Cellular hypertrophy

1. Cellular hypertrophy • Control of protein synthesis • Endogenous • Nutrient status • Functional adequacy • History • Exogenous • Nutrient availability • Growth factors • Space • General phenomenon, muscle context

2. Immediate controls on protein synthesis • Substrate availability • m-/t-RNA • Amino acids • Catalyst availability & activity • rRNA & S6 phosphorylation • eIF2, 4 • eEF1, 2

3. Stimuli for muscle size change • Developmental • Strongly dependent on growth factors • Feedforward • Mechanical • Overload (high force, short time) • Overwork (low force, long time) • Endogenous factors • Feedback • Integrative • Autocrine/paracrine factors

4. Linking growth stimuli to growth • Insulin/IGF-1 • IGF1IGF1RIRS1 Grb2SOSRasRafMEKERKMNK--|4EBP1 PI3K • PI3K • IGF1/FAKPI3KPIP3PDK1akt --|TSC--|RhebmTOR RSKS6translational apparatus --|4EBP--|eIF4Etranslational activity --|eEF2K--|eEF2translational activity --|GSK3b--|eIF2translational activity

5. Negative controls on growth • AMPK • AMPAMPK TSC--|mTOR --|IRS1 GSK3b--|eIF2 • FOXO, esp FOXO3 • Oxidative/heat stress/Ppar-g  FOXO p27Kip--|cell cycle MuRF, atroginubiquitinylation myostatin (FOXO1) • TGF-b • TGFRSMADapoptosis, cell cycle arrest…

6. Conditions that change growth • High force generation • Functional adequacy • Intrinsic force sensors • Damage • Nutrient/metabolite status – ATP/O2/Ca2+ • Stretch • Functional adequacy? • Force/deformation sensors? • Unloading • Functional superfluity

7. Paracrine signaling • Prostaglandins • PGE2, PGF2a • Rapid activation, w/o upregulation of PLA2 • IGF-1 • Upregulated over hours • Distinct from endocrine IGF-1 or insulin • Myostatin • TGF-b member • Growth inhibitor

8. 1.2 1.0 0.8 Glucose Insulin 0.6 Response Glucose uptake PI3K 0.4 p70S6k 0.2 Protein synthesis 0.0 0 5 10 15 20 25 30 -0.2 Time after exercise (h) Time course • Blood composition • Intracellular signaling • Protein synthesis • Sequential and slow Normalized response of several growth-related molecules after a single bout of resistance exercise Hernandez, et al., 2000

9. Integrative control • Mechanical demand • FAK, Ca2+, other force sensors • Energetic demand • AMPK, GSK, Ragulator • Net growth of cell depends on balance • Overloaded, high energy cell grows • Overloaded, starved cell atrophies • Infrequent overload is sufficient to maintain or gain functional capacity • mTOR is a signal integrator