Development and growth of the muscle tissue

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(1)Development and growth of the muscle tissue. Isabelle Cassar-Malek isabelle.cassar-malek@inra.fr. Inra UMR Herbivores 63122 Saint-Genès-Champanelle.

(2) Myogenesis. Muscle development. Myogenesis. Fetal growth. Postnatal growth 2.

(3) 1-ORGANOGENESIS Skeletal muscles of higher vertebrates arise from the embryonic mesoderm. 3.

(4) Fetal development 1st trimester. F. 1st month. gastrulation neurulation. 3rd. 3rd 2nd month month. body, limbs. nervous system. Morphogenesis. somitogenesis Embryogenesis. 2nd. Growth, Differentiation, Maturation. Human. 4.

(5) Embryogenesis Stage 6. (~13 d p. ovulation). Stage 7. (~ 16 d p. ovulation). Gastrulation. Stage 8. (~ 17-19 d p. ovulation). (~ 19-21 d p. ovulation). Somite formation. Neurulation. 13-20 somite pairs. Stage 9. 20-21 somite pairs. Stage 10. (~ 21-23 d p. ovulation). 4-12 somite pairs. 30-40 somite pairs. 1st month Human Stage 11. (~ 23-25 d p. ovulation). http://www.visembryo.com/baby. Stage 12. (~ 25-27 dp. ovulation). Stage 13. (~ 27-29 dp. ovulation) 5.

(6) 3 primary germ layers. established during gastrulation 6.

(7) Differentiation of the mesoderm layer intermediate paraxial Neural streak. latéral. Human: 22 days. Mouse: 8 days. http://www.med.unc.edu/embryo_images/unit-mslimb/mslimb_htms/mslimb001a.htm 7.

(8) Subdivision of the mesoderm. 8.

(9) Somitogenesis Sillon neural. somite. TN. TN. NC notochorde. Human: 23 days. Mouse: 9 days. The paraxial mesoderm cells is segmented into cylindrical structures (somitomeres) early in the third week. 9. http://www.med.unc.edu/embryo_images/unit-mslimb.

(10) Somites. Neural tube. somite. Notochord. ectoderm. NT. = pairs of cylindrical, epitheliallyorganized mesenchymal segments. NC. epithelial somite. Lateral mesoderm. 10.

(11) Somitogenesis Somitomeres  somites Excepted Sm 1 to 7. A. TN. Final number =31. EcD. S. P Sm.  Human embryo (28 days). Metamerisation. 11.

(12) Take-home message The somites are transient structures that form progressively along the anteroposterior axis by segmentation of the paraxial mesoderm and reorganize without cell differentiation (primary organs).. 12.

(13) Take-home message The somites are responsible for the segmental organization of the body. They govern the metamerism of somite-derived tissues and spinal ganglia. Metameric division of the spine, the neural tube, the abdominal wall and thorax (ribs) depends on the organization of somites.. 13.

(14) Subdivisions of somites Hs 27 days. The somite subdivides into : • the sclerotome (ventral medial part) • the dermomyotome (dorsal part) 14.

(15) Derivatives of somites • the sclerotome that gives rise to cartilage, vertebrae and most of the ribs. • the dermomyotome, a double-layered structure composed of myotome in the lower layer and dermatome in the upper layer :  myotome : skeletal muscles (body, limbs)  dermatome, that generates dermis (skin). 15.

(16) Formation of the dermomyotome. - epaxial : dorsolateral - hypaxial : ventrolateral 16.

(17) Derivatives of the dermomyotome Epaxial dermomyotome Paraspinal and intercostal muscles (back) dermatome TN. NC. dermis. Hypaxial dermomyotome. Trunk and limb muscles. Cells migrating to the limb buds sclerotome cartilage, bones, vertebraes, ribs. Pre-muscle mass (limbs). Adapted from Relaix et Buckingham, 1999. 17.

(18) Epaxial vs. hypaxial muscles. Adapted from Dietrich et al., 1999 18.

(19) Limb muscles Cell migration. 28 jours. Limb colonisation. In the limb buds, the mesenchyme arises from • the lateral plate mesoderm ( skeleton) • the ventrolateral part of the myotome ( muscles) 19.

(20) Craniofacial muscles A : ocular muscle B : lateral rectus C : masseter. B A. C D. D : facial muscles. F G. E Région cardiaque. E : tongue. H. F : pharyngeal muscles G : laryngeal muscles H : neck muscle. They arise from cephalic somitomeres. and from rostro-occipital somites.. 20.

(21) Take-home message - ectoderm - endodem - mesoderm: - lateral - intermediate - paraxial :. s1-s7 : m. cranio-facial. .  somitomeres somites - sclerotome (cartilage, vertebrae) - dermomyotome : - dermis - myotome : -epaxial (back muscles) -hypaxial (limb and trunk muscle) 21.

(22) REGULATION Morphogenetic signals. 22.

(23) Morphogenic signals Signals secreted by the surrounding tissue (paracrine) orchestrating muscle development. Neural Tube. Notochord 23.

(24) Morphogenic signals Wingless Wnt1. Wnt7. Sonic hedgehog. Wnt signals control the induction of muscle tissue morphogenesis • Shh is necessary for the maintenance and proliferation of cells in the epaxial region •. 24.

(25) Morphogenic signals A gradient of BMP4 protein (lateral mesoderm) delays muscle differentiation in the ventrolateral area vs. the dorsomedial part.. BMP4 induces lateralization of the somite. 25.

(26) Morphogenic signals Growth factors secreted by the lateral mesoderm play an essential role in inducing the migration of precursor cells of hypaxial muscle.. TGFs. beta. FGFs  HGF (c-met receptor) . 26.

(27) C. Florian Bentzinger et al. Cold Spring Harb Perspect Biol 2012;4:a008342. ©2012 by Cold Spring Harbor Laboratory Press.

(28) REGULATION Genes controlling the commitment of cells into the muscle lineage and myogenic differentiation 28.

(29) Myogenesis (at the cell level) Determination Proliferation. Exit from the cell cycle. Precursor cell (somite) pre-myoblast. myoblast. Alignment. Fusion. Terminal differentiation. myotube Satellite cell. fibre 29.

(30) Definitions Cell fate specification: Labile state where a cell has reversibly acquired fate.. Determination: state where a cell has irreversibly acquired. fate (ligneage commitment regardless of the environment ; changes in gene expression transmitted to offspring cell).. Differentiation: changes involved in the diversification of the structure and function of cells. Acquisition of the characteristics that allow different cell types to perform their functions. 30.

(31) TRANSCRIPTION FACTORS Key genes (transcription factors) control the expression of target genes. examples covered: 1-Pax3 and cell specification 2-myogenic regulatory factors (MRFs). 31.

(32) 1-Paired-box homeotic factor 3 Pax3 Expression. • paraxial mesoderm Pax3 Pax3. • dermomyotome • cells colonizing limb buds • neurogenic precursors. 32.

(33) Pax3/epaxial m. vs hypaxial m.. Adapted from Dietrich et al., 1999. 33.

(34) Pax3 function and action No hypaxial myotome and limb musculature in Pax3 -/- mice.. •. Pax3 induces myogenesis in totipotent cells. • Overexpression of a dominant negative Pax3 abolishes myogenesis in mice. • Pax3 controls the expression of myogenic factors •. Role in myogenic specification 34.

(35) 2-Myogenic Factors (MRFs) The muscle IDENTITY is conferred by the expression of "myogenic regulatory factors" . MyoD. Myogenic determination factor 1. Davies et al., 1987. Myf-5. Myogenic factor 5. Braun et al., 1989. Myogenin. Myogenin. Wright et al., 1989. MRF-4. Myogenic regulatory factor 4. Rhodes et al.,1989. MyoD family 35.

(36) Experimental demonstration Fibroblasts from mouse embryos cultured in the presence of 5-azacytidine differentiate mainly in myoblasts.. MyoD family. 36.

(37) Identification. Identification of MyoD1, myogenin, Myf5, MRF4. 37.

(38) Structure E12 E47. Id. Helix Loop. +. -. Helix. Basic domain (DNA binding). Basic Helix-Loop-Helix (bHLH) Transcription factors Heterodimerization with bHLH proteins. 38.

(39) Activity COOH. COOH. NH2. H1. H1. +++. +++. E box. NH2. Muscle gene. • Transcriptional activity • Bind to consensus E-box sequence (CANNTG): Found in promoters of many muscle-specific genes • Autoregulatory loop 39.

(40) Regulation By positive partners • E12/E47 • MEF2 family members (muscle enhancer factors: MEF2A, b, c, d) •MLP (Muscle LIM Protein) By negative partners Direct Interactions b. NH2. Twist I-mfa. Indirect Interactions. HLH cJun. COOH cdk4. Id. MyoD. MyoD. Id. ZEB. I-mfa. Id nucleus. Mist E12/E47 MyoR. E box. MyoD. E12/E47. E box. E box 40.

(41) Expression Days pc. 8 8,5. 9,5. 10,5. 11,5. 12,5. 13,5. 17,5. birth. adult. Somites/Myotome myf5 myogenin myoD MRF4. Limb buds myf5 myogenin myoD MRF4. Sequential expression during mouse development (in situ hybridization). According to Buckingham, 1992. 41.

(42) Expression in vitro Proliferation. Fusion. Differentiation. Myf5, MyoD Myogenin MRF4. 42.

(43) Function Invalidation experiments (knock-out) Genotype. Somitic cell. Myoblasts. Myotubes References. myf5-/-. Braun et al., 1992. myoD-/-. Rudnicki et al., 1992. myoD-/- et myf5-/-. Rudnicki et al., 1993. • Myf5 and MyoD: myogenic induction program (Determination) • Partially redundant functions • Myf5: epaxial muscle ; MyoD: hypaxial muscle 43.

(44) Function Gene-targeting experiments (knock-out) Genotype. Somitic cell. Myoblasts. Myotubes. References. myogenin-/-. Hasty et al., 1993 Nabeshima et al., 1993. MRF4-/-. Braun et Arnold, 1995 Patapoutian et al., 1995 Zhang et al., 1995. • myogenin: crucial role in differentiation • Compensation of MRF4 loss by myogenin ? 44.

(45) Function Knock-in experiments (gene x replaces gene y) Genotype. Somitic cell. Myoblasts Myotubes. References. myogenin KI myf5. Wang et al., 1996. MRF4 KI myogenin. Zhu et Miller, 1997. myogenin KI myf5 myogenin -/-. Wang et Jaenisch, 1997. • myogenin: role downstream of Myf5 and MyoD • Mrf4 can compensate for the absence of myogenin •importance of spatiotemporal expression 45.

(46) Regulation of myogenic induction. ≠ muscle in epaxial and hypaxial muscle Bryson-Richardson and Currie, 2008. 46.

(47) Features head / trunk Mechanisms are ≠. Pax3. Bryson-Richardson and Currie, 2008; Tzahor, 2009. 47.

(48) Myogenic lineages Somitic dermomyotome. Progenitor cells (pax3/pax7). Muscle precursors. Myotomal cells. Embryonic myoblasts. Muscle cells. Myoblasts (myotome). Primary fibres Myogenesis. Fetal myoblasts. Secondary fibres. Satellite cells. Satellite cells Fetal and postnatal growth, regeneration. 48.

(49) Take-home message SPECIFICATION. Pax3, (Six,Eya). DETERMINATION. Myf5 MyoD MRF4. DIFFERENTIATION. Myogenin. TERMINAL DIFFERENTIATION. MRF4. 49.

(50) 2-FETAL MUSCLE DEVELOPMENT. 50.

(51) Expression profiles during myogenesis. Semitendinosus muscle (D110 pc). Semitendinosus muscle (Adult). The protein profile and transcript profile are specific to the developmental stage and the type of muscle. 51.

(52) Histogenesis of the muscle Connective tissue. Myoblasts. Myotubes. Satellite cells. Fibres. Connective tissue. 52.

(53) Muscle connective tissue Bovine Totalcollagen. CT PM <TB< BF <ST= MA. Type I collagen. CT, MA. Type III collagen 110. 180-230. PM, BF, TB, ST 260. 15 birth. Age (days). The collagen content increases during the development of fibres and decreases during their growth and differentiation. 53.

(54) Muscle connective tissue Collagen isoforms at the end of fetal life. I. III. V. VI. Semitendinosus Muscle (D260 pc) (250X). IV. XII. XIV. 54.

(55) Myogenesis in cattle. 1st trimester. 3rd trimester. 2nd trimester. Adult. 55.

(56) Myogenesis in vitro Bovine Myoblasts. Proliferation. Alignment Myotubes. Fusion. Differentiation. 56.

(57) Stages of differentiation. Cycle exit. Early stage. fusion. morphological. specialised functional contractile enzymatic equipment apparatus. contractile. metabolic. 58.

(58) Key stages in cattle birth. 180 dpc 1st trimester. 2nd trimester. 3rd trimester Fixed total number of fibres. contractile metabolic. 59.

(59) Precocity of myogenesis in cattle Total number of fibres. Bovine Human Sheep. Birth or hatching. Swine. Rat Rabbit. Birds 60.

(60) Different generations of muscle fibres 40%. 2nd generation 3rd generation. 78%. 180 days. Total number of fibres. 1st generation. 66%. I. 30 dpc. I IIX. 90 dpc. IIA. 110 dpc 210 d. MyHC dev. MyHC 2a. 210 d. MyHC 2x. 210 j. Gagnière et al, 1999; Duris, 1999. 61. IIA X IIC, I.

(61) Precocity of muscle development in cattle Developmental switch. Disappearance of the fetal MyHC -10. birth. Appearance of adult fast MyHC 10. 20. 30 days. Bovine cattle: Picard et al, 1994 Rabbit: Gondret et al, 1996. Swine. Rabbit Rat. Swine: Lefaucheur et al, 1995 Rat: d ’Albis et al, 1989. 62.

(62) Contractile proteins MyHC. Immunoblotting. ELISA assay. MyHC 1 60. 260 CT MA. MyHC 2 60. 260 CT MA. 60. 260 CT MA. MyHC F 63.

(63) Muscle metabolism OXIDATIVE. GLYCOLYTIC ST CT. MA ST. MA. CT. 3rd trimester. 3rd trimester. Lactate deshydrogenase. Isocitrate deshydrogenase. Cattle 64.

(64) Intramuscular adipose tissue. ST muscle (fetus). Cattle. ST muscle (adult). AT appears late (Late pregnancy, early postnatal life)  See M Bonnet lecture 65.

(65) Take-home message (1/2) • Most of myogenesis occurs during fetal life (precocity) • Three generations of fibres • Fixed. total number of fibres by the end of the second trimester of gestation • The last third of gestation is marked by the acquisition of contractile and metabolic properties • Postnatal myogenesis is characterized by the growth of the fibres and the plasticity of their properties. 66.

(66) Bovine myogenesis : key stages (2/2) 1st trimester. 2nd trimester. 3rd trimester. 3rd generation. Hypertrophy, contractile and metabolic differentiation. 2nd generation 1st generation 60 dpc. Total number of fibres 110 dpc. 180 dpc. 210 dpc. 270 dpc. Fibres I,IIA,IIX. Iary Myotubes. IIary IIIary Myotubes. B. Picard et al, 2002. (no IIB). Myofibres. 67.

(67) 3-GROWTH In the fetus. 68.

(68) Muscle growth in the fetus Bovine ST muscle : mass x500 between 80 and 260 dp.c. Hyperplasia Hypertrophy. 69. Robelin, 1990.

(69) Regulation Growth factors. Fetal muscle. Innervation Hormones ? 70.

(70) GROWTH FACTORS FGF. proliferation differentiation. TGF beta myostatin. differentiation proliferation. Families EGF. proliferation. IGF. proliferation differentiation 71.

(71) The example of Myostatin Mutation in the myostatin (gdf8) gene Muscular Hypertrophy. Mice (knock-out). Double-muscled charolais (selection for mh mutation). 72.

(72) Myostatin phenotypes. Whippet (race dog). Overgrowth of muscle tissues = hypertrophy Human 73.

(73) Double-muscled cattle Hypermusculature (double-muscled) •. hyperplasia. • fibre hypertrophy. increased glycolytic fibres % • decreased collagen content • decreased intramuscular fat content •. • originating in fetal life. A model to understand the mechanisms underlying muscle growth and hypertrophy 74.

(74) A monogenic, autosomal segregation pattern • A gene initially suspected : mh (BTAU2) • The gene encoding myostatin was mh locus (mstn as a candidate gene). found at the. • Loss-of-function mutations in mstn gene lead to doublemuscling •a wild type "+" allele and a recessive “-" allele, causing the double-muscled phenotype in the homozygous condition.. 75.

(75) Mutations in cattle 5’. EXON 1. nt419(del7-ins10). EXON 2. Q204X. E226X. * N. PS. nt419(del7-ins10) STOP codon. EXON 3. nt821(del11). *. Pro-region. Q204X STOP codon. *. E291X. *. *. BTAU2. C313Y. CysTyr. C-term. E226X STOP codon. 3’. nt821(del11) STOP codon. C. C313Y Cysteine loss. An intronic mutation was recenly identified in Blonde Aquitaine (fixed in the population):  aberrent transcript (Bouyer et al, 2014 ) 76.

(76) Une nouvelle mutation du gène myostatine •. Substitution T (3811) G (3811) dans l'intron 2 du gène de la myostatine en B Aq. •. Création d’un site cryptique illégitime d’épissage  transcrit anormal. • Allèle mutant fortement exprimé. •  myostatine fonctionnelle et phénotype hypertrophique modéré de la B Aq? Bouyer et al. 2014. PLoS ONE 9(5): e97399. doi:10.1371/journal.pone.0097399.

(77) Function Mutations in the MSTN/gdf8 gene  reduce the production of functional myostatin  overgrowth of muscle tissue • • •. The protein normally restrains muscle growth, ensuring that muscles do not grow too large (statin function), is involved in muscle mass homeostasis, is involved in regulation of adipogenesis. 78.

(78) Muscle-specific expression Regulation of expression during myogenesis Myostatin Fibre-specific expression. Muscle mass regulation 79.

(79) Unités densitométriques arbitraires. m. semitendinosus 110 d.p.c. 10000. 180 d.p.c. a. 8000. b. 6000. b. b. 4000 2000. 260 d.p.c. m. biceps femoris b. 14000 12000 10000. a. ab. a. 8000 6000 4000 2000 0. 0. Bovine fetus. m. masseter Unités densitométriques arbitraires. 230 d.p.c. Unités densitométriques arbitraires. Expression. 10000 8000 6000 4000 2000 0. bc a. abc. c. • low expression (but > to postnatal) • changes during development • differentially according to muscle-type 80.

(80) Location Hybridization in situ 90 dpc. 180 dpc. 260 dpc. Bovine ST Muscle. A low number of muscle cells express the myostatin gene.. 81.

(81) « Fibre-specific » expression • in 2nd et 3rd generations • in the less differentiated cells mstn. MHCa. control. MHC l. MHC f. MHC r. 180 dpc. mstn. MHC a. MHC f. In IIA fast fibres at 260 dpc control. MHC r. 260 dpc. MHC I/IIB. 82.

(82) Expression in vitro Fusion. Fibroblasts myostatin. Differentiation. Myoblasts p c/f d1 d2 mt. cyclophilin. mt. Transient myostatin expression in the early differentiation stages 83.

(83) Regulation of MSTN expression Metalloproteases inhibitors HIMPs:. •Titincap Active Myostatin. • TAPI • BB-3103 • GASP-1. •hSGT. Golgi Apparatus. • FoxO1 • MRFs (MyoD, Myf5) • Hormones (Glucocorticoids...) • P38 MAPK, MKK6. Bioactive Peptide Second cleavage. Pro-region. Endoplasmic reticulum. NH2. COOH First cleavage. NH2. COOH Inactive Myostatin. - Glutamine - Anabolic Hormones : GH, Insulin, IGF-1. 84.

(84) Regulation of MSTN activity Active Myostatin. • FKBP12. BMP. P. P. Calveolin-3. ActRIIB. Rc Heterodimerization. ActRIIB. Activin. ActRI ActRI. ActRIIB ActRI ActRI ActRIIB. • BAMBI. • Follistatin • FLRG • GASP-1 • myostatin Propeptide • Proteoglycans: Decorin, β-glycans,Biglycan. SARA R-Smads. Smurf-1. Smad 7, Ski. P P R-Smads. Co-Smads Smad 6. Ub R-Smads. ERK P Co-Smads R-Smads 85.

(85) Myostatin target pathways Myostatin p21CKI. Myogenin, MyoD. Cdk2. Inhibition of proliferation (number of fibres). Inhibition of differentiation (number and size of fibres). p38MAPK Gène Atrogin-1/MAFbx. Proteolytic degradation (Atrophy). Muscle mass 86.

(86) Inhibition of differentiation Recombinant Myostatin. N. 23 aa. 109 aa Bioactive domain. C. Poly-(His) 0. 10. 100. 1000. peptide (ng/ml). control. 87.

(87) Delay in myogenesis in DM cattle Conventional. Conventional H. DM Inra95. EFαL. EFαLR. DM BBB. D4. EFαLR EFαLR EFαL FαLR. EFαL EFαR. EFαL. EFαL EFαLR. EFαR. EFαR L. L. 210 dpc EFαLR 260 dpc. D6. EFαR. L R. EFαLR. ?. EFαR. D8. L EFαR EFαLR. R. EFαR EFαLR 88.

(88) Molecular action Proliferation cycle. Survival? MYOSTATIN. Differentiation. myoD, myogenin. Regulation of the number of fibres. 89.

(89) Take-home message A member of the TGF-β superfamily Expression: Muscle + + + Mamary gland Adipose tissue. ↑ adipose depots Orientation towards adipogenesis ↑ metabolic effect. Myostatin. Negative regulator of muscle growth antiproliferative (number of fibres) (DM, constitutive ko in mice). anti-osteogenic factor Control of muscle mass (satellite cells, balance hypertrophy/atrophy) (Ab, conditional ko in mice) 90.

(90) A ROLE FOR INNERVATION. fibre. *. nerve. *. * Neuromuscular Junction. Early synaptogenesis (10th week in humans) 91.

(91) Innervation in the fetus Poly-innervation and thereafter mono innervation. Innervation. Differentiation of secondary fibres. Acquisition fast fibres properties. 92.

(92) HORMONAL REGULATION proliferation. T3. withdrawal from cycle. differentiation. T3 enhances myogenesis and muscle-gene expression (MyHC, metabolic enzymes) 93.

(93) 4-GROWTH During post-natal life. 94.

(94) Postnatal growth  mass between birth and adult stage (x 30)  length of fibres (bone growth) Bovine Muscle.  fibre section (x 3,6)  DNA content (x 5) Protein / DNA ratio (x 500) 95.

(95) Hypertrophic growth µm2. Fibre cross-section area IIX. 8000. Moy. 6000. IIA. 4000. I. 2000. 0 0. 5. 10. 15. 20. 25 months. 96.

(96) Crucial role for satellite cells • A larger number of nuclei / fiber is required to maintain the "DNA unit “ during growth. • In fibres, nuclei are post-mitotic.. Satellite cells= source of new nuclei Fusion with fibre. Activation Division. Quiescence. the number of nuclei in the fibres increases, the number of satellite cells is maintained « DNA unit »: volume of cytoplasm controlled by a nucleus. 97.

(97) Skeletal muscle and the satellite cell niche. C. Florian Bentzinger et al. Cold Spring Harb Perspect Biol 2012;4:a008342 ©2012 by Cold Spring Harbor Laboratory Press.

(98) Satellite cells • Quiescent • involved in growth and regeneration of muscle. nuclei. Fibre Satellite cell. • • • •. Adult muscle cells located at the periphery of the fibre mononucleated 4 à 15 % of nuclei. Satellite cell nucleus. 99.

(99) Properties. D’après Vincent Mouly, John Beauchamp. Qu’est-ce qu’une cellule musculaire satellite? M/S n° 6-7, vol. 19, juin-juillet 2003, p696 100.

(100) Cell cultures • Grinding and enzymatic digestion (fetal myoblasts) • Primo-explantation (satellite cells) Satellite cells. Myoblasts (260 dpc). Explant. 100 µm. 101.

(101) Postnatal growth and plasticity Fibre types. Puberty. %. I. 60 IIX. 40. IIA. 20 0. 3 wk. 9. 15. High growth rate  IIX. I. 19. months. Lower growth rate  IIX. IIA. After puberty: •  fast glycolytic fibres • more red oxidative muscles. IIX. 102.

(102) Regulation Hormones. Postnatal growth. Growth factors IGFs, myostatin. Activity, Innervation 103.

(103) Hormones Insulin Growth hormone. Thyroid Hormones. Glucocorticoids Steroids. HYPERTROPHY : Anabolic processus Protein synthesis Satellite cells 104.

(104) IGFs Enhance the size of muscle fibres - IGF-I (K.O). Hypotrophy Hypoplasia. +IGF-I (transgenic). Muscle Hypertrophy (x 2). Targets: • protein synthesis, • proliferation et differentiation of satellite cells 105.

(105) IGF-I Mice selected on their high levels of IGF-I at 12 weeks of life have an offspring with more developed muscle mass and less fat deposition than normal mice.. 106.

(106) IGF-I Its expression is regulated in muscle postnatally • in response to hormones GH, Insulin, steroids, thyroid hormones corticosteroids •  exercice •  malnutrition 107.

(107) Myostatin Inhibition of myostatin maturation Conditional K.O. Blocking antibodies. MUSCLE HYPERTROPHY Satellite cells. The muscle mass is maintained 108.

(108) Thank you for your attention!. 109.

(109)