1) PS 11B – Module 1

2) Skeletal Muscle
3) Structure and Function:
a) Despite diversity in ways muscle function, there are common features of organization
i) The precursor cell type has become specialized in different ways through evolution
4) What does muscle do?
a) Transduces chemical energy into mechanical Energy (breakfast burrito -> walking to class)
i) Converts complex molecules into mechanical action.
b) Site of energy storage
i) Some converted (chem -> mech) is used locally, but also stored and released into the
circulation and used for their physiological processes
5) Functions:
a) Locomotion
Voluntary
b) Posture
c) Cardiac Pump
d) Lining Gut
e) Light/Dark Adaptation Involuntary
Iris Morphology
f) Accommodation
g) Thermal Regulation
i) Shivering, sweating, vasocontriction
6) Muscle:
a) Striated
i) Voluntary: Skeletal
ii) Involuntary: Cardiac
b) Smooth (involuntary)
7) 1 Muscle cell = 1 muscle fiber
a) 1 muscle fiber has many myofibrils
b) Myofibrils have same length as muslce fiber
8) Sarcomere
a) Sarco = "meat" mer[e] = "unit"
b) Sarcomere is standard meat unit, 2.1 micrometers (changes)
c) Myofilaments:
i) Myosin Thick (~1.6µm)
ii) Actin Thin (~1.0µm)
9) Contraction:
a) Myofilament shortening hypothesis (not observed)
i) Thin filaments coil on contraction
b) Sliding filament hypothesis
i) By changing sarcomere lengths and adding stimulation, test to see if amount of overlap of
myofilaments affects force production.
ii) Optimal sarcomere length is between 2.0 and 2.2 µm
iii) At 1.6 and at 3.6 µm force production (tension) drops to zero
10) Length-Tension Curve
 a) Active force production
i) Stimulations to produce force (force over length)
ii) Observes interactions between thin and thick filaments
b) Passive element
i) Eliminate force production (activation) to test stretch resistance
ii) Observes the presence of other structural molecules
11) Molecular Dissection of Sarcomere
a) Thin filaments:
i) 1 µm X 5 nm
ii) Isolated by size, charge, and solubility
iii) G-Actin (major component) (length of thin filament)
(1) Polymerize end to end into single end to end into single α-helix
(2) Two α-helices wrap to form helix of helices
iv) Tropomyosin
(1) Rod-like molecule that wraps around the outside of the Actin polymer
v) Troponin complex
(1) Is distributed periodically along the length of the thin filament
(2) Important regulating complex to whether contraction can occur
b) Thick filaments:
i) Myosin Heavy Chain (MHC) ~1.6 µm
(1) Forms a dimer, each with a head and α-helical tail | the tails form double α-Helix
(2) Dimers polymerize to make MHC in side by side arrays (200 left of m-line and 200 right
of m-line)
(3) 400 dimers form full length [ >>>>--<<<< ]
ii) Myosin Light Chain (MLC)
(1) Has 2 polymers attached to each MHC head.
12) Cross bridge Cycling:
a) Experiment:
i) Myosin heads interact with Actin (troponin complex) to turn chemical energy into
mechanical energy.
ii) Myosin heads travel (row) 10 nm (90° -> 45°) in 50 msec (or 20 nm per 50 msec for whole
sarcomere)
b) Necessary molecules:
i) MHC
(1) ATPase
(a) Binds ATP
(b) Hydrolyzes ATP
(c) Release energy necessary to drive changes in molecule
ii) Calcium
(1) Important for modulating contraction

c) Cycle:
 i) Relaxed, non-contracting skeletal muscle:
(1) 90° no contact with ADP·P bound to MHC-heads
(2) Low [calcium]
ii) Increase in [calcium] causes a change in the interaction between the MHC-head and thin
filament
iii) ADP·P released from MHC-head
(1) Causes a 10 nm shift (MHC-head -> 45°)
iv) ATP binds to MHC-head
(1) Cause the MHC-Head to release thin (still at 45°)
v) Hydrolysis at MHC-Head of ATP --> MHC-Head with bound ADP·P
d) Cycle converts 45% of chemical (ATP) Energy into mechanical Energy -> 55% turns into heat
e) If loss of ATP but plenty of calcium, muscle becomes rigor (rigor-mortis) if crossbridges are
formed but cannot release.
13) Force production vs. Speed of contration
a) 2 sarcomeres in...
i) Series:
(1) Increase distance per unit time (2 SM ==> 20/50 [nm/msec] + 20/50 [nm/msec] = 40/50
[nm/msec])
(2) But series reduces the force ( |-> <-|cancel|-> <-| )
ii) Parallel:
(1) Increase Force per unit time (2 SM ==> 1[N] + 1[N])
(2) Does not affect velocity since x-position of 1 = 2
b) Speed of contraction:
i) Unloaded Muscle:
(1) Slower at ascending arm of length-tension curve.
(2) Peaks at 2.0-2.2 µm like force
(3) Is not affected in descending arm since it is a chemical reaction:
(a) If not lifting a weight, the rate of contraction is the same.
ii) Experiment:
(1) Procedure:
(a) Choose afterload
(b) Set preload (length of muscle: ^preload = ^muscle length = ^sarcomere length)
(c) Stimulate muscle
(d) Remove the stop so the lever arm can move
(e) Measure velocity of contraction
(2) Unloaded muscle:
(a) Afterload 0 (F=0) at L0 (unloaded 2.2 µm) contracts with speed Vmax
(3) Loaded muscle
(a) Each curve corresponds to a different initial muscle (sarcomere) length in
conjunction with their afterload increments
iii) Between F0 (maximum force production of muscle) and 1.6F0 the muscle is in an isometric
contration
iv) Less than F0 the muscle is in a concentric contraction
 v) Greater than 1.6F0 the muscle is in an eccentric contraction
vi) The position of the myosin head is changed when the muscle is in iso-, con-, or ec-
contraction. (90°, 45°, 135°, respectively)
14) Excitation – Contraction coupling
a) Stimulation of motor neuron
i) ACh-R open
ii) Voltage-gated Na+ channels open
iii) Voltage-gated Ca2+ channels open (also called DHP receptors)
b) Depolarizing of muscle cell membrane
i) Depolarization is carried down T-tubules
(1) DHP-R is connected to Ryanodine receptor (RyR: calcium release channel)
(2) Stimulation causes a physical changed in RyR which induces a release of Ca2+ from the
Sarcoplasmic Reticulum into the sarcoplasm to initiate muscle contraction
c) ATP driven pump: Ca2+ pump returns Calcium to SR for rest.
15) Calcium Regulation of Contraction
a) In high [Ca2+] in sarcoplasm, calcium binds to Troponin-C causing a change in the position of the
troponin – tropomyosin complex allowing for the MHC binding site of the G-Actin to bind to the
Actin binding site of the MHC-head.
b) In reduced [Ca2+] in sarcoplasm, Troponin-C slides back into resting position (and therefore so
does the Troponin-Tropomyosin complex) blocking the MHC and Actin binding sites,
respectively.
16) Regulation of Calcium Regulation
a) Neuronal activity (Action Potentials) causes excitation (see 12) which regulates calcium
concentrations in the cell.
b) When AP's have ceased, the Calcium is pumped back into the SR thereby reducing [Ca2+] in the
sarcoplasm.
c) AP's can be in three patterns:
i) Twitch:
(1) A single AP is fired and the contractile activity is allowed to completely return to a
relaxed state
ii) Twitch Summation:
(1) 2, or more, AP's fire successively but not at such a high rate as to achieve tetanus
iii) Tetanus:
(1) AP's succession is rapid enough that the contractile activity cannot relax between
stimuli, this stops contractile activity from dropping below maximal sustained
contraction.
17) Passive stiffness
a) Protects against muscle injury
b) Attributable to structural proteins other than those in cross bridge formation
i) Titin:
(1) 1 complex Titin molecule per half sarcomere (m to z line) therefore there is 2 Titin
molecules that are mechanically continuous in a single sarcomere.
(2) Most important for providing passive stiffness
 (3) Also, for myocardium Titin is less coiled (~163 AA's) than in skeletal muscle (>2,000 AA's)
c) Experiment:
i) Eliminate thin and thick filament interactions:
(1) Low [Ca2+] in cytoplasm, no interactions of between filaments (no cross-bridge)
(2) High [ATP] in cytoplasm, if cross-bridges form, ATP will remove them
ii) Stretch sarcomere (to 2.7µm) and find a lot more force is needed for a little more stretch
iii) Hypothesis:
(1) By using relaxed muscle:
(a) No cross bridge contribution
(b) No thin/thick filament contribution
(c) 3rd filament.... Titin
18) ATP: contraction
a) ~5mM reserves are kept in muscle fibers
b) Generated by:
i) Oxidative phosphorylation (36 ATP)
ii) Glycolysis (2 ATP)
iii) Creatine phosphate
(1) High energy phosphate bond that can be hydrolyzed to form Creatine by CPK (creatin
phosphokinase)
(2) Substrate level phosphorylation (1:1)
(3) Limited to 20mM concentration of Creatine Phosphate which could give you 25 – 30 sec
of activity
(4) As you use CP, your body increases rate of glycolysis and Ox/phos
c) In skeletal muscle, there is a huge variability of ATP demand
i) But in immediate intense activity 5mM would deplete in 5-6 sec
19) Metabolic properties of Muscle
a) Anaerobic metabolism/muscle
i) Glycolytic (2 ATP/Glc)
ii) Little oxygen demand
iii) Relatively inefficient
iv) Relatively rapid ATP replenishment
v) High levels of glycogen
vi) Fatigue rapidly (Fatigable)
vii) Few Mito, enz, O2 and binders, low iron -> (White Muscle)
viii)
b) Aerobic metabolism/muscle
i) Oxidative Phosphorylation
ii) High oxygen demand
iii) Relatively slow replenishment of ATP
iv) Relatively efficient (36 ATP/Glc)
v) High Mitochondria
vi) Highly vascular
vii) High Mitochondrion enzymes
 viii) High concentration of oxygen binding molecules (Increase [Fe] -> Red Muscle)
(1) Myoglobin
(2) Hemoglobin
ix) Low Fatigability
(1) Can generate ATP for a continuous long time (not fast and strong)
(2) Endurance performance
20) Muscle types
a) Fatigue
i) Reduction in force generating capacity of a muscle
ii) ATP replenishments:
(1)
b) MHC Isoform expression
i) Slow Myosin
(1) Hydrolyzes ATP slowly
ii) Fast Myosin
(1) Hydrolyzes ATP quickly
c) Properties:
Traits Type I Type IIa Type IIb
Oxidative
Metabolism Both Glycolytic
Phosphorylation
MHC Isoform Slow Fast Fast
Mitochondria High High Low
Glycogen Low Int High
Vasculature High High Low
Fiber Size Thin Int Thick
[Ca2+] is SR Low High High
i) Think of Fiber diameter as the distance the oxygen has to travel to get to the mitochondria
ii) How muscles are used will help determine the metabolic type (shiftable)
(1) By using the fast/strong properties, will cause a shift in more type IIb fiber metabolism.
(2) Endurance will increase type I fiber metabolism.
iii) Changing innervations can cause myosin isoform expression
(1) Transplanting a fast nerve onto a slow muscle will cause the slow muscle to express fast
myosin expression.
d) Innervations
i) 1 motor neuron can innervate many fibers
(1) those fibers will express the same myosin isoform
(2) Activated simultaneously
(3) Function as a single motor unit
(4) Not located side by side in a gross muscle
21)