Download skeletal muscular physiology

Muscles Alive!
Excitation, Mechanics and Adaptations
Anatomy and Physiology
Spring 2017
Stan Misler
<[email protected]>
A. structure –> function in skeletal muscle
1. Muscle considered as machina carnis (machine made of flesh): Tissue using chemical energy
stored ATP to generate cycles of internal tension -> moving of joint across arc or fixing joint
against a load. Muscle force transmitted to bone via tendon
2. Muscle = parallel bundles of multinucleated cells. Unit of function of movement within muscle
cell is sarcomere of interdigitating actin and myosin filaments (a)
3. Individual muscle fibers are grouped into motor units innervated by a single motor neuron
originating in the spinal cord (b & c). The spinal motor neuron is activated by a stretch reflex or
by descending input from brain (c)
4. At intervals along the muscle fiber plasma membrane (sarcolemma) dips down into muscle
protoplasm (sarcoplasm) and makes contact with elaborate outpouchings of endoplasmic
reticulum called sarcoplasmic reticulum (d). Linkage of action potential in sarcolemma to
subsequent muscle contraction is called excitation-contraction coupling
B. Skeletal Muscle Physiology: The Basics
Propagation of a wave of electrical excitation (or action
potential, AP) along a muscle fiber releases Ca from stores
in the sarcoplasmic reticulum into the cell cytoplasm ->
muscle either generating constant tension (as in lifting a
barbell) or generating rhythmic muscle contraction
/relaxation (as in a sprint). This occurs by the sliding of
contractile filaments, actin (A) and myosin (M) past each
other and the making / breaking of cross bridges between
the two types of molecules. Contraction is an active process
requiring electrical and contractile events. Return of muscle
to its resting length is due to its passive elasticity.
Critical questions:
1. What does the action potential in muscle consist of?
(wave of Na entry followed by K exit)
2. How does action potential -> release of internally
stored Ca (excitation-contraction coupling) and
subsequent cross bridge formation between the two
major contractile proteins actin + myosin? (changing
configuration of molecules)
3. How does cross bridge formation between actin and
myosin -> weight bearing or muscle shortening
Actin myosin overlap ->
cross bridges
actin
Myosin
Skinned muscle fiber exposing
intracellular organelles including bundles
of actin and myosin and mitochondria
1. How myocytes maintain a resting membrane
potential
All cells separate concentrations of ions, especially Na and K, across
their cell membranes. The outside fluid, which bathes the cell, is rich in
Na (130 mM) and Cl (120 m) but poor in K (5 mM), while the inside
fluid, or cytoplasm, of the cell is rich in K (130 mM) but poor in Na and
Cl (both ~10 mM) . These differences in ion concentrations across the
cell membrane are known as ion concentration gradients.
The fact that at rest the plasma membrane is permeable to K & Cl but
barely permeable to Na produces a voltage across the membrane called
a resting membrane potential ( = RMP). This is usually 1/12 of a volt
inside negative (or -80 to -85 mV) and is measured by poking the cell
with a glass microelectrode filled with a high KCl solution.
2. How a muscle cell generates its signature electrical signal the
action potential
Muscle cells, like nerve cells, are special because they are excitable. In
response to a stimulus (chemical, voltage pulse or stretch) that charges the
membrane potential from a resting voltage of -85 mv to a threshold voltage of
-50 mv, a myocyte rapidly changes its membrane’s relative permeability to Na
and K (PNa and PK): From a high K permeability resting state, the cell
membrane becomes overwhelmingly permeable to Na (PNa), and Na moves
down its concentration gradient into the cell (i.e., from high [Na] outside to low
[Na] inside). This changes the amplitude and polarity of the membrane
potential (MP) from -85 mV inside to +20 or + 30mV inside, a depolarization,
over 0.5 ms. However by 1 ms after reaching threshold the membrane loses
its enhanced permeability to Na and increases its permeability to K resulting in
the recovery of the membrane potential back to, or slightly negative to, RMP.
This spike of voltage change (from -85 to +20 or +30 and back again to -85 mV,
propagates down the muscle fiber as an electrical wave, called an action
potential (AP), at velocities up to 10s of meters per seconds
PNa increases as
PK decreases
PNa decreases
& PK increases
- 50 mv
PK = PCl
PK returns to baseline
a. Evolving concepts of the ion channel
Mackinnon model, 2004:
Hille model, 1967:
Protein lines holes in
lipid bilayer of
plasma membrane
Complex multisubunit proteins spanning
lipid bilayer of plasma membrane
respond to a stimulus, by changing their
shapes and revealing a pore down its center
through which ions are rapidly and
selectively conducted down their
concentration gradients. Some of these
channels open or close in response to a
change in voltage across the membrane
b. Activity cycles of voltage-gated channels
(MP brought closer to 0 mv)
with selectivity filter
Relief of criss-crossing of tails -> open channel
3. Synaptic transmission -> muscle cell excitation
Skeletal muscles must be stimulated by nerve to contract.
An action potential of nerve terminal -> releases neurotransmitter
acetylcholine (Ach) -> action potential in muscle (follower cell) -> release
of Ca into the cytoplasm -> muscle tension or contraction
(i) In nerve terminal activation of Ca channels
near vesicle attachment sites raises the local
concentration of [Ca] immediately adjacent to
the pre-synaptic membrane from ~100nM
(nanomolar) to 10s of uM (micromolar).
Vesicles, containing thousands of transmitter
molecules, fuse with presynaptic cell membrane
and release their contents, here acetylcholine
(Ach), into synaptic cleft by a process known as
exocytosis
Note: To keep muscle excitation very
brief, so that muscle can have a brief
twitch, released Ach is broken down in
the synaptic cleft by an enzyme or else
diffuses out of cleft
(ii) Ach binds to Ach receptor channels
(combination of Ach receptor and cation
selective channel) -> Na entry into muscle cell
giving rise to depolarizing post-synaptic (or
endplate) potential. If 50-100 vesicles fuse
within 1 ms after the presynaptic AP the amount
of Ach released brings MP to threshold for
activating an AP in the muscle cell
4.Excitation-contraction coupling (ECC) in musc;le
(a) Plasma membrane and T-tubules conduct action
potentials (APs = rapid conducting electrical impulses
bringing the membrane potential from rest at -85 mv inside
to overshoot of +30 mv ->
(b) “T tubule – SR electro-mechanical synapse”
Change of T-tubule membrane potential -> pulling out of
stoppers from Ca release channel in sacroplasmic reticulum
T-tubule has 5-7 times
(SR) which has high [Ca] within ->
surface area as plasma
(c) Diffusion of Ca out of SR ->increased cytosolic Ca-> (4)
membrane
Binding of Ca to troponin -> development interaction of
myosin head to action -> cycle of Ca dependent cross-bridge
formation and ATP dependent cross-bridge breakage ->
(d) Generation of rapidly increasing and then rapidly
decreasing transients of muscle tension ->
The movement of part of
(e) Generation of external force by actin - myosin (A-M)
DHPR (stopper) pulls on foot
bridges in sarcomere either (i) holds sarcomere at nearly
of SR Ca release channel
same length (as in holding up a heavy barbell) = isometric
contraction or (ii) shortening sarcomere by actin and myosin
filaments sliding past each other (as in a sprint)
(f) A-M bridge formation is terminated by rapid uptake of
cytosolic Ca into SR by a Ca pump
5. Sliding Filament Hypothesis
a. Interdigitating actin and myosin filaments where myosin projections
(heads) are uniformly distributed over myosin filaments except at
middle region. With contraction sarcomeres are reduced in length, but
the lengths of actin and myosin filaments and sarcomere volume is
unchanged suggesting that actin and myosin filaments slide past each
other. Also, during contraction heads of myosin attach to actin and tilt,
and detach = transient cross bridge formation and cycling.
b. Since length of the cross-bridge is small, when compared with
sarcomere contractions, during a single contraction there must be
repeated cycles of attachment/ ratcheting pull /detachment
6. Crossbridge cycling:
(a) in health muscle in presence of ample ATP and Ca
reuptake (left) vs.
(b) in rigor mortis where ATP dependent processes are
blocked by absence of ATP = contracture (right)
7. Types of muscle contraction
Isometric tension generation: length of muscle does not change
(internal elastic element gets stretched as sarcomere contracts a
few %) but amount of tension generated increases. Responsible
for constant length of postural muscles such as holding spine
erect while sitting or standing = resting muscle tone or
supporting weight of bar bell. Alternation of use of muscle units
Isotonic contraction: amount of tension produced is constant,
but length of muscle decreases. Ex. Movements of arms or
fingers including waving and using a keyboard.
Most muscles can be used in either mode: walking or opening
heavy door
8. Muscle mechanics
a. Active Length-tension curve in muscle
Optimization of pre-contraction sarcomere length to 2.1 um provides optimal
actin/myosin filament overlap and opportunity for maximal cross bridge
formation thereby giving largest isometric tension with tetanic stimulation
Note: Fall off of tension at smaller (<1.6um) or larger (> 2.5 um) sarcomere
lengths
b. force - velocity curve
Reciprocal relationship
The lower the load the sarcomere
must support,
(i) the smaller the average number
of cross-bridges needed to support
the load;
(ii) the faster the dissociation of
actin – myosin complex (less
resistance to head tilting); and
(iii) the faster the muscle shortens
9. Activation of nerve terminals synapsing on muscle
Nerves coming from spinal cord activate groups of muscle cells (motor
units) in the knee jerk reflex
1A
a
(i) Reflex arc:
stretch of muscle -> activation of
stretch receptor fibers in muscle ->
activation of 1A afferent sensory
nerve to spinal cord -> synaptic
transmission (pre-synaptic release
and post-synaptic reception of
glutamate) -> activation of a motor
neuron to muscle -> release of Ach
at neuromuscular junction -> muscle
contraction to restore length
(ii) Voluntary contraction:
Impulse generated in cerebral cortex
of brain travels down upper motor
neuron to activate a motor neuron
synapsing on muscle
10. Adaptation of skeletal muscle function
11. Adapting muscle to specific task.
Increasing # sarcomeres in series (longer fiber) ->
greater speed and extent of maximum contraction
while increasing # of sarcomeres in parallel (thicker
fiber) -> greater maximum force of contraction
12. Effects of repetitive training
(a) physical activity and motor unit properties:
high intensity contraction 1 hour performed several times a week ->
increased contraction and motor unit force
while prolonged periods of low intensity contraction reduce motor unit
propensity to fatigue (increased oxidative capacity = ATP production of
mitochondria accompanied by increases in capillary and mitochondrial
densities
b) choose type of exercise for type of muscle adaptation
13. Muscle fatigue = decreased capacity to
do work and reduced efficiency of
performance after period of activity
Psychological: central nervous system perception that
further generation of muscle is not possible. May be
overcome by encouragement
Muscle fatigue: ATP depletion (insufficient breakdown of
glycogen and uptake of glucose to enter metabolic
pathways) as in lower limbs of runners or upper limbs of
swimmers
Synaptic fatigue: release of transmitter from vesicles
exceeds storage into vesicles
Muscle soreness after exercise: damage to muscle fibers
with release of cytosolic contents such as specific
enzymes + overstretching of connective tissue
Summary of Skeletal Muscle Physiology
A. Tension generates movement of part of body in relation to external environment
(force on tendon and movement of joint). This is critical for coarse movements
(walking) or fine movements needed for communication (speech, writing and
pointing)
B. Individual non-communicating muscle fibers are grouped into motor units
innervated by a single motor neuron originating in the spinal cord. The spinal motor
neuron is activated to conduct an action potential (rapid positive change in membrane
potential) by afferent fibers of a stretch reflex or descending supraspinal input . The
branching terminals of the motor neuron have voltage dependent Ca channels that
open during AP and promote Ca dependent release packets of depolarizing
neurotransmitter acetylcholine onto sensitive regions of the muscle plasma
membrane known as end-plates.
C. The depolarizing end-plate potential sets off an muscle action potential of several
ms long that propagates along the muscle surface as well deep into the fiber via Ttubules. This triggers the releases Ca from internal stores in SR. Muscle twitches of ~
50 ms in duration are set off