Skeletal muscles are dynamic tissues that possess regenerative abilities, which require multiple processes and regulatory factors. Ubiquitin C-Terminal Hydrolase L1 (UCHL1), which is primarily expressed in neuronal tissues, was upregulated in skeletal muscles in disease conditions but its functional role in skeletal muscles is unknown. Using mouse myoblast cells C2C12 as an in vitro model, this study reported that UCHL1 elicits different regulation in myoblast cell proliferation and differentiation. We first observed that UCHL1 protein level was continuously declined during cell differentiation. Gene knock-down of UCHL1 by siRNA resulted in a significant decrease in cell proliferation but marked acceleration of cell differentiation and myotube formation. Meanwhile, UCHL1 gene knockdown upregulated myogenic factors myoD and Myogenin (MyoG). In mice, UCHL1 was significantly upregulated in denervated skeletal muscle. Overall, these novel data suggest that UCHL1 may play a role in myogenesis by promoting myoblast proliferation and inhibiting differentiation. (C) 2017 Elsevier Inc. All rights reserved.