1. Chapter 8. Muscle molecular mechanism in strength training PF. Gardiner, Advanced neuromuscular exercise physiology

2. Overview Mitogenic: growth-promoting Stress and strain on muscular structures as signals through mechanotransduction receptors via several pathways Acute resistance exercise ↑protein synthesis and degradation – Effect may last for hours to days – Relatively short exposure is sufficient in animal studies

3. Acute resistance exercise increase both protein synthesis and breakdown

4. Stretch as a Signal for Adaptation Force as a signal to resistance-related adaptations ↑muscle weight when rabbit muscles are immobilized in a lengthened position – result of increased muscle fiber length – electrical stimulation added effect – stretch, independent of increased contractile activity, can stimulate protein synthesis via several pathways

5. Mitogen-activated protein kinases, MAPK Central factor for stretch-related signal transduction Induced by G-protein pathway Downstream – FOS, JUN – MAPK-regulated transcription factors stretch causes physical deformation of the 3D configuration of the transmembrane receptors – Activation of that receptor, similar to attachment of its ligand – integrin

6. 6 Transcription Factors

7. Ex Biochem c25-act transcript7 25.7 Response Elements Are Recognized by Activators Response elements may be located in promoters or enhancers. Figure 25.11

8. Stretch-related signal transduction

9. Detailed MAPK pathways http://en.wikipedia.org/wiki/File:MAPKpathway.jpg

10. Ex Biochem c25-act transcript10

11. Insulin-like growth factor -1, IGF-1 Produced by liver and muscle Stimulate cell hypertrophy in cultured myotubes ↑ initiating factors in translation: eIF4E- eIF4G (eukaryotic initiating factor) IGF-1 mRNA and protein ↑after resistance exercise

12. Akt and mTOR Cascade Akt (protein kinase B, PKB) activated by IGF-1 mTOR (Mammalian target of rapamycin): activated by Akt – Also activated by leucine Downstream targets of mTOR: proteins that control translation – S6K1 (p70 S6K ), eIF4G, and eIF4E binding protein 4EBPl After exercise: ↑, then↓ – a transient increase in translation initiation – when repeated after each training session, results in muscle hypertrophy

13. Role of mTOR in response to resistance training

14. Ex Nutr c8-protein14 mTOR (mammalian target of rapamycin) 訊息傳遞路徑：上游 Laplante & Sabatini, 2012

15. Ex Nutr c8-protein15 mTOR 訊息傳遞路徑：下游 Laplante & Sabatini, 2012

16. Proto-Oncogenes FOS, JUN, and MYC Rapid ↑after mechanical stimulus Bind to DNA Important in muscles FOS, JUN: bind to promoter region of several growth-related genes MYC: involved in mitosis 有絲分裂

17. JUN, FOS, MYC pathways

18. Passive stretch of rabbit muscles

19. Passive stretch and electrical stimulation of rabbit muscles

20. Other factors Muscle Regulatory Factor (MRF) Genes – active during muscle development, but present at negligible levels in normal adult muscles – Myf-5, MyoD1. MRF4. and myogenin – ↑after mechanical stimulus Myostatin – negative influence on muscle growth – ↓ after mechanical stimulus

21. Posttranslational changes ↑ RNA activity: units of protein synthesis per unit time per unit RNA after acute stimulus ↑ribosome – ↑ribosomal protein, ↑total RNA (mostly ribosomal RNA) ↑ numerous eukaryotic initiation factors (eIF) that facilitate peptide initiation at the ribosome mRNAs). Downregulated Downregulate (↓) genes in catabolic effects – elongation factor-2 kinase (which inactivates elongation factor 2) – cathepsin C (a lysosomal protease)

22. Intracellular Proteolytic Systems calcium-activatcd ncutral proteases (calpains) The Iysosomal proteases ATP-ubiquitin-dependent pathway – May be ↓ by ß-hydroxy-ß-melhylbutyrate (HMB) All ↑after acute resistance exercise Apoptosis ( 細胞凋亡, programmed cell death) ↑after acute resistance exercise

23. Ubiquitin pathway

24. Ex Biochem c8-protein synthesis24 8.2 Protein Synthesis: Initiation, Elongation, and Termination The ribosome has three tRNA- binding sites. An aminoacyl-tRNA enters the A site. Peptidyl-tRNA is bound in the P site. Deacylated tRNA exits via the E site Translocation: ribosome move one triplet along mRNA Figure 8.3

25. Ex Biochem c8-protein synthesis25 Figure 8.23: 43S complex binds to mRNA-factor complex. PABP: poly(A)-binding protein

26. Ex Biochem c8-protein synthesis26

27. Role of connective tissue ↑collagen synthesis in tendons ↑muscle collagen synthesis ↑ Iysyl oxidase), an enzyme involved in cross- linking collagen

28. Ex Nutr c8-protein28 重量訓練後補充蛋白質 時機與效果 Kerksick, 2012

29. Ex Nutr c8-protein29 各種蛋白質來源對肌肉合成的效果 結合長期重量訓練 Kerksick, 2012