in these patients.
“It is of importance to identify and target the downstream signaling pathways of GDF11 in the muscle, which is a potential method to develop targeted drugs for muscle wasting in patients with PAH,” the authors wrote. “Inhibition of STAT3 and 26S ribosomal protein units by a specific inhibitor could rescue GDF11-induced atrophy, making STAT3 inhibition a potential target to prevent muscle wasting in PAH.”
The research team aimed to determine systemic and local levels of GDF11 in 8 patients with PAH and 8 controls, as well as in a monocrotaline (MCT)-induced rat model of PAH. They explored key signaling pathways in which GDF11 acts on muscle tissue, with the ultimate objective of identifying therapeutic targets by which muscle wasting could be inhibited or even reversed.
Read more about PAH experimental therapies
The team found significantly higher serum GDF11 concentrations in patients with PAH than in controls, and serum GDF11 levels were also elevated in the MCT rats with PAH compared to the controls. GDF11 induced a significant increase in STAT3 in a concentration-dependent manner in these groups, leading to direct proteolytic effects, reduced protein content in myotubes, and skeletal muscle wasting.
The authors then successfully employed Stattic, a STAT3 inhibitor, in vitro and in the MCT rat model to reverse the myotube atrophy and wasting induced by GDF11. In the rat model, Stattic administration prevented loss of body weight and a decrease in the cross-sectional area of the animals.
The authors caution that muscle samples in human PAH patients were not assessed and future studies could add further evidence to the results obtained.
Xiang G, Ying K, Jiang P, et al. Growth differentiation factor 11 induces skeletal muscle atrophy via a STAT3-dependent mechanism in pulmonary arterial hypertension. Skelet Muscle. 2022;12(1):10. doi.10.1186/s13395-022-00292-x