Physiology -- Muscle

Front 1

Epimysium, Perimysium, Endomysium

Back 1

- Epimysium:
Outermost partitioning layer, surrounds multiple fascicles.
- Perimysium:
Middle partitioning layer that separates individual fascicles.
- Endomysium:
Innermost partitioning layer that separates muscle fibers.

Front 2

Muscle fascicle

Back 2

Muscle unit made up of bundles of muscle fibers.

Front 3

Muscle fiber

Back 3

Muscle unit made up of myofibrils.

Muscle fibers are also another name for muscle cells.

Front 4

Myofibrils

Back 4

- The majority of cell volume (85 - 90%) of muscle fibers is made up of cylindrical units called MYOFIBRILS.

- Each myofibril runs the entire length of the fiber, and they are made up of repeating contractile units called SARCOMERES, which are in series with one another.

- Each myofibril has a cross-sectional area of approximately 1 squared-micrometer. (Therefore, a muscle fiber of approximately 1000 aquared-micrometeres has ~1000 myofibrils)

Front 5

Sarcomeres

Back 5

- Building blocks used to assemble myofibrils.

- Often referred to as the contractile units of skeletal muscle.

- Number of sarcomeres in parallel determines the maximal force, whereas the number in-series determines the length excursion and shortening velocity.

- Typically, each sarcomere is 2.5 micrometeres in length, so in a 100mm muscle fiber, there would be ~40,000 sarcomeres in series.

Front 6

Longitudinal or Parallel muscles

Back 6

- Composed of muscle fibers who longitudinal axis runs parallel to that of the whole muscle.
- Sartorius and rectus abdominis are examples of this.

Front 7

Fusiform muscles

Back 7

- In fusiform muscles, the fibers run parallel to the longitudinal axis of the muscle, but they taper at the ends of the muscle.

- Soleus and brachioradialis muscles are examples of these.

*STRUCTURE AND FUNCTION:
- Muscles that have fusiform architecture will have muscle fibers that are typically longer than those found in BIPENNATE MUSCLE.
- The functional consequence of this is that the fusiform muscles will be able to shorten and lengthen to a greater degree than the bipennate muscle, and, assuming similar cross bridge cycling rates, will be able to generate much higher shorterning velocities.

Front 8

Pennate muscles (unipennate, bipennate)

Back 8

- Architecture whereby the longitudinal axis of the individual muscle fiber runs
diagonal to that of the whole
muscle.

- BIPENNATE = gastrocnemus

- MULTIPENNATE = biceps brachii

*STRUCTURE and FUNCTION
- Bipennate muscles optimize the physiological cross sectional area of the muscle, meaning that there are a greater number of muscle fibers and sarcomeres in parallel.
- Therefore, the bipennate design is better optimized for the production of force than high shortening velocities.

Front 9

Angular, fan-shaped, or convergent muscles

Back 9

- Radiate from a narrow attachment at one end and fan out, resulting in a broad attachment at the other end.

- Pectoralis major

Front 10

Circular muscle

Back 10

- Orbicularis Oris

Front 11

Z-line

Back 11

- Thin, dense structures that are found in the middle of the I-BAND.
- Composed of alpha-actinin.
- Defines the ends of sarcomeres.
- Represents an anchor point to which thin filaments are attached (approximately 3000 to 6000 thin filaments).
- The ratio of thin to thick filaments is 3:1.
- The area between adjacent z-lines (the sarcomere) shorten during contraction, but the z-lines themselves do not shorten.

Front 12

I-Band

Back 12

- Region of ONLY thin filaments.
- Bisected by the z-line.
- The I-band shortens during contraction.

Front 13

A-Band

Back 13

- The length of the A-Band is equivalent to the length of the thick filament.
- Normally, there is partial overlap between the thick and thin filaments.
- The lighter region in the middle of the A-band is the region where there are only thick filaments.
- Nothing happens to the A-band during contraction (because the length of the thick filaments remains unchanged).

Front 14

H-zone

Back 14

- Region in the middle of the A-band that appears lighter because there is no overlap of thick and thin filaments.

Front 15

Thin filament components

Back 15

-Actin
-Troponin
-Tropomyosin

Front 16

Desmin

Back 16

- INTERMEDIATE FILAMENT protein betweeen two sarcomeres that hold them in perfect alignment.

Front 17

Titin

Back 17

- Called "passive elastic component."

- Springs muscles back to their starting positions after contraction.

Front 18

M-line

Back 18

- Midpoint of the sarcomere that bisects the H-zone.

- Contains:
*M-PROTEIN
*MYOMESIN
*M-CREATINE KINASE

***CREATINE KINASE IS IN A PERFECT POSITION AT THE M-LINE because it provides the cross bridges with an IMMEDIATE SOURCE OF ATP (by the equation:
PC + ADP ---CK---> C + ATP)

- The muscle isoform of CK in the blood is indicative of a heart attack (same is true of lactate DH).

Front 19

"Contractile Proteins"

Back 19

Actin and myosin

Front 20

"Regulatory contractile proteins"

Back 20

- Defined as those that A) turn on/off the contractile apparatus, and B) those that can modulate the activity of the myosin heavy chain.

A) These are associated exclusively with the actin filament. They include tropomyosin, troponin-T, troponin-I, and troponin-C.
B) The myosin light chains are also classified as regulatory contractile proteins, and they are associated with the lever arm of the myosin heavy chain (apparently, they modify the kinetics of crossbridge cycling).

Front 21

Structural and costameric proteins

Back 21

- Help to A) align the z-lines of parallel sarcomeres in a very orderly fasion, and B)develop a mechanical linkage between sarcomeres and the extracellular matrix.

A) Desmin, vimentin, synemin
B) Dystrophin, ankyrin, integrin

The latter are referred to as costameric proteins and they "connect inside world with the outside world."

Front 22

Myosin molecule anatomy

Back 22

- Hexameric complex (composed of six proteins).

- 2 OF THE SIX are known as MYOSIN HEAVY CHAINS (MHC's)
*Each MHC is has one ESSENTIAL MYOSIN LIGHT CHAIN (MLC1 or MLC3), and ONE REGULATORY MYOSIN LIGHT CHAIN (MLC2) bound to its globular head group.
*Each myosin heavy chain is made up of: i) a long rod region, ii) sub fragment-2 (S2), iii) a globular head (also known as S1).

THE ROD REGION of the MHC is important from a structural perspective because it determines the PACKING of MHCs within the thick filament (with each thick filament composed of ~300 individual MHCs).

THE GLOBULAR HEAD consists of 3 DOMAINS, known as i) the catalytic domain [which binds actin and ATP, and hydrolyzes ATP], ii) the converter domain [thought to be involved with the transduction of energy], and iii) the lever arm [which transports the load].
*Mutations within the globular head are believed to play a key role in hypertrophic cardiomyopathy.

Front 23

MHC Isoforms

Back 23

The speed related to properties of skeletal muscle are due primarily to the existence of MHC isoforms, and that the kinetics of crossbridge cycling can be secondarily modulated by MLC isoforms.

Skeletal isoforms in humans:
- slow Type I
- fast Type IIA (fastest ATPase activity)
- fast Type IIX

Front 24

MLC Isoforms

Back 24

- MLC1 and MLC3 are "essential light chains."
- MLC2 is a "regulatory light chain."
*These are both misnomers.

As in MHC, there are also different isoforms in MLCs:

- sMLC1 and fMLC1
- sMLC2 and fMLC2
- ONLY ONE TYPE OF MLC3 (fMLC3)

Front 25

Crossbridge Cycle

Back 25

- Under resting conditions, myosin is detached from actin (referred to as the "cocked state"). ADP and inorganic phosphate are also attached to the myosin head.
- When, calcium binds to troponin-C, the head of the myosin heavy chain will attach to actin (Cross-Bridge or Attached State).
- Inorganic phospate is then released from the myosin heavy chain and, the power stroke occurs. (Myosin returns to its non-energized state).
- ADP is then released, as well.
- When a new ATP binds the myosin, it is released from actin.
- ATP is hydrolyzed to ADP, and the myosin head returns to its resting, energized conformation.

Front 26

Excitation

Back 26

- In presynaptic cell, neurotransmitter molecules are synthesized and packaged into vesicles.

- An action potential arrives at the presynpatic terminal and VOLTAGE-GATED calcium channels open.

- A rise in calcium triggers fusion of synaptic vesicles with the presynaptic membrane.

- Transmitter molecules (ACh) diffuse across the synaptic cleft and bind to specific receptors (nAChR) on the post-synaptic cell (the muscle cell). [NT's are broken down and taken up by the presynaptic cell or another cell.]

- The activated nAchR's allow sodium and potassium influx and this results in membrane depolarization.

- Opening of subsequent voltage-gated sodium ion channels leads to propagation of action potential along SARCOLEMMA.

- This depolarization spreads down the T-tubules, which leads to the opening of calcium ion release channels in the SR.

Front 27

Acetylcholine receptor

Back 27

- 2 alpha subunits, 1 beta, 1 delta, and 1 gamma.

- The alpha subunit is composed of 4 transmembrane regions, M1, M2, M3, M4.

- NICOTINIC ACh receptors are activated by ACh, and they become permeable to sodium and potassium ion influx (DEPOLARIZING THE MEMBRANE).
- This leads to an action potential, and muscle contraction.

- METABOTROPIC RECEPTORS are G-PROTEIN RECEPTORS.
- ACh binds and there is a release of the beta subunit of the G-Protein complex, and GTP.
- The beta subunit activates the "rectifier potassium ion channel" which allows potassium EFFLUX.
- This leads to membrane hyperpolarization (and decrease in HR).

Front 28

Coupling

Back 28

- The depolarization of "excitation" results in a conformational change of the Dihydropyridine Receptors (DHPRs) of the t-tubules. [DPHRs are voltage-gated calcium ion channels]

- It is important to note here, that one t-tubule is associated with TERMINAL CISTERNAE of the SR on either side. This is referred to as a TRIAD.

- In the terminal cisternae of the SR, there are calcium release channels called RYANODINE RECEPTORS.

- The conformational state of RyR's in skeletal muscle is regulated by the voltage-gated calcium channels (DHPRs) on the t-tubules.

- DHPRs are arranged in tetrads, and every RyR is associated with a tetrad.

- When depolarization of the t-tubule occurs, a conformational change in the DHPR acts via direct contact with the RyR.

- This VERY FAST interaction between the DHPR and RyR causes calcium ion to be released into the cytoplasm.

- Once in the cytoplasm, calcium binds to TROPONIN C, causing TROPOMYOSIN to shift its conformation, exposing the MYOSIN BINDING site on ACTIN.

Front 29

Troponin-C

Back 29

The isoform of troponin that binds calcium ion.

- There are different isoforms of TROPONIN-C:
*The FAST ISOFORM has 2 high and 2 low affinity binding sites for calcium.
*The SLOW (CARDIAC) isoform has one high and one low affinity calcium binding site.

Front 30

Troponin-T

Back 30

Binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex.

Front 31

Troponin I

Back 31

Binds to ACTIN, holding the complex in place.

Front 32

Ryanodine Receptors

Back 32

- Calcium release channels of the sarcoplasmic reticulum that are in direct contact with dihydropyridine receptors of the t-tubules.

- When an action potential is propagated down a t-tubule, the voltage-gated DHPRs change conformation, which causes a shift in RyR conformation via direct contact.
- This results in an opening of the calcium channels during COUPLING in muscle contraction.

Front 33

SERCAs

Back 33

- CALCIUM ATPase PUMPS that sequester calcium ion after repolarization of the sarcolemma, and closing of the RyR.
- SERCA2a is found in slow skeletal muscle, while SERCA1 is found in fast skeletal muscle.

- In its dephosphorylated state, PHOSPHOLAMBAN (PLB) acts to inhibit the ATPase activity of SERCAs (slowing relaxation); whereas, phosphorylated PLB causes it to dissociate from SERCAs allowing relaxation to occur more quickly.

Front 34

Motor Unit

Back 34

One motor neuron + all of the muscle fibers it innervates.

Front 35

Size Principle

Back 35

Henneman's Size Principle says that the body will first recruit the smallest motor neurons to accomplish a task (Slow); once those are all being used, it will then recruit bigger ones (fast fatigable); and, finally the biggest motor neurons (fast, fatigue resistent).

INNERVATION RATIO:
Number of muscle fibers controlled by a single motor neuron is LOW in SLOW; and HIGH in F.F.R. and F.F. (this is what it means by "size of motor unit."