L8. Physiology - Cardiac Function I

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Questions and Answers

What effect does increased cytosolic calcium have on muscle contraction?

It opens more binding sites to generate tension. (correct)

It increases the inhibitory lock on troponin.

It causes binding sites on actin to close.

It decreases myosin binding affinity.

What role does PKA phosphorylation play in muscle contraction regulation?

It enhances the binding of actin and myosin.

It inhibits the power stroke of the myosin ATPase cycle.

It increases the calcium dissociation rate of TnC subunit. (correct)

It decreases the calcium dissociation rate of TnC subunit.

How does tropomyosin affect muscle contraction?

It is easily pharmacologically regulated for contraction.

It binds to actin to increase calcium binding.

It can undergo mutations that alter its movement. (correct)

It directly stimulates ATP hydrolysis in myosin.

In which muscle type does the β-MHC isoform primarily belong?

Slow-twitch skeletal muscle. Signup and view all the answers

What is the significance of the 'super relaxed' (SRX) state in myosin heads?

It blocks ATPase activity. Signup and view all the answers

What is cooperative activation in muscle contraction?

The opening of a nearby binding site when myosin binds. Signup and view all the answers

What potentially alters the isoform expression of myosin in response to disease?

Higher expression of either α-MHC or β-MHC isoforms. Signup and view all the answers

Which of the following best describes the myosin ATPase cycle?

Myosin binds to actin before hydrolyzing ATP to ADP-Pi. Signup and view all the answers

What triggers calcium-induced calcium release in cardiac muscle?

Calcium influx through L-type calcium channels Signup and view all the answers

What is the role of SERCA in cardiac muscle contraction regulation?

Sequesters calcium back into the SR Signup and view all the answers

How does RyR2 in cardiac muscle differ from RyR1 in skeletal muscle?

RyR2 allows for calcium-induced calcium release Signup and view all the answers

What effect does phosphorylation by PKA have on phospholamban (PLB)?

Prevents it from inhibiting SERCA Signup and view all the answers

Which step occurs immediately after depolarization in the contraction process?

RyR calcium-induced calcium release Signup and view all the answers

What happens to cytosolic calcium levels during a contraction in cardiac muscle?

It increases from around 10-7 M to nearly 10-5 M Signup and view all the answers

What is the primary action of the myosin ATPase during muscle contraction?

Generates force through binding to actin Signup and view all the answers

What is the significance of the T-tubules in cardiac muscle?

They allow action potentials to penetrate deep into the muscle Signup and view all the answers

Which of the following best describes the process that leads to thin filament activation?

Calcium binds to troponin, opening binding sites Signup and view all the answers

What is the role of caffeine in calcium release during muscle contraction?

Makes RyR2 opening more likely Signup and view all the answers

What is the trade name of Mavacamten, the FDA approved treatment for obstructive hypertrophic cardiomyopathy?

Camzyos Signup and view all the answers

Which of the following correctly describes preload in muscle physiology?

The load on the muscle prior to excitation. Signup and view all the answers

What role does myosin binding protein C play in muscle contraction?

It can both inhibit myosin ATPase and impact thin filament activation. Signup and view all the answers

Which two proteins primarily define the properties of the muscle at a given preload?

Titin and Collagen Signup and view all the answers

How does titin function in muscle physiology?

It resists stretch and helps restore length when compressed. Signup and view all the answers

What is the primary difference between preload and afterload?

Preload refers to muscle length, while afterload refers to muscle tension. Signup and view all the answers

In the context of cardiac function, what does afterload commonly refer to?

The pressure exerted within the arterial system. Signup and view all the answers

Which statement best describes the effects of phosphorylation on myosin binding protein C?

Phosphorylation alternates the effects of opening binding sites and inhibiting myosin ATPase. Signup and view all the answers

How can stiffness of Titin be regulated?

Through changes in isoform and phosphorylation Signup and view all the answers

What is the primary role of collagen in the myocardium?

To form the extracellular matrix surrounding myocytes Signup and view all the answers

What effect does heavy deposition and crosslinking of collagen have on tissue?

It increases passive stiffness Signup and view all the answers

In which scenario does tension in the muscle primarily correlate with length?

At maximal activation in skeletal muscle Signup and view all the answers

What is a significant way to change the stiffness of Titin?

Through phosphorylation and isoform changes Signup and view all the answers

Which factor has a more substantial influence on passive stiffness at physiological preloads?

Titin properties Signup and view all the answers

What is the primary visual distinction between long and short isoforms of Titin?

Their stiffness characteristics Signup and view all the answers

What role does phosphorylating Titin play?

It regulates stiffness properties Signup and view all the answers

What does the higher slope represented by the solid line indicate in this experiment?

Length dependent activation affecting tension Signup and view all the answers

Which of the following explains why the actual tension is greater than expected at higher calcium levels?

Length dependent activation effects Signup and view all the answers

What would be the consequence if filament overlap was the only determinant of force?

Normalized forces should equal the same sarcomere length Signup and view all the answers

How does the actual tension at longer lengths compare to expected tension as represented in the graph?

It exceeds the expected tension as shown by the solid line Signup and view all the answers

What was the role of preload in the experiment regarding muscle tension?

It determined the sarcomere length affecting tension Signup and view all the answers

What does the term 'Length Dependent Activation' refer to in this context?

The impact of sarcomere length on contractile strength Signup and view all the answers

How does the tension-length relationship deviate in the presence of high calcium?

It reveals an increased slope indicating greater contractility Signup and view all the answers

What would optimal conditions leading to maximal tension in muscle fibers require?

High calcium concentrations with appropriate preload Signup and view all the answers

Study Notes

Excitation-Contraction Coupling

Depolarization allows extracellular calcium to enter the cell
Calcium-induced-calcium release occurs (RyR-2)
Cytosolic calcium rises from ~10-7 M to nearly 10-5 M
SERCA removes cytosolic calcium, regulated by PLB

Depolarization

Occurs near sarcoplasmic reticulum (SR)
T-tubules are essential to keep the action potential near the SR
Cardiac muscle expresses the RyR-2 gene
Ryanodine Receptor 2 (RyR2) allows for calcium-induced-calcium release
Not coupled to T-Tubule like RyR1
T-tubules take action potentials and calcium deep inside the muscle

Calcium Sequestration

Calcium sequestered back to the sarcoplasmic reticulum via the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA)
SERCA is regulated by Phospholamban (PLB, sometimes PLN)
More active SERCA means more calcium in SR

Differences between cardiac and Skeletal Muscle

Cardiac Muscle:
- RyR2 (ryanodine receptor) is not mechanically coupled to the T-tubule
- RyR2 requires calcium influx through L-type calcium channels
- Calcium release from SR causes a large increase in cytosolic (intracellular) calcium
- "Calcium induced calcium release"
Skeletal muscle:
- T-tubules couple to the Sarcoplasmic Reticulum via the DHC receptor
- When the L-type calcium channel is activated (membrane depolarization), mechanical coupling to the RyR1 (ryanodine receptor) causes cytosolic calcium release
- Does not require inward calcium movement to cause RyR1 activation

Regulation of Calcium

Release: RyR2
- ATP and caffeine also make opening more likely
- Can be phosphorylated to phosphorylated (PKA) to make opening more likely
Reuptake: SERCA
- Regulated by Phospholamban (PLB, sometimes PLN)
- PLB itself is regulated by PKA, PKA phosphorylation prevents PLB from inhibiting SERCA
- Increased SERCA activity means more calcium can be sequestered in the SR, causing a greater calcium release

Contraction

Two steps to achieve contraction:
- Thin Filament Activation
- Myosin ATPase

Thin Filament Activation

Calcium binds and opens the binding sites on actin
Troponin undergoes a conformational change, removing an inhibitory lock
Tropomyosin is moved aside to make myosin binding easier
Regulation:
- More cytosolic calcium=more available binding sites to generate tension
- Troponin complex:
  - PKA phosphorylation increases calcium dissociation rate of TnC subunit
  - Other phosphorylation can change tropomyosin inhibition
- Tropomyosin:
  - Difficult to pharmacologically regulate, but mutations can change its movement
  - Impacts cooperative-activation:
    - Cooperative activation is the opening of a nearby binding site when myosin binds
    - Can regulate deactivation of the thin filament

Myosin ATPase (contraction)

Myosin ATPase will cycle, generating tension if the thin filament is activated
The myosin ATPase (crossbridge) cycle includes steps such as:
- myosin hydrolyzing ATP to ADP-Pi
- myosin binding actin
- the power stroke where Pi and ADP are released
- the rigor bride
- ATP binding and myosin release from actin
Cardiac muscle has two myosin isotypes:
- α-MHC (fast)
  - MYH6 gene
  - ATPase and power stroke cycle quickly
- β-MHC (slow)
  - MYH7 gene
  - Type I skeletal myosin
  - ATPase and power stroke cycle more slowly and generate more force

Regulation of Myosin ATPase

The ATPase can also be regulated without modifying the isoform
The myosin heads may self-regulate
There is research into a “super relaxed” (SRX) state where the ATPase activity is blocked
Mavacamten (Camzyos) is an FDA-approved drug for obstructive hypertrophic cardiomyopathy that reduces the amount of force (contraction) generated by regulating the ATPase
Myosin light chains bind to the myosin molecule:
- Two forms: Essential and Regulatory light chains
- Impact myosin binding to actin and the myosin ATPase
- Can be phosphorylated
Myosin Binding Protein-C is associated with several cardiomyopathies:
- Might impact thin filament activation (opening of binding sites) and could inhibit the myosin ATPase

Cardiac Load

Load is alternately referred to for muscle length or tension
Preload:
- Load on the muscle prior to excitation, i.e.the pre-contraction load
- Usually the length of the muscle before contraction
- Defined by titin and the extracellular matrix (collagen)
Afterload:
- Load on the muscle after contraction has started
- Usually the tension on the muscle after contraction
- Interchangeably with pressure, e.g., arterial pressure when referring to the heart

Preload Mechanisms and Stiffness

Titin:
- Giant molecular spring that lies across the sarcomere
- Resists stretch and tries to restore length if it is compressed
- Associated clinically with dilated cardiomyopathies
- Stiffness can be regulated by changing its isoform and phosphorylation
Collagen (Extracellular Matrix):
- Surrounds myocytes
- Can be deposited more heavily (or less) or crosslinked, which will make it harder to stretch
- Contributes to passive stiffness (e.g., the tension at a specific preload/length)
- Titin is thought to contribute more at physiological preloads.

Length Dependent Activation

Overlap of the thick filament (containing myosin) and the thin filament (containing actin) alters the number of binding sites
Tension is related to the length (preload) when all binding sites are open
This is true in skeletal muscle, especially at maximal activation
Changes in calcium levels affect tension at different sarcomere lengths
The slope of the tension-length relationship becomes higher than expected due to length-dependent activation.

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Description

This quiz explores the critical processes of excitation-contraction coupling specifically in cardiac muscle physiology. Key topics include the roles of calcium entry, ryanodine receptors, and calcium sequestration mechanisms such as SERCA and its regulation by phospholamban. Dive into the differences between cardiac and skeletal muscle functions and their implications.