Inhibition of activin and myostatin activities using ligand traps such as follistatin, soluble receptors, and propeptides have been shown to ameliorate skeletal muscle wasting in multiple mouse models of cancer cachexia and muscular dystrophies. Though effective, clinical transition of these approaches has been hindered as a result of their systemic activities promoting off-target effects. Toward the goal of seeking tissue-specific activin/myostatin interventions, we explored the ability of membrane bound TMEPAI (transmembrane prostate androgen-induced) to block wasting within skeletal muscle. TMEPAI, a transcriptional target of exogenous activin, is a known inhibitor of TGF-β1 mediated SMAD2/3 signalling. In this study we show that TMEPAI can also block activin A, activin B, myostatin and GDF-11 in vitro signalling. Adeno-associated viral (AAV) gene delivery of TMEPAI into healthy C57/BL6 mice increased local muscle mass by as much as 30%. Increased muscle mass was attributed to hypertrophy of fibers in TMEPAI expressing muscles, and coincided with an upregulation in protein synthesis pathway markers. The ability of TMEPAI to block activation of the canonical activin/myostatin SMAD2/3 pathway, was determined by co-delivering activin A and TMEPAI into the muscles of healthy mice. TMEPAI effectively attenuated muscle loss induced by activin A in this setting, and prevented atrophy of muscle fibers. Activin-induced phosphorylation of SMAD3 protein was suppressed in muscles co-expressing TMEPAI, as was transcription of activin target genes. Finally, we show that TMEPAI can protect local muscle wasting in the C26-colon cancer model of cachexia in mice. These results support that viral gene delivery of TMEPAI can effectively increase muscle mass, specifically within skeletal muscle, via inactivation of the activin/myostatin SMAD 2/3 pathway.