Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load

• Published in: Scientific reports 2021-02, Vol.11 (1), p.3447-3447, Article 3447
• Main Authors: Kuramoto, Naoki, Nomura, Kazuhiro, Kohno, Daisuke, Kitamura, Tadahiro, Karsenty, Gerard, Hosooka, Tetsuya, Ogawa, Wataru
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 3-Phosphoinositide-Dependent Protein Kinases - genetics; 3-Phosphoinositide-Dependent Protein Kinases - metabolism; 692/4017; 692/4020; Adrenergic beta-Agonists - pharmacology; Adrenergic receptors; Animals; Cell Line; Clenbuterol; Clenbuterol - pharmacology; Gene expression; Humanities and Social Sciences; Hypertrophy; Insulin - metabolism; Kinases; Mechanical Phenomena; Mechanical properties; Mice; Mice, Knockout; multidisciplinary; Muscle, Skeletal - anatomy & histology; Muscle, Skeletal - metabolism; Musculoskeletal system; Phosphorylation; Protein biosynthesis; Protein synthesis; Protein turnover; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Adrenergic, beta-2 - metabolism; Ribosomal protein S6; Ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases - metabolism; Science; Science (multidisciplinary); Signal Transduction; Skeletal muscle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-83098-z

Phosphatidylinositol 3-kinase (PI3K) plays an important role in protein metabolism and cell growth. We here show that mice (M-PDK1KO mice) with skeletal muscle–specific deficiency of 3′-phosphoinositide–dependent kinase 1 (PDK1), a key component of PI3K signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of mechanical load–induced muscle hypertrophy. Whereas mechanical load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by mechanical load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of kinase cascades such as the S6K-S6 axis, which plays a key role in protein synthesis. Administration of the β 2 -adrenergic receptor (AR) agonist clenbuterol activated the S6K-S6 axis in skeletal muscle and induced muscle hypertrophy in mice. These effects of clenbuterol were attenuated in M-PDK1KO mice, and mechanical load–induced activation of the S6K-S6 axis and muscle hypertrophy were inhibited in mice with skeletal muscle–specific deficiency of β 2 -AR. Our results suggest that PDK1 regulates skeletal muscle mass under the static condition and that it contributes to mechanical load–induced muscle hypertrophy, at least in part by mediating signaling from β 2 -AR.