The regulation of cell size depends on a delicate balance between protein synthesis and breakdown. Skeletal and cardiac muscle adapt to hormonal and neuronal stimuli and can rapidly hypertrophy and atrophy; however, the extent to which these processes occur in smooth muscle is less clear. Atrophy in striated muscle results from enhanced protein breakdown and is associated with a common transcriptional profile and activation of the ubiquitin-proteasome pathway, including induction of the muscle-specific ubiquitin protein ligases atrogin-1 and muscle ring-finger protein 1 (MuRF-1). Here we show that atrogin-1 is also expressed in smooth muscle, and that both atrogin-1 and MuRF-1 are upregulated in the uterus following delivery, as rapid involution occurs. While these two genes are similarly induced in all types of muscle during rapid loss of cell mass, other striated muscle atrophy-specific transcriptional changes are not observed during uterine involution, suggesting different underlying molecular mechanisms. These results raise the possibility that activation of atrogin-1 and MuRF-1 may be a common general adaptation in cells undergoing a rapid reduction in size.