Author(s): BRITTO, F., DI GALLO, M., LAUNAY, T., PEREIRA, D., SOTIROPOULOS, A., BENOIT, V., PASCAL, M., Institution: UNIVERSITÉ DE PARIS CITÉ/INSTITUT COCHIN, Country: FRANCE, Abstract-ID: 159

INTRODUCTION:
Mice skeletal muscle is composed of 4 different myofibers which display heterogenic response during muscle hypertrophy or atrophy. Fast glycolytic myofibers IIb are notably resistant to overload-induced hypertrophy. In addition, overload drives to myofibers shift from glycolytic to slow oxidative phenotype. However, the cellular mechanisms involved fibers IIb resistance to hypertrophy as well as the role of fibers shifting during hypertrophy are still poorly understood.
METHODS:
In order to answer these questions, we had performed plantaris overload in wild type (low oxidative metabolism), muscle SIX1 KO (high oxidative phenotype), muscle SIX1 hypomorphic (moderate oxidative phenotype) and muscle AMPK KO mice and then performed cross sections to analyze CSA, typology and energetic metabolism. In addition, we performed a single nucleus RNA sequencing in overloaded plantaris to depict the mechanisms involved in fibers specific response to hypertrophy.
RESULTS:
We showed that fibers IIb overexpressed genes repressing muscle growth such as inhibitors of mTORC1 pathway (REDD2 and Deptor) and activators of Myostatin pathway (Myostatin, ActRIIb, Smad3, ALK4). We also demonstrated that SIX1 mutation (hypomorphism) leading to fibers shifting from glycolytic to oxidative phenotype improves hypertrophy. In contrast, despite a greater fibers shifting, SIX1 deletion (SIX1 KO) droved to huge glycolysis defect and abolished hypertrophy. Finally, we show that AMPK and glycolysis are important for muscle adaptation to growth process.
CONCLUSION:
Our results suggest that fast glycolytic fibers could are metabolically and genetically limited for hypertrophy in comparison to slow oxidative fibers and that the phenotype shift could be necessary for muscle hypertrophy.