title: S6K1 Is Required for Increasing Skeletal Muscle Force during Hypertrophy.
abstract: 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.
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Marabita
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Baraldo
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Solagna
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
authors.forename: Judith Johanna Maria
authors.initials: JJM
authors.lastname: Ceelen
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sartori
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nolte
authors.affiliation: Institut Necker-Enfants Malades, Inserm, Université Paris Descartes, CS 61431 Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nemazanyy
authors.affiliation: 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.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pyronnet
authors.affiliation: Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Kruger
authors.affiliation: Institut Necker-Enfants Malades, Inserm, Université Paris Descartes, CS 61431 Paris, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy; Department of Biomedical Sciences, University of Padova, 35137 Padova, Italy. Electronic address: bert.blaauw@unipd.it.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D006801:Humans; D006984:Hypertrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000235:genetics; D010455:Peptides / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D066329:Protein Aggregates / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D055948:Sarcopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; C072437:P62 peptide; D010455:Peptides; D010750:Phosphoproteins; D066329:Protein Aggregates; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020123:Sirolimus
keywords: AKT; S6K1; hypertrophy; mTOR; muscle force; p62; protein aggregates; rapamycin; skeletal muscle