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Cullin E3 Ligase Activity Is Required for Myoblast Differentiation.
Jordan Blondelle1, Paige Shapiro1, Andrea A Domenighetti2
1Division of Cardiology, University of California San Diego, La Jolla, CA-92093 USA.
Journal of Molecular Biology
|February 28, 2017
Summary
Cullin E3-ligase activity is essential for muscle cell differentiation and neuromuscular junction formation. Inhibiting this process raises concerns for muscle homeostasis and regeneration in patients undergoing cancer treatment.
Area of Science:
- Muscle biology
- Cellular signaling
- Biochemistry
Background:
- Cullin E3-ubiquitin ligases are known for their role in muscle atrophy.
- Their function in muscle differentiation and neuromuscular junction formation is less understood.
Purpose of the Study:
- To investigate the role of cullin E3-ligase activity in myoblast differentiation and neuromuscular junction formation in vitro.
- To assess the impact of neddylation inhibition on muscle cell differentiation.
Main Methods:
- Utilized C2C12 myoblasts and primary satellite cells (mouse and human).
- Employed the NAE1 inhibitor MLN4924 (Pevonedistat) and siRNA against nedd8.
- Examined early and late stages of myoblast differentiation.
Main Results:
- Cullin E3-ligase activity, modulated by nedd8, is crucial for all stages of in vitro muscle cell differentiation.
- Inhibition of cullin activity impairs myoblast differentiation and neuromuscular junction formation.
- Identified potential cullin E3-ligase substrates (ZBTB38, Bhlhe41, Id1) involved in terminal differentiation.
Conclusions:
- Cullin E3-ligase activity is indispensable for the muscle cell differentiation program in vitro.
- MLN4924's clinical use raises concerns regarding muscle homeostasis and regenerative capacity in cancer patients, who often suffer from cachexia.
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