S6K1 Is Required for Increasing Skeletal Muscle Force during Hypertrophy
Manuela Marabita,
Martina Baraldo,
Francesca Solagna,
Judith Johanna Maria Ceelen,
Roberta Sartori,
Hendrik Nolte,
Ivan Nemazanyy,
Stéphane Pyronnet,
Marcus Kruger,
Mario Pende,
Bert Blaauw
Affiliations
Manuela Marabita
Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy
Martina Baraldo
Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy
Francesca Solagna
Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy
Judith Johanna Maria Ceelen
Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy
Roberta Sartori
Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy
Hendrik Nolte
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
Ivan Nemazanyy
Institut Necker-Enfants Malades, Inserm, Université Paris Descartes, CS 61431 Paris, France
Stéphane Pyronnet
Université de Toulouse, Institut National de la Recherche Médicale (INSERM-UMR-1037), Centre de Recherches en Cancérologie de Toulouse (CRCT), Equipe Labellisée Ligue Contre le Cancer, 31432 Toulouse, France
Marcus Kruger
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
Mario Pende
Institut Necker-Enfants Malades, Inserm, Université Paris Descartes, CS 61431 Paris, France
Bert Blaauw
Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy
Loss of skeletal muscle mass and force aggravates age-related sarcopenia and numerous pathologies, such as cancer and diabetes. The AKT-mTORC1 pathway plays a major role in stimulating adult muscle growth; however, the functional role of its downstream mediators in vivo is unknown. Here, we show that simultaneous inhibition of mTOR signaling to both S6K1 and 4E-BP1 is sufficient to reduce AKT-induced muscle growth and render it insensitive to the mTORC1-inhibitor rapamycin. Surprisingly, lack of mTOR signaling to 4E-BP1 only, or deletion of S6K1 alone, is not sufficient to reduce muscle hypertrophy or alter its sensitivity to rapamycin. However, we report that, while not required for muscle growth, S6K1 is essential for maintaining muscle structure and force production. Hypertrophy in the absence of S6K1 is characterized by compromised ribosome biogenesis and the formation of p62-positive protein aggregates. These findings identify S6K1 as a crucial player for maintaining muscle function during hypertrophy.