L1: Cardiac muscle 1 Flashcards
general features of the cardiac muscle
- Involuntary
- Myogenic (contraction initiated by specialised myocytes).
- Cardiomyocytes are electrically coupled.
- Cardiomyocytes are mainly oxidative in metabolism.
- AP triggers excitation-contraction coupling (CICR).
- Heart beats with a constant rhythm that can be modified
by neural or hormonal input. - Cardiomyocytes have fast contraction, & are non-
fatiguable
main cell types in the heart and proportion
Main cell types:
– Cardiac fibroblasts
* majority of cells in the heart
* secrete & maintain connective tissue fibres
– Cardiomyocytes (~30% of all cells)
* Provide majority of myocardial mass
* Carry out myocardial work (contraction)
* Some are very specialized cells (purkinje & nodal)
– Endothelial cells (vascular and endocardial)
– Vascular smooth muscle cells
– Neurons
The muscular tissue of the heart
what cell type provide the majority of myocardial mass yet only make up 30% of all cells in the heart?
cardiomyocytes
intercalated discs at intercellular junctions consist of…
-nexus or gap junctions
-fascia adherens or
intermediate junctions
-macula adherens or
desmosomes (“spot
welds”)
ECM composition:
Extracellular matrix (ECM)
Comprised of:
~60% vascular (each myocyte in close
proximity to capillaries)
~23% substance resembling glycocalyx
7% connective tissue cells
6% empty space
4% collagen
LTCC in skeletal muscle vs cardiac muscle
Similar to skeletal muscle in cardiac muscle: have RyR on junctional SR
Unlike skeletal muscle which has a voltage- dependant interaction between the LTCC( L-type Ca2+ channel) and the RyR (ryanodine receptor) to release Ca2+
-In cardiac myocytes the LTCC is a patent channel-V-gated and the channel itself opens and allows influx of Ca2+
During the AP when depolarisation occurs LTCC opens up-> Ca2+ influx causes big rise in the concentration of Ca2+ in this specialised area( gap between t-tubule and RyR) that triggers the opening of RyR, which are the Ca2+ release channels of the junctional SR.
T-tubule organization in cardiac muscle
Most of the T-tubules are occurring as transverse tubules
T-tubules link along the longitudinal axis of the cell
So when the AP is propagated along the surface sarcolemma and down these t-tubules within the cell it is continuing this propagation in the longitudinal direction. This means that cardiac muscle potential is synchronised throughout the cell to trigger excitation-contraction coupling within a few ms.
mitochondria make up ~ __ % of cardiomyocyte cell volume
40%
Excitation- contraction coupling & Ca2+ induced Ca2+ release
Ca2+ induced Ca2+ release:
Depolarisation of the surface sarcolemma causes the V-gated Ca2+ channels to open( LTCC), a little bit of trigger Ca2+ comes into the cytosol in the region close to where the RyR are on the junctional SR. RyR open-> Ca2+ released into the cytosol.
Ca2+ conc. Is increased very rapidly throughout the whole cytosol of the cell by about 10 x the resting Ca2+ lvl.
Ca2+ is then free to diffuse to the contractile proteins in the myofilaments. Ca2+ binds to troponin-C, triggering cross-bridge cycling.
Contractile proteins are very close to the junctional region of the SR, so the diffusion distance for Ca2+ to trigger cross-bridge cycling is very short within the myocyte!
*Ca2+ ions that come from the outside the cell or from the SR into the cytosol are NOT destroyed they are recycled.
During relaxation- we have removal of cytosolic Ca2+ mostly by reuptake into the SR by SERCA and some of it will be transported out across the sarcolemma by 3Na+/Ca2+ exchanger(! an important component of Ca2+ balance/homeostasis because Ca2+ that comes into the cell during LTCC current/inflow must be removed back from the cell via 3Na+/Ca2+ exchanger). Also have the 3Na+/ 2K+ pump.( maintain Na+ gradient). And V-gated Na+ and K+ channels that trigger the AP. ( part of AP)
With each electrical stimulation get a rapid increase in intracellular Ca2+, which then decreases again equally rapidly as Ca2+ is taken back up into SR and pumped outside the sarcolemma via 3Na+/Ca2+ exchange.
During steady state with each heartbeat in every muscle cell we have this highly regular amount of Ca2+ released and cycled per beat.
Importance of t-tubules
For excitation-contraction coupling to be efficient we have to have the LTCC in the t-tubules close to the RyR. In a diseased cell whereby the junctional SR is slightly distorted or t-tubules have been lost in some parts of the cell altogether the excitation-contraction coupling is not going to be as well synchronised, so instead of a very rapid upstroke with a Ca2+ transient, will have a much slower upstroke, with a much slower/ delayed twitch/contraction occurring-> weaker heartbeat altogether.
Cav-3 is a marker of the surface sarcolemma in the t-tubule membranes.
RyR2 in blue.
In a healthy cell- very regular striations.
Pulmonary artery hypertension: Heart failure: hypertrophy of the right ventricle: can see that the t-tubular system is distorted , have lost RyR and in other areas- have higher density of RyR but with no t-tubules.
These hypertrophy cells prior to HF are not performing well, so this animal model developed HF within a few weeks.
Just prior to HF- can see disruption of the t-tubular system seems to occur prior to HF.
Think of a diseased cardiomyocyte where all the t-tubules were disrupted and not close to RyR throughout the whole cell. When LTCC open- have influx of Ca2+ but will dissipate before it reaches RyR. The gain of E-C coupling is reduced, because of the distorted t-tubules -> weaker contraction. If the entire heart is like that-> trouble.
L-type Ca2+ channels(DHPR) are inhibited by…?
-SR Ca2+ release
-inhibited by dihydropyridines ( Ca2+ channel blockers), Mg2+ etc
-inhibited by low plasma [Ca2+] and vice versa. The channels themselves close or are inhibited by low cytosolic Ca2+ conc. During diastole it is important that we don’t have Ca2+ leaking via LTCC.
L-type Ca2+ channels(DHPR) are stimulated by…?
-activated by depolarisation > -40mV
-stimulated by catecolamines
L-type Ca2+ channels(DHPR) are stimulated by…?
-activated by depolarisation > -40mV
-stimulated by catecolamines
what happens if not all Ca2+ is removed during diastole?
In a situation where Ca2+ is not being removed completely during diastole ( happens in diseased hearts) the gradient for Ca2+ to move into the cell through LTCC is reduced-> can cause a much weaker contraction in the cells.
what is calsequestrin and what’s its role?
Calsequestrin is a calcium-binding protein primarily found in the sarcoplasmic reticulum (SR) of muscle cells. It is especially abundant in the SR of cardiac and slow-twitch skeletal muscle fibers.
The primary function of calsequestrin is to act as a calcium buffer and regulator within the SR. It has a high calcium-binding capacity, allowing it to bind and store large amounts of calcium ions (Ca^2+) within the SR lumen. By binding to calcium, calsequestrin helps maintain a high concentration of calcium within the SR, which is crucial for muscle contraction.