EIF4A3-Induced Circular RNA CircDdb1 Promotes Muscle Atrophy through Encoding a Novel Protein CircDdb1-867aa

Area of Science:

• Molecular Biology
• Genetics
• Physiology

Background:

• Skeletal muscle atrophy is a debilitating condition with limited understanding of underlying molecular mechanisms.
• Circular RNAs (circRNAs) are emerging as key regulators in various biological processes, but their role in muscle atrophy remains largely unexplored.

Purpose of the Study:

• To investigate the involvement of circRNAs in skeletal muscle atrophy.
• To identify specific circRNAs that regulate muscle atrophy and elucidate their mechanisms of action.

Main Methods:

• Expression analysis of circRNAs in various muscle atrophy models (in vivo and in vitro).
• Gain-of-function and loss-of-function studies of identified circRNAs.
• Identification of protein-protein interactions and downstream signaling pathways.

Main Results:

• A conserved circRNA, circDdb1, derived from the DDB1 gene, is significantly upregulated in multiple muscle atrophy conditions, including aging.
• Ectopic expression of circDdb1 induces muscle atrophy, while its inhibition ameliorates atrophy caused by various stimuli (dexamethasone, TNF-α, Ang II, denervation, immobility).
• circDdb1 encodes a novel protein (circDdb1-867aa) that enhances eEF2 phosphorylation, reducing protein translation and promoting atrophy.

Conclusions:

• circDdb1 acts as a shared molecular regulator across diverse muscle atrophy pathologies.
• circDdb1 represents a promising therapeutic target for combating skeletal muscle wasting.