title: Cullin E3 Ligase Activity Is Required for Myoblast Differentiation.
abstract: The role of cullin E3-ubiquitin ligases for muscle homeostasis is best known during muscle atrophy, as the cullin-1 substrate adaptor atrogin-1 is among the most well-characterized muscle atrogins. We investigated whether cullin activity was also crucial during terminal myoblast differentiation and aggregation of acetylcholine receptors for the establishment of neuromuscular junctions in vitro. The activity of cullin E3-ligases is modulated through post-translational modification with the small ubiquitin-like modifier nedd8. Using either the Nae1 inhibitor MLN4924 (Pevonedistat) or siRNA against nedd8 in early or late stages of differentiation on C2C12 myoblasts, and primary satellite cells from mouse and human, we show that cullin E3-ligase activity is necessary for each step of the muscle cell differentiation program in vitro. We further investigate known transcriptional repressors for terminal muscle differentiation, namely ZBTB38, Bhlhe41, and Id1. Due to their identified roles for terminal muscle differentiation, we hypothesize that the accumulation of these potential cullin E3-ligase substrates may be partially responsible for the observed phenotype. MLN4924 is currently undergoing clinical trials in cancer patients, and our experiments highlight concerns on the homeostasis and regenerative capacity of muscles in these patients who often experience cachexia.
authors.affiliation: Division of Cardiology, University of California San Diego, La Jolla, CA-92093 USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Blondelle
authors.affiliation: Division of Cardiology, University of California San Diego, La Jolla, CA-92093 USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Shapiro
authors.affiliation: Rehabilitation Institute of Chicago, Chicago, IL-60611 USA; Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, IL-60611, USA.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Domenighetti
authors.affiliation: Division of Cardiology, University of California San Diego, La Jolla, CA-92093 USA. Electronic address: slange@ucsd.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lange
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D032446:Myoblasts / Q000201:enzymology* / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D044767:Ubiquitin-Protein Ligases
keywords: E3-ubiquitin ligase; MLN4924; cullin; muscle development