The signal transduction cascades that maintain muscle mass remain to be fully defined. Herein, we report inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in vitro decreases myotube size and protein content after 3d treatment with a MEK inhibitor. Neither p38 nor JNK inhibitors had any effect on myotube size or morphology. ERK1/2 inhibition also up-regulated gene transcription of atrogin-1 and MuRF-1, and down-regulated the phosphorylation of Akt and its downstream kinases. Forced expression of EGFP-tagged MAPK phosphatase-1 (MKP1) in soleus and gastrocnemius muscles decreased both fiber size and reporter activity. This atrophic effect of MKP1 was time-dependent. Analysis of the reporter activity in vivo revealed that the activities of nuclear factor kappa B (NFkB) and 26S proteosome were differentially activated in slow and fast muscles, suggesting muscle type-specific mechanisms may be utilized. Together, these findings suggest that MAPK signaling is necessary for the maintenance of skeletal muscle mass as inhibition of these signaling cascades elicits muscle atrophy in vitro and in vivo.