2. Muscles

• Skeletal muscles: striated, control movement
• Smooth muscles: involountary contractions, control movement of fluids through inner organs
• Cardiac muscles: involountary contraction, striated/striped, moves the blood through the body

Out → In: Fascia, Epimysium, Perimysium, Fascicle, Endomysium, Muscle fibre/Cell

Out → In: Muscle fibre, Sarcolemma (the membrane), Myoplasm/Sarcoplasm, Myofibrils

[PIC]

• T-tubules = Transverse tubules
• Increases the surface are of a muscle cell
• Provides signals from the surface of the cell down into the cell, specifically to the sarcoplasmic reticulum (SR)
• Allow the AP to reach all parts of the muscle cell almost simultaneously. Wthout this, problems would occur in signaling into the cell.
• Adequate exchange of nutrients

• Sarcoplasmic Reticulum (SR):
• Like ER but in the cell
• Stores Ca²⁺ ions
• Has pumps for transport of Ca²⁺ from sarcoplasm --> SR
• Ca²⁺ gates through which Ca²⁺ flows out at impuls
• Terminal cisternaes, one at each side of the T-tubule, where Ca²⁺ is stored
• Triad = 2 cistarnaes, 1 T-tubule

• The Contractive element of a muscle cell
• Composed of 2 types of filaments (thin & thick)
• Many subunits composed of filaments (sacromeres = smallest subunit in a muscle)

• Myosin (head & tail)
• Actin - has a myosin binding site onto which the head attaches (bead)

• Titin (anchor thick filament to the Z-disc)
• Desmin

• Tropomyosin: regulaes muscle contraction by interfiering with the binding og myosin & actin (moves & exposes the myosin binding site of the actin → myosin head can bind!). Has 3 subunits, I = inhibitatory, C = calcium binding, T = tropomyosin
• Troponin: Ca2+ binds to it when a contraction of a muscle is initiated

1. AP causes a Ca²⁺ influx through the voltage-gated calcium channels.

2. The Ca²⁺ influx causes vesicles containing the neurotransmitter acetylcholine to fuse with the plasma membrane, releasing acetylcholine out into the extracellular space between the motor neuron terminal and the motor end plate of the skeletal muscle fiber.

3. The calcium binds to the troponin → conformational change (troponin moves and exposes the myosin binding sites of the actin) → myosin can bind.

4. Myosin (which has ADP and inorganic phosphate bound to its nucleotide binding pocket and is in a ready state) binds to the newly uncovered binding sites on the thin filament (binding to the thin filament is very tightly coupled to the release of inorganic phosphate). Myosin is now bound to actin in the strong binding state. The release of ADP and inorganic phosphate are tightly coupled to the power stroke (actin acts as a cofactor in the release of inorganic phosphate, expediting the release). This will pull the Z-bands towards each other, thus shortening the sarcomere and the I-band.

5. ATP binds myosin, allowing it to release actin and be in the weak binding state (a lack of ATP makes this step impossible, resulting in the rigor state characteristic of rigor mortis). The myosin then hydrolyzes the ATP and uses the energy to move into the "cocked back" conformation. In general, evidence (predicted and in vivo) indicates that each skeletal muscle myosin head moves 10-12 nm each power stroke, however there is also evidence (in vitro) of variations (smaller and larger) that appear specific to the myosin isoform.

6. Steps 4-5 repeat as long as ATP is available and calcium is present on thin filament.

7. While the above steps are occurring, calcium is actively pumped back into the sarcoplasmic reticulum. When calcium is no longer present on the thin filament, the tropomyosin changes conformation back to its previous state so as to block the binding sites again. The myosin ceases binding to the thin filament, and the contractions cease.

• 1: Somatic motor neuron releases ACh at neuromuscular junction.
• 2: Net entry of Na⁺ into the cell through ACh receptor channels --> muscle AP
• 3: AP in T-tubule --> conformational change of DHP-rec.
• 4: DHP opens RyR on SR --> Ca²⁺ enters the cytoplasm due to low [Ca²⁺] in the cytoplasm at rest.
• 5: Ca²⁺ binds to troponin --> strong actin-myosin binding.
• 6: Myosin heads execute power stroke = pulls actin fil. past myosin fil.
• 7: Actin fil. slides toward the center of sacromere

Ending: Stop of NT/ACh release --> no signal/AP --> closure of RyR channel

Problem: High [Ca²⁺] in myoplasm, has to go back to where it came from. Does so by active transport: ATP --> ADP + Pi. Energy released, used to move Ca²⁺ back to SR

• Isometric: no work is performed, no diff in muscle length
• Isotonic: tension or force generated by the muscle i greater than load = muscle shorten. The same resistance throughout the whole movement/contraction
• Concentric: muscle is shortening
• Eccentric: muscle is actively lengthening
• Isokinetic: musce contracts & shortens at a constant speed

Twitch: The response of a skeletal mscle to a single stimulation (or AP)

• Three phases of a muscle twitch:
• 1. Latent period: the sarcolemma and the T tubules depolarize, calcium ions are released into the cytosol, cross bridges begin to cycle but there is no visible shortening of the muscle
• 2. Contraction phase: myosin cross bridge cycling causes sarcomeres to shorten
• 3. Relaxation: calcium ions are actively transported back into the terminal cisternae, cross bridge cycling decreases and ends, muscle returns to its original length

• A second stimulus during relaxation (well aoutside the refractory period) → developement of significant addiotional force
• Reason: additional release of Ca²⁺ from SR - adds to the Ca²⁺ already there → reactivation of actin & myosin interactions
• Tetanus: Rapid stimulation of a muscle, no relaxation between stimuli. Tetanus cannot continue forever due to fatique

• Wave summation: The summation of all stimuli give to a muscle, even from different motor units
• Motor unit summation: The summation of all stimuli given to a muscle my one neuron

• The more interactions with the signaling neuron, the greater force obtained.



• The more Ca²⁺ is released into the myoplasm, the greater the force (due to Ca²⁺-troponing binding)



• When the stimulation is very frequent, the intracellular [Ca²⁺] will reach a max level



• The curve flattens at high frequency because there is no troponin left for the Ca²⁺ to bind to = no increase in force is possible

• Passive/Resting force is the force generated from muscle extention and is due to blood vessles, collagen proteins, etc.
• Active force is generated by action/myosin interactions and is depented on the length at which a muscle is held (se pic below)
• The sum of these are the total force

• X-crossbridges (se pic above) can occur at short - optimal length.
• The active force increases until the muscle reaches its optimal length (L_o). This is when the H-zone reaches 0 and the thin and thick filaments can intergrate to their maximum

• 
• After L_o
• Passive force is generated and aids to prevent overextension.
• Further stretch = less actin-myosin interactions = less force
• Max stretch = no attachments = no force

• V_max = max rate of crossbridge cycling
• At 30% of the velocity, max power is generated

• Smaller cell diameter
• Red due to more myoglobin
• Myoglobin bind, release & store O₂ (abundant in muscle fibres that depend on aerobic metabolism for their ATP supply)
• More mitochondria
• More capillary density
• More oxidative
• Less glycolytic (use fat as energy supply)
• Fatique resistant

• Larger cell diameter
• Little myoglobin
• Glygolytic metabolism
• Contain stored glycogen
• Fast, crossbridges move faster
• Have more ATPase
• Relax more rapidly due to more SR-pumps that pump Ca²⁺ back into the SR

• 1: Oxidative phosohorylation (occurs in mitochondria, aerobic)
• 2: Glycolysis (occurs in myoplasm, anaerobic)
• 3: Creatine phosphate (occurs in myoplasm, anaerobic)
• ATP → ADP + Pi.
• PCr → Cr + Pi.
• Both PCr and free ATP in muscles ares limited. Max force depletes ATP in 2 seconds, PCr in 10 seconds

• At low intensity, the ATP comes from fat & carbohydrate sources and can be maintained for a long time
• At high intensity, the ATP comes from anaerobic sources and can only be maintained for a short time
• Anaerobic sources: glycogen & lactid acid

the x-axis = % of VO_2MAX

• Muscle fatique = decline of contractile functions
• Anaerobic metabolism in skeletal muscle; PCr --> Cr + Pi
• The accumulation of Pi (inorganic phosphate) may cause a downregulation of contractile functions

• Smooth muscles lack T-tubules & troponin
• The troponon/actin interaction is regulated by calmodulin
• Myosin head contains 4 C_L
• Ca²⁺ in SR or extracellular fluid
• Ca^₂₊ release is induced by IP₃ r Ca²⁺

• Contraction:
• 1: Signal → influx of Ca²⁺ from ECM
• 2: 4 Ca²⁺ bind to CaM
• 3: Ca²⁺-CaM complex activates myosin light-chain kinase (MLCK)
• 4: MLCK; ATP → ADP + Pi
• 5: Pi attaches to crossbridge
• 6: phosphorylated crossbridge → interaction with actin → circle

• Relaxation:
• 1: dephosphorylation by MLCPhosphatase
• 2: Ca²⁺↓ → MLCK↓ myosin affinity for actin ↓ → relaxation

• Dephosphorylation at attached state:
• "latch" state = much slower cycling → force generation during long time

• Summary:
• Contraction of smooth muscle is generated by posphorylation of crossbridge. This phosphorylation is not needed to maintan force. Once phosphorylated, the muscle keeps on cycling and generation force but slower.