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Muscles are remarkably adaptive. Any doubts?

Muscles are remarkably adaptive. Any doubts?. Musculoskeletal Issues. Disease / genetics Muscular dystrophy Cancer / AIDS cachexia Obesity / diabetes Casting Bedrest Spinal cord or nerve injury Surgery / rehab / disuse Aging Microgravity. Sarcomere (Basic Contractile Apparatus).

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Muscles are remarkably adaptive. Any doubts?

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  1. Muscles are remarkably adaptive. Any doubts?

  2. Musculoskeletal Issues • Disease / genetics • Muscular dystrophy • Cancer / AIDS cachexia • Obesity / diabetes • Casting • Bedrest • Spinal cord or nerve injury • Surgery / rehab / disuse • Aging • Microgravity

  3. Sarcomere (Basic Contractile Apparatus)

  4. Cellular Energy Production

  5. Tetanic Contraction

  6. Muscle Mass (g) · cosine Θ ρ (g/cm3) · Fiber Length (cm) PCSA (cm2) = Θ is the pennation angle of the muscle fibers

  7. Effects of Muscle Length and Contraction Velocity

  8. Muscles Respond to Loads • Transduction of mechanical load • Forces transmitted through extracellular matrix • Generate chemical signals • Activate voltage gated channels • Activate IGF secretion (autocrine signaling) • Transduction of neural activation • Ca2+ increase – activate Ca2+ - calmodulin, calcineurin pathway • Alter gene expression in favor of protein synthesis

  9. Protein Synthesis

  10. Protein Degradation

  11. Muscle Development and Maintenance • Proliferate after heavy use or muscle injury

  12. Tidball, J. Appl. Phsyiol., 2005

  13. Haszele and Price, Endocrinology, 2004.

  14. Interest in Myostatin • Myostatin is a member of the TGF-b superfamily that regulates development and tissue homeostasis; • Myostatin is expressed almost exclusively in skeletal muscle and acts as a negative regulator of muscle growth; • Rodent models of experimental disease states show upregulated myostatin mRNA • Studies in humans show that a lack of functional myostatin results in increased muscle mass due to hyperplasia and/or hypertrophy.

  15. TGFβ Superfamily Se-Jin Lee, Annual Review Cell Dev Bio, 2004

  16. Myostatin Effects Activation of Myostatin Pathway Muscle Wasting / Cachexia Syndrome Activation of Myostatin Pathway Myostatin Pathway Blockade Skeletal Muscle Growth / Leanness

  17. Myostatin’s Obvious Effects Naturally deficient myostatin gene Genetically created deficient myostatin gene (Knockout)

  18. Myostatin and Humans But not just cattle and mice …….

  19. Inhibition of the Myostatin Inhibitor Se-Jin Lee, Annual Review Cell Dev Bio, 2004

  20. Myostatin Signaling

  21. Myostatin vs. Other Established Muscle Metabolism Pathways Mature Myocyte Myoblast CdK2 CdK inhibitors (p21) MYOSTATIN IGF1 ? Differentiation Myogenesis Phospho ActRIIb Phospho SMAD2/3 PI3K/Akt MyoD MEF2 GSK3 FOXO mTOR ? Ubiquitin-Proteasome Pathway (Atrogin-1, MuRF-1) 4EBP1 S6K eIF2B + PROTEIN (e.g. MHC) DEGRADATION PROTEIN SYNTHESIS -

  22. Potential for Blocking Myostatin • Skeletal muscle wasting is prevalent in a variety of diseases • Weightlessness during space flight • Cancer cachexia • Muscular dystrophy • Geriatric sarcopenia • Obesity/diabetes • Skeletal muscle wasting results in reduced muscle strength, disability, and impaired quality of life; • No current therapy to prevent or reverse muscle atrophy.

  23. Disuse Models • Suspended at 30º for 14 days • Access to 100% of cage • Food and water ad libitum • 12-h photoperiod • Human bedrest (6º Head Down Tilt) • Durations - days to months • Cardiovascular, muscle and bone effects • Controlled diet

  24. 16 14 12 Soleus Wet Mass (mg) 10 8 6 4 2 7.9 10.9 0 TS P US P Hindlimb Suspension Effects Muscle Mass Isolated Muscle Strength Whole Animal Leg Strength

  25. Body Mass

  26. Lean Body Mass US > TS P<0.001 D > P P<0.001

  27. Study Design • Subjects – 10 male volunteers, 18-45 years old • 10 day strict horizontal bed rest with restricted 5 day lead in and 4 day follow up periods • Controlled diet – 55% carb, 30% fat, 15% protein • Caloric intake set to maintain body weight

  28. Double Threshold Analysis Raw Image Partially Processed Image

  29. p < 0.001 Mean CSA / Slice (cm2) Δ Change Mean CSA (%) Quadriceps Size Change • MRI images obtained with Tr = 550ms, Te = 10ms • Slice thickness = 1cm with 0 overlap • Pre-BR and end-BR slices aligned on anatomical features • Analysis from distal end of rectus femoris to highest portion of thigh excluding the gluteus maximus

  30. Pre-BR GDF8/GAPDH 0.0 1.0 2.0 3.0 4.0 0% -2% r = - 0.66 p < 0.05 -4% Δ Quads Mean CSA (%) -6% -8% -10% GDF8 vs. Δ Muscle Size • Correlation found between absolute level of GDF8 expression pre-bed rest with change in muscle size • Correlations between Δ muscle size and Δ myostatin expression were not observed

  31. Summary of Muscle Feedback Circulating IGF-1 Insulin + IGF-1 Transduction * Mechanical * Electrical External Loads / Demands Muscle Strength (PCSA) Myostatin -  Protein Synthesis  MuscleHypertrophy  - ProteinDegradation - + MuscleHyperplasia - Satellite CellActivation 

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