Deubiquitinase UCHL1 Regulates Myogenesis in Skeletal Muscles

Abstract

Myogenesis is crucial for skeletal muscle regeneration in injury and disease. This multi‐step process is closely regulated by several myogenic factors. Timely activation and inactivation of these factors require ubiquitin‐proteasome system (UPS)‐mediated protein degradation. In this aspect, deubiquitinases (DUBs) could also play a role in myogenesis. Ubiquitin C‐terminal hydrolase L1 (UCHL1) is a DUB that is highly expressed in the brain. Though undetectable in adult skeletal muscles, UCHL1 protein level is significantly increased in injured muscles. However, the functional significance of UCHL1 in skeletal muscles is unknown. Using in vitro and in vivo approaches, this study tested a hypothesis that UCHL1 can play a role in skeletal muscle myogenesis and regeneration.Our data show that UCHL1 protein level was gradually downregulated during myoblast C2C12 differentiation. Knockdown of UCHL1 expression significantly reduced C2C12 cell proliferation. In contrast, UCHL1 knockdown markedly accelerated cell differentiation, evidenced by more myotubes in UCHL1 deficient cells, which was accompanied by significant upregulation of myogenic factors.In mouse muscles, UCHL1 was expressed by type I and IIa muscle fibers. Denervation increased UCHL1 protein levels in muscle fibers, which was completely abolished in muscles from the mice with UCHL1 skeletal muscle specific knockout (smKO). smKO mice showed reduced satellite cells in soleus and declined type I fiber number. Moreover, smKO muscles exhibited right shift of fiber distribution and a remarkable loss of type I muscle fiber upon denervation as compared with wildtype ones. These observations further suggest the potential involvement of UCHL1 in myogenesis for the regeneration of type I fibers.Support or Funding InformationNIH grants No. 1R15HL118696 and 1R03AG051926 and USD SSOM BBS bridge grant, CBBRe pilot grant, PQCD pilot grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.