The molecular mechanisms underpinning the loss of skeletal muscle mass and strength associated with insulin resistance remain to be extensively investigated. There is mounting recognition that certain ligands of the transforming growth factor (TGF)-? family are upregulated in insulin resistant states, including obesity. This study analyses the expression of potent ligands of this family, TGF-?1 and myostatin (MSTN) and downstream components of the canonical TGF-? family signaling pathway (Smads) in skeletal muscle from lean and insulin resistant obese subjects. Design and Methods: Biopsies taken from the rectus abdominis muscle of lean (n = 13) and obese subjects (n = 20) were analyzed for the expression of TGF-?1 and MSTN as well as TGF-? signaling components, Smad2, 3, and 4, and transcription of the muscle regulatory factors (MRFs), MyoD and myogenin. Results: Increases in Smad2 and Smad3 phosphorylation, Smad4 and total Smad3 were observed to be coincident with altered transcription of MyoD and myogenin. TGF-?1 and MSTN protein levels were not significantly altered. Conclusion: Thus, increased Smad signaling is likely to account for, at least, a proportion of obesity and insulin resistance-related muscle atrophy through reduced MRF, particularly MyoD, transcription. The major regulatory ligand may not be MSTN and further members of the TGF-?1 superfamily should be considered.