Campbell 7e reads:
C49 - 1080-1086   &   Campbell 8e reads: 1105-1117.

          Model: skeletal neuromuscular junction
                -  striated skeletal muscle cell*    pic     pic
                -  innervated muscle fiber*          pic  &   neuromuscular junction


            Muscles can not push, they may only only CONTRACT (pull)
            A muscle contraction is called a muscle TWITCH
4 parts of a Muscle twitch     [ CONTRACTION  CYCLE *]
 1) latent period - 5 msec  time between application of AP & initiation of contraction 
 2) contraction - 40 msec  muscle shortens & does its work
 3) relaxation - 50 msec  muscle elongates & returns to original position
 4) refractory period - 2 msec  time of recovery between stimulations of muscle 


some definitions related to muscle contraction...
Summation - a 2nd contraction before 1st subsides  fig*  (cause is time differential of nerve/muscle)
       Tetany - sustained contractions (requires energy - ATP) -
Harvey Project - muscle twitch
       Fatigue - under repeat stimulation, contractions get feebler, lactate accumulates,
                                         pH changes lead to stoppage of contractions
       Shivers - involuntary-summed muscle contractions which release waste heat, that warms body


 Major muscle TYPES
...  ability of muscle to contract is based upon muscle proteins...   
MYOSINS are protein motors.        Upon interaction with actin filaments, they use energy
                                                             from ATP hydrolysis to generate a mechanical force.
Muscles are class typed based upon the types of myosin protein fibers present
                                                             (also called heavy meromyosins*): 

                there are different isoforms (structural versions) of the muscle myosins
                       TYPE I (Slow Twitch)           &              Type IIa/IIx (Fast Twitch)

                                     MUSCLE  FIBER  TYPES*



 2 TYPES of MUSCLE FIBERS...   determined both genetically & functionally
              based upon how fast they can produce a contractile twitch 
              every muscle composed of varying % composition of two types
   Tonic muscles (darker:  red) - Leg muscles
   Tetanic muscles (paler: white) - Pectoral muscles
slower contraction times (100-110 msec) faster contraction times (50 msec)
contain myoglobin (red) no myoglobin (white)
continuous use muscles - prolonged performance
    for endurance performance ( marathoners)
one time use muscles - brief performances
     for power & speed (sprinters
marathoner: 80% type I   &   20% type II sprinter: 20% type I  &  80% type II 
                      Distribution of Slow & Fast Twitch muscle in Humans*                      down
best in long slow sustained contractions best in rapid (short) contractions 
not easily fatigued easily fatigued
more capillary beds, greater VO2 max  less capillary beds
smaller in size larger in size
lower glycogen content higher glycogen content
poor anaerobic glycolysis *  predominantly anaerobic glycolysis
    easily converts glycogen to lactate  w/o O
*  predominant aerobic enzymes & metabolism some aerobic capacity
higher fat content lower fat content 
more mitochondria - Beta Oxidation high fewer mitochondria- Beta Oxidation low
poorly formed sarcoplasmic reticulum well formed sacroplasmic reticulum
slower release of Ca = slower contractions quick release of Ca = rapid contractions 
tropinin has lower affinity for Ca troponin - higher affinity for Ca






Relative Distributions of Slow Twitch & Fact Twitch Myosin Isoforms (Type I & Type II)
  Type I (slow) Type II (fast) Type IIa Type IIx
Average person 50% 50% 40%  10%
spinal injury 4% 96% 48% 48%
sprinter 20% 80% 45% 35%
couch potato 40% 60% 30% 30%
marathoner 80% 20% 20% 0%
These myosin isoforms are conserved evolutionarily
Comparing myosin isoforms from different mammals reveals remarkably little variation species to species.  Rat type I is more similar to human type I myosins, than it is to rat type II's.  Thus selective evolution has maintained a functional difference between type I's & type II's over eons of evolution. 







Model:  Vertebrate Skeletal Musclemultinucleate cell*   -  muscle  to  myofibril*          
  SARCOMERE - basic repeat unit of striated muscle, delimited by Z-lines
       I   band - "paler zone" around Z-line             (Isotropic - passes light in all directions)
       A  band - "dark region" in center of sarcomere (Anisotropic - in different directions)
       M  line - mid point of the sarcomere
       H  zone - "paler zone" in the center of sarcomere around M line
SLIDING FILAMENT THEORY of Muscle Contraction (Hugh Huxley-1954)
                  A  band remains constant in its size dimensions
                  H  Zone becomes denser                                                      contraction**      
                  I  band varies in length becoming shorter & disapperaring
                      relaxed/contracted   at molecular level*   actin/myosin*     
                                         contraction animation*





Muscle Cell Proteins  [4 types involved in contraction cycle]
1.   THICK FILAMENT  (A band)
         myosin* - 6 polypeptides twisted to form fiber helix with globular end
                         which has ATPase activity & an affinity to bind to actin

myosins are...   Molecular Motors  kinesin animations  
2.   THIN FILAMENT (I band)
         G-actin* - globular protein which polymerizes into polymeric fiber
                          each globular actin unit contains a myosin binding site 
3.      Tropomyosin* - fiber-like protein which wraps helically around thin filament 
4.      Troponin - globular protein complex which binds Ca+2 & initiates contraction cycle
          is a complex of 3 proteins, Troponins C, I, & T, which bind Ca;  Troponin C (18 kD) binds Ca reversibly.
                        TnC binds TnI (23 kD) & TnT (37 kD), which change conformation in response to TC binding Ca, but not actin.







Muscle Contraction Cycle,  Sarcoplasmic Reticulum,  &   Role of Ca ...

  1.   myofibril - sarcoplasmic reticulum (ER)*   
  2.  T-tubes conduct impulses       Some animations examples
  3.  Ca release at T-tubes**       a.  Brooks & Cole muscle Structure 
  4.  troponin binds Ca & opens myosin sites       b.  Harvey Project muscle twitch & structure
  5.  actin+myosin & ATP contraction cycle*       b.  U Wisconsin Muscle Cell Contraction
  6.  REVIEW cycle - web muscle movie**       d.  K.C. Holmes, Max Planck Inst. - ATP
  7.  step thru a complete cycle: Blackwell Pub.**       e.  list of Muscle System Animations

     end                                                                                          nrc-2010








SKIP the MATERIAL  below this point

             Anabolic Steroids & muscle physiology   &   Doping and Muscle Cell Growth    


    The Performance Enhancing Drugs of the Future...

        not steroids, but the introduction of artificial genes:    Figure*

            1.  genes for myosin type transcriptions factors,  that will activates genes
                genes for long dormant myosin isoforms of our ancient ancestors...
                                     say an ancient  type IIb isoform
                                     that's faster than any known Type II isoform of today

            2.  or IGF-I (insulin-like growth factor)
                              IGF-I is a growth factor structurally related to insulin and IGF-I is produced in
               response to GH and then induces subsequent cellular activities, particularly on bone growth. IGF-I
               has autocrine and paracrine activities, and like the insulin receptor, it has intrinsic tyrosine kinase
               activity. Owing to their structural similarities IGF-I can bind to the insulin receptor.






 Muscle Cell Growth includes:
        1.   satellite cell recruitment*, which proliferate & fuse with muscle cell fibers
        2.  pro-growth factors as IGF-I, which promotes satellite cell proliferations
        3.  growth inhibition factors, such as myostatin

Current research - H.L. Sweeney at U. Penn
have used adeno-associated virals (AAV) to infuse IGF-I gene* into recipient muscle cells

    in normal mice:   experiments have overall size & growth rates up 15% to 30%
    in mice genetically engineered to overproduce IGF-I:   seen 20% to 30% larger muscle mass
                               overproduction also hastens muscle repair in mice with M.D.
    injection of AAV-IFG-I into one leg of lab rats with an 8 week weight training program
                =  2x increase in strength in treated leg
                =  longer period before gained strength is lost
                =  sedentary rats showed 15% increased strength

     Human trials for IFG-I injections to treat myotonic (prolonged contraction) dystrophy
                        are set to begin next year...
 next                                                                 to be followed by athletic gene doping?




Myostatin... is a muscle inhibitory growth factor [blocks muscle growth],
                                  myostatin is also called GDF-8 (growth differentiation factor)
                        it promotes atrophy and slow muscle cell growth,
may function antagonistically with IGF-I, which promotes muscle growth.
       described by A.C.McPerrron & Se-jin Lee at Johns Hopkins in 1997
                  defective myostatin genes = considerably larger muscle mass
                           Belgian Blue cattle*   and   the Breed & its cause
                                                                       a human case study*  -->


             may be useful in muscle debilitating diseases, which include:
                                   muscular dystrophy -
                                   sarcopenia - age realted muscle loss
                                   cachexia - aggressive muscle loss in cancer & HIV patients
                                   myoclonus - abnormal muscle contractions
            Wyeth pharmaceuticals is at work on myostatin inhibitors
                              1st drugs to date are antibodies to myostatin and
                               some clinical trials are set to begin in M.D. patients





Training, Muscle Fiber Recruitment, &  Performance  &  Marathoner pics

  Muscle Performance, Training, & Fiber Recruitment

              Disuse of a muscle, as in space travel (weightlessness),
                               or a couch potato can shrink a muscle by 20% in 2 weeks.


              Weight Training can increase muscle mass to 150% of normal size.


How do muscles get bigger and better?

     by making more muscle proteins...    nuclei of muscle control translation, 
                          thus one needs more nuclei, but muscle cell nuclei don't divide. 
            New nuclei come from independent adjacent cells (Satellite
stem cells*).

            when muscles under rigorous exercise they "tear", and the damaged area 
                          attracts satellite cells into the tears, depositing more nuclei.  

          weight training thus leads to heterotrophy of muscles......  
more nuclei equals muscle enlargement due to more protein synthesis.





Recruitment of Muscle Fibers   (Slow   <--->   Fast)     Is it Possible ?
                          has implications for spinal injury & athletics

    1.  Cross innervation: experimentally switch nerve innervations (slow to fast)
                        animal experiments have lead to some conversions
    2.  Spinal injury: a lack of nerve impulse & muscle atrophy leads to a sharp
                        decrease of the slow myosin isoform (type I), 
                        while the amount of the fast isofrom increases (type II table*

    Conclusion: neural input (electrical stimulation) is necessary for the 
                         proper genetic expression of the Slow - Type I isoform.
                         Electrical stimulation can reintroduce the slow fiber into
                         paralyzed muscles.




    3.  Weight Training and Different Myosin Types
               sedentary people have higher amounts of IIx
               active people have more IIa fibers


                   heavy weight-load repetitions.....
                        decreases Fast IIx fibers and converts them to Fast IIa fibers
                             nuclei stop expressing IIx gene and express IIa genes
                             after 1 month all IIx  -->  IIa    (muscle also become more massive)

     4.  Tapering - can we change amounts of  IIx  fibers?         
                 in experiments involving sedentary young adults:      
                        heavy resistance training (3 months) reduced IIx from 9% to 2%
                        but, a taper (rest for 3 months) & IIx returned above basline (9%)
                                to a level of 18%, i.e.,  more fastest twitch fibers.    fig

      5.  Can we recruit   slow  --->   fast ?   maybe...
                        but no good evidence to date for slow to fast recruitments.





  a protein called PPAR-delta, discovered by Ron Evans of Salk Institute
                                                 regulates other genes involved in fat metabolism.
             High activity of  PPAR-d burns more fat, results in leaner, more fit individuals.

  recent experiments (PLoS - Oct 2004)
              revealed that mice genetically modified to produce more PPAR-d
                      - had 2x more slow twitch (I) muscle compared to litter-mates. [fig]*
                      - PPAR-d mice could run 1,800m (2x normals) before reaching exhaustion.

              these changes are similar to those induced by sustained training & exercise
              long lasting vigorous exercise produces a higher ratio od slow twitch (I) muscle.

  a new drug (GW501516) activates PPAR-d directly leading to similar changes
                      - could help obese and heart disease patients who can't exercise.  
              GlaxoSmithKline is currently testing this drug in obese, diabetics







the end.