Transforming growth factor-β (TGF-β) superfamily proteins that signal via activin type II receptors (ActRIIA/ActRIIB), including activin A, activin B, myostatin and GDF11, are essential regulators of adult tissue homeostasis. Blocking the activity of these proteins using soluble forms of ActRIIA or ActRIIB has been shown to increase muscle and bone mass, correct anaemia and protect against diet-induced obesity. While exciting, these multiple actions of soluble ActRIIA/IIB limit their therapeutic potential and new reagents are required that target only one, or a subset, of ActRIIA/IIB ligands. Here, we modified the activin A and activin B prodomains, regions required for mature growth factor synthesis and activation, to generate specific activin antagonists. Initially, we fused the prodomains to the Fc region of a mouse IgG2A antibody and, subsequently, we incorporated “fastener” residues (Lys45, Tyr96, His97 and Ala98,activin A numbering) that help confer latency to pro-myostatin. For the activin A prodomain, these modifications generated a reagent that potently (IC50 5nM) and specifically inhibited activin A signalling in vitro and activin A-induced muscle wasting in vivo. Interestingly, the modified activin B prodomain inhibited both activin A and B isoforms in vitro (IC50 ~2nM) and in vivo, suggesting it could serve as a general activin antagonist. Importantly, unlike soluble ActRIIA/IIB, the modified prodomains did not inhibit myostatin or GDF11 activity. Finally, to underscore the therapeutic utility of specifically antagonising activin signalling, we demonstrate that the modified activin prodomains can promote significant increases in muscle mass.