Poster abstracts
Poster number 43 submitted by Jennifer Petrosino
BEX1 mediated translational control of muscle growth
Jennifer M. Petrosino (Biomedical Sciences Graduate Program; Department of Physiology and Cell Biology, College of Medicine), Colin D. Angell (Department of Physiology and Cell Biology, College of Medicine ), Mike Adam (Cincinnati Childrens Hospital Medical Center), Steve S. Potter (Cincinnati Childrens Hospital Medical Center), Federica Accornero (Department of Physiology and Cell Biology, College of Medicine )
Abstract:
In adult skeletal muscle, myogenesis counteracts damage by promoting muscle regeneration. When muscles regenerate following injury or stress, mRNA translation becomes de-repressed, thus allowing for muscle repair. The cumulative effect of activating myogenic translation to promote myofiber repair is enhanced global rates of protein synthesis, which can consequently result in increases in muscle fiber cross-sectional area (hypertrophy). Using single and repeated intramuscular injections of barium chloride to model conditions of acute and chronic injury, we identified that Brain Expressed X-Linked Protein 1 (BEX1), a protein highly induced during myogenesis, is required for muscle repair and growth. Genetic ablation of BEX1 resulted in impaired growth and repair mechanisms in injured skeletal muscle. To gain mechanistic insights into how regeneration is affected by the loss of BEX1, we performed single-cell droplet sequencing on injured wild-type and BEX1 knockout muscles and identified that in the absence of BEX1, myogenic cells specifically fail to upregulate translation-specific pathways required for repair. Without upregulation of these pathways, BEX1 KO muscles failed to repair back to baseline size, demonstrating that the loss of BEX1 in regenerating muscles has anti-hypertrophic consequences. To begin to understand the molecular details of how BEX1 functions in regulating translation and muscle size, we undertook an extensive analysis of the BEX1 protein interactome by proteomic screening. This approach and follow-up experiments revealed that BEX1 is part of the multi-tRNA synthetase complex that enhances the efficiency of translation. To see if the ability of BEX1 to target protein translation affects the potential for muscles to undergo overload-induced hypertrophy, we utilized a model of synergistic muscle ablation and found that the loss of BEX1 was sufficient to completely abrogate increases in muscle growth. Additionally, delivery of adeno-associated virus BEX1 (AAV2-BEX1) to wild-type mice, and a dystrophic model with impaired protein synthesis, resulted in increases in muscle size and functional hypertrophy. Together with the finding that BEX1 is required for, and promotes, the hypertrophic response of skeletal muscle, our data implicate BEX1 as a regulator of muscle growth.
Keywords: translation , tRNA synthetases, skeletal muscle growth