Myocyte contraction coupling

Describe key components of cardiac muscle structure

syncytium ie one cell multiple nuclei so beats as one unique unit made up of 2 types of links:

• mechanical: intercalated disks ie junctional complexes made up of desmosomes and fascia adherens

• electrical through gap junctions

What are some key structures required for excitation contraction coupling?

• structure unit - sarcomere

• actin and myosin cross bridges - overlap important

• calcium dependent

• additional proteins eg troponin and tropomyosin

Describe the relationship between calcium and cardiac contraction

longer Ca2+ transient compared to the electrical activity, and the later tension development

What are 2 ways in which calcium flows into cardiac muscle? Which is the largest contribution?

• Influx from ECF via L – type Ca² channels (Cav1.2), Release from SR via activation of ryanodine receptor type 2 - CICR

Both sources – contraction

• RYR2 largest contribution – open for longer

• Absolute requirement for Ca²⁺ influx via L type channels (unlike skeletal muscle)

Once calcium enters cardiomyocytes, how is muscle contraction triggered? Which receptors are involved?

Calcium coming in activates sar2 receptors so calcium leaves SR = increase in IC Ca = increase tension and contraction

Describe calcium efflux leading to myocyte relaxation

Efflux – plasma membrane 

H⁺/ Ca²⁺ exchanger -  PMCA

3Na⁺ / 1 Ca²⁺ exchanger -  NCX1 – note importance Na⁺/K⁺ ATPase

How is calcium stored following myocyte contraction?

Sarcoplasmic reticulum - H⁺/ Ca²⁺ exchanger SERCA2

Mitochondria – MiCa channels 

Mitochondrial membrane potential is -160 mV

What underlies strength/velocity of contraction in myocyte?

Calcium increases and sensitivity contractile proteins to calcium

What underlies strength/velocity of contraction in muscle?

pre-load/EDV and afterload/arterial pressure

Define isometric

held at a specific length, tension changes eg plank

Describe passive tension.

tension generated @ set sarcomere length - no APs or muscle stimulation, just a change in tension

Which molecules are involved in passive tension?

titin and desmin (connects sarcomeres) - cardiac has shorter titin

Describe active tension. How does it differ between cardiac vs skeletal myocytes?

tension generated by stimulation of the muscle @ set sarcomere length

Skeletal muscle has a wider range of lengths over which its tension is near-optimum. At about 75% of the optimal length, skeletal muscle tension is close to maximum already, whereas for cardiac muscle the active tension is zero at that length

What does proteins being closer in cardiac muscle fibre increase?

probability of an X bridge formation

What is the impact of increased tension on stretch-activated calcium channels?

more calcium enters from ECF

What is the amount of stretch equal to?

pre-load and EDV

Which law underlies amount of stretch/pre-load/EDV?

Starling’s law

Describe Starling’s law

the mechanical energy set free on passage from the resting to contracted state depends on the length of the fibres

i.e. the strength of contraction depends on sarcomere length

What is the effect on contraction when a sarcomere has a larger length?

greater contraction

What is the relationship between diastole and systole in starlings law?

they have to match

Are diastole vs systole passive or active?

diastole passive, systole active

What intrinsic autoregulatory mechanism ensures cardiac output matches venous return?

force of ventricular contraction is directly proportional to the initial length of cardiac muscle fibers, meaning a greater filling (stretch) of the ventricle during diastole leads to a stronger contraction and higher stroke volume

More blood in ventricles =

greater contraction

What is set and differs in isometric shortening?

length set, tension differs

What is set and differs in isotonic shortening?

tension set, muscle length differs

Describe the set up to measure velocity of shortening

• tension generated first, adjustable stop sets length/preload

• stop removed, muscle shortens and velocity depends on afterload/arterial pressure

What does the isometric phase of contraction modulate in vivo?

isovolumetric contraction phase (valves closed)

What does the isotonic phase of contraction modulate in vivo?

ejection phase

What does the slope represent?

velocity of shortening

What type of tension is left vs right?

left is passive tension vs right is active tension

What is the impact of afterload changes on shortening velocity ?

• muscle lifting lightest afterload = faster shortening

• muscle lifting heaviest afterload = slower shortening

At a given afterload, velocity of shortening is greater if … is greater

a pre-load

once contraction starts greater tension generation capacity actually helps speed things up

High pre-load impact on length

= longer length

Low pre-load impact on length

= shorter length

Contraction is isometric when velocity =?

0! indication maximum tension that can be generated

At a given velocity of shortening, muscle exerts greater tension if larger

preload

Impact of large volume and high arterial pressure on contraction

strong and slow

Impact of large volume and low arterial pressure on contraction

strong and fast

Impact of low volume and high arterial pressure on contraction

weaker and slow

Impact of low volume and low arterial pressure on contraction

weaker and fast

What is a difference in contractility vs rate termed?

inotropic vs chronotropic

Impact of high HR on tension and calcium availability

increased tension and calcium availability

What is there less time for during high HR?

for efflux to occur: HR = SERCA2a to take calcium into SR rather than efflux into ECF = more calcium released from SR

What is the impact of an increase in heart rate on calcium release?

hr higher so tension generated higher - increase in contraction tension due to faster heart rate - less time for calcium efflux so calcium taken into SR instead of effluxed across membrane of cells so next HR signal has more calcium in SR than usual so release of IC calcium is going to be higher = higher hr/contraction

What are 2 possible factors impacting strength of contraction?

IC Calcium increases and protein sensitivity

Pre load vs afterload impact ?

contraction strength vs velocity shortening

Define the Bowditch staircase phenomenon

an increase in HR increases the force of contraction generated by the myocardial cells with each heartbeat, despite accounting for all other influences due to increased calcium sensitivity of muscle cell