Fig. 3

Myostatin inhibition MOA as add-on to SMN correctors in SMA. SMN protein promotes normal motor neuron function, which in turn provides the signals that activate and sustain muscle tissue (left). In SMA, insufficient SMN protein leads to degeneration of motor neurons and subsequent skeletal muscle atrophy (center). SMN correctors help to increase SMN protein production, stabilize neurodegeneration, and improve or maintain motor function, but may not return muscle to its normal size and function (right) Myostatin circulates as a complex of inhibitory prodomains. When the prodomains are proteolytically cleaved, the active myostatin dimer can bind to its receptor ActRIIB, The heterocomplex translocates to the nucleus where it regulates transcription. Several inhibitors of this signaling pathway have been developed including modified myostatin prodomain, modified follistatin, neutralizing monoclonal antibody and adnectin, ActRIIB-Fc, and ActRIIB blocking antibody. These strategies all lead to blocking myostatin binding to its receptor. Myostatin inhibition in combination with SMN correctors may directly address muscle atrophy and further restore motor function [12, 13, 82,83,84]. Apitegromab is a monoclonal antibody that selectively blocks the precursor, or inactive form of myostatin, blocking its activation in skeletal muscle. Myostatin is a negative regulator of skeletal muscle growth. Apitegromab specifically targets the upstream pro and latent forms of myostatin, which avoids cross-reactivity with other TGF-ß ligands and inhibits activation of myostatin. Apitegromab improves muscle mass and strength with fewer off-target effects and related toxicities than possible with less selective myostatin inhibitors [82, 85]. Figure property of Scholar Rock, Inc