Case 9 Flashcards
what are the cells of the bone?
Bone contains four types of cells: Osteocytes, Osteoprogenitor cells (stem cells), Osteoblasts (osteogenesis) and Osteoclasts (osteolysis).
what are osteoprogenitor cells? what do they do?
- These are mesenchymal stem cells that divide and differentiate into osteoblasts.
- These maintain populations of osteoblasts and are important in the repair of a fracture.
- Osteoprogenitor cells located in the periosteum and the bone marrow (endosteum).
what are osteoblasts? what do they do?
- These originate from osteoprogenitor cells.
- Form new bone matrix in a process called osteogenesis. In other words, osteoblasts form the osteoid, which is then calcified into bone.
- Osteoblasts also assist in the calcification of osteoid into bone.
- As osteoblasts surround themselves with extracellular matrix, they become trapped in their secretion and become osteocytes.
what is osteogenesis?
- Osteoblasts secrete collagen molecules and ground substance (extrafibrillar matrix – gel-like substance surrounding the collagen molecules).
- Collagen molecules combine to form collagen fibres.
- The resultant tissue is called osteoid (non-calcified bone).
- Hydroxyapatite crystals form on the collagen fibres. The osteoid is now calcified and this is bone.
what are osteocytes? what do they occupy? what do they do?
- These are mature bone cells that cannot divide.
- Each osteocyte occupies one lacuna, occupying layers called lamellae.
- Lamellae are connected by canaliculi, providing nutrients from the central canal.
- If released from their lacunae, osteocytes can convert to a less specialized type of cell, such as an osteoblast or an osteoprogenitor cell.
what are osteoclasts? what are they derived from? what do they do?
- Derived from granulocyte/monocyte progenitor cells.
- Multinucleated cells involved in bone resorption (bone removal and recycling).
- Osteoclast membrane secretes enzymes which dissolve the matrix and release the stored minerals into the blood stream.
- This process is called osteolysis, this process is important in the regulation of calcium and phosphate concentrations in body fluids.
what is a myofibril? what is it composed of? how organised?
• Myofibril (muscle fibril) – is a basic rod-like unit of muscle.
• They are composed of long proteins such as actin, myosin and titin, and other proteins that hold them together.
• These proteins are organised into thin filaments and thick filaments, which repeat along the length of the myofibril in sections called sarcomeres.
Thin filaments are actin.
Thick filaments are myosin.
light bands
- what do they contain
- what are they called
- contain only actin filaments (+ Z discs)
- called I bands
dark bands
- what do they contain
- what are they called
- contain myosin filaments + actin filaments (where they overlap the myosin)
- called A bands
what are the ends of the actin filaments attached to?
a Z disc
what does the Z disc do?
The Z disc passes crosswise across the myofibril and also crosswise from myofibril to myofibril, attaching the myofibrils to one another all the way across the muscle fibre. Therefore, the entire muscle fibre has light and dark bands, as do the individual myofibrils. These bands give skeletal and cardiac muscle their striated appearance.
what is a sarcomere?
the portion of the myofibril that lies between two successive Z discs
what are the spaces between the myofibrils filled with? what does this comprise of?
sarcoplasm
• It comprises of: Significant amounts of myoglobin, an oxygen-binding molecule. Potassium, magnesium, phosphate ions. Sarcoplasmic reticulum Protein enzymes
• Mitochondria lie parallel to myofibrils.
what is titin?
- One end of the titin molecule is elastic and is attached to the Z disc, acting as a spring and changing length as the sarcomere contracts and relaxes.
- The other part of the titin molecule tethers it to the myosin thick filament.
what does actin consist of? (+ what is wrapped around it) and the function of different components?
- The backbone of the actin filament is a double-stranded F-actin protein molecule.
- Each strand is composed of G-actin molecules.
- Attached to each one of the G-actin molecules is one molecule of ADP – The active site.
• Tropomyosin is wrapped spirally around the sides of the F-actin helix.
• In the resting state, the tropomyosin molecules lie on top of the active sites of the actin strands so that attraction cannot occur between the actin and myosin filaments to cause contraction.
• Attached intermittently along the sides of the tropomyosin molecules are troponin.
Troponin I has a strong affinity for actin
Troponin T has a strong affinity for tropomyosin
Troponin C has a strong affinity for calcium ions.
- This complex is believed to attach the tropomyosin to the actin.
- The strong affinity of the troponin for calcium ions is believed to initiate the contraction process.
myosin
- what made up of
- what different components do
- what are cross-bridges
• The myosin filament is made up of many individual myosin molecules.
• Myosin molecules are composed of a head, neck and tail.
The myosin head binds the actin filament.
The myosin head functions as an ATPase enzyme.
The myosin neck acts as a linker and as a lever arm for transducing force generated by the motor domain.
The myosin neck can also serve as a binding site for myosin light chains, which have regulatory functions.
The myosin tail connects the myosin head to the body of the myosin molecule.
• The protruding tails and heads together are called cross-bridges.
Each cross-bridge is flexible at two points called hinges - one where the tail leaves the body of the myosin filament, and the other where the head attaches to the tail.
There are no cross-bridge heads in the centre of the myosin filament because the hinged tails extend away from the centre.
• The myosin filament itself is twisted so that each successive pair of cross-bridges is axially displaced from the previous pair by 120 degrees. This ensures that the cross-bridges extend in all directions around the filament.
describe what happens at the neuromuscular junction and after that
- Impulse (action potential) arrives at axon terminal.
- Ca2+ ions rush in (as action potential activated Ca2+ gates); Ca2+ reacts with synaptic vesicles.
- Synaptic vesicles fuse with cell membrane of axon terminal.
- ACh (acetylcholine) released through a process known as exocytosis.
ACh is synthesised in the axon terminal through the use of ATP. - ACh binds with motor end plate receptors: depolarization occurs as Na+ rushes into the muscle cell, causing an end plate potential (EPP).
ACh is destroyed by acetylcholinesterase. - Impulse travels through T-tubules which excite the sarcoplasmic reticulum (SR).
- Ca2+ ions released from the SR.
- Ca2+ binds with troponin.
- Shift of tropomyosin, which makes the binding sites available for myosin S1 units to bind.
- ATPase splits (hyrolysis) ATP = ADP + Pi + Energy
- Myosin can now bind to active sites on actin.
- Sliding action of actin over myosin called the Power Stroke.
- Impulse stops to muscle; calcium ions pumped back into SR by Ca2+ (active transport) pumps.
- Tropomyosin returns over the active sites on actin and muscle action ceases.
why is the normal neuromuscular junction said to have a high safety factor? what is fatigue of the neuromuscular junction?
- Each impulse that arrives at the neuromuscular junction causes about three times as much end plate potential as that required to stimulate the muscle fibre.
- Therefore, the normal neuromuscular junction is said to have a high safety factor.
- However, continuous stimulation of the nerve fibre at great rates diminishes the number of acetylcholine vesicles so much that impulses fail to pass into the muscle fibre. This is called fatigue of the neuromuscular junction.
what is resting membrane potential in skeletal fibres?
about -80 to -90 millivolts
what is a motor end plate?
- A motor nerve fibre forms a complex of branching nerve terminals that invaginate into the surface of the muscle fibre but lie outside the muscle fibre plasma membrane.
- The entire structure is called the motor end plate.
- It is covered by Schwann cells that insulate it.
- motor end-plate is the specialised part of muscle fibre where motor neurone innervates
describe excitation-contraction coupling
• When an action potential passes over muscle membrane, the action potential spreads to the interior of the muscle fibre along the membranes of the transverse (T) tubules.
• This action potential results in two effects:
1. The T tubule action potentials act on the membranes of the longitudinal sarcoplasmic tubules to cause release of calcium ions into the muscle sarcoplasm from the sarcoplasmic reticulum, resulting in contraction.
2. Calcium-induced calcium release:
• The T tubule action potentials also open voltage-gated calcium channels in the membranes of the T Tubules themselves, which causes calcium ions to diffuse directly into the sarcoplasm.
• The diffusion of calcium ions activates calcium release channels, also called ryanodine receptor channels, in the sarcoplasmic reticulum membrane of the longitudinal sarcoplasmic tubules.
• This triggers the release of calcium ions from the sarcoplasmic reticulum into the sarcoplasm.
• Calcium ions in the sarcoplasm then interact with troponin to initiate cross-bridge formation and contraction.
• This is called calcium-induced calcium release.
what would happen without extra calcium from the T tubules? what does strength of contraction of muscle depend on?
- Without this extra calcium from the T tubules, the strength of muscle contraction would be reduced considerably.
- The strength of contraction of muscle depends to a great extent on the concentration of calcium ions in the extracellular fluids.
what happens at the action potential (after excitation-contraction coupling)?
At the action potential, the influx of calcium ions to the interior of the muscle fibre is suddenly cut off, and the calcium ions in the sarcoplasm are rapidly pumped back out of the muscle fibres (via the Na+/Ca2+ exchanger) into both the sarcoplasmic reticulum (SERCA Ca2+ pumps) and the T tubule–extracellular fluid space through the plasma membrane (PMCA Ca2+ pumps), stopping contraction or it is stored in the sarcoplasmic reticulum.
how do the cross-bridges affect force of contraction? what is the reason for this?
- Each one of the cross-bridges is believed to operate independently of all others, each attaching and pulling in a continuous repeated cycle.
- Therefore, the greater the number of cross-bridges in contact with the actin filament at any given time, the greater the force of contraction.
describe what causes muscular contraction (power stroke)?
- the hydrolysation of ATP into ADP and inorganic phosphate allows the myosin head to return to the resting position
- ADP + Pi are bound to myosin as myosin head attaches to actin
- ADP + Pi release causes head to change position and actin filament to move
- binding of ATP causes myosin head to detach from the actin filament
- Attached state -> ATP binds to myosin head, causing the dissociation of the actin-myosin complex ->
- Released state -> ATP is hydrolysed, causing myosin heads to return to their resting conformation ->
- Cocked state -> a cross-bridge forms and the myosin head binds to a new position on actin ->
- Cross-bridge state -> phosphate is released – myosin heads change conformation, resulting in the power stroke – the filaments slide past each other ->
- Power-stroke state -> ADP is released ->
- Attached state
what happens to the sarcomere during contraction?
H & I bands shorten
A bands stay the same size
what is summation in muscular contraction?
Summation occurs in two ways:
By increasing the number of motor units contracting simultaneously, which is called multiple fibre summation.
By increasing the frequency of contraction, which is called frequency summation and can lead to tetanisation (sustained muscle contraction?).
what is the size principle?
- As the synaptic activity driving a motor neuron pool progressively increases, low threshold S motor units are recruited first, then FR motor units, and finally, at the highest levels of activity, the FF motor units.
- As a result, this systematic relationship has come to be known as the size principle.
why is there an asynchronous motor unit drive?
The different motor units are driven asynchronously (not occuring at the same time) by the spinal cord, so contraction alternates among motor units one after the other, thus providing smooth contraction even at low frequencies of nerve signals.
what are the different types of muscle contraction?
• Isometric muscle contraction – when the muscle does not shorten during contraction. The length of the muscle remains unchanged.
E.g. pushing against a wall.
• Isotonic muscle contraction – when the length of the muscle shortens but the tension on the muscle remains constant throughout the contraction.
• Concentric muscle contraction – in the direction of contraction of a muscle (towards origin of muscle).
• Eccentric muscle contraction – in the opposite direction of contraction of a muscle (towards insertion of muscle).
isotonic contractions are either concentric (working muscle shortens) or eccentric (working muscle lengthens)
Muscles contract better at their optimum length – most of our muscles are maintained within this optimum range most of the time
Contraction is stronger and faster the closer the muscle initial length is to the optimum length
muscle contraction results in energy expenditure during what?
Interaction of actin and myosin filaments during contraction.
Pumping of Ca2+ from the sarcoplasm back into the sarcoplasmic reticulum after contraction.
Restoration of the intracellular ionic environment after muscle contraction because of the actions of the Na+/K+ pump.
how is ATP generated for long activity?
Oxidative phosphorylation
This type of phosphorylation is an aerobic process in which ATP is liberated from fats, carbohydrates, and protein.
how is ATP generated for heavy activity?
Anaerobic glycolysis
This causes the breakdown of glucose to lactate and pyruvate with the release of energy.
This energy is used to convert ADP to ATP.
ATP is generated at double the rate of oxidative phosphorylation.
This is predominant in type II muscle fibres that have few mitochondria but many glycogen granules.
This is only an intermediate-term source of energy, because lactate and pyruvate accumulate in the cell.
how is ATP generated of intense activity?
• Creatine phosphokinase
Phosphocreatine contains high-energy phosphate bonds, which can be used to phosphorylate ADP to ATP by the enzyme creatine kinase.
It is located in the Z line.
• Myokinase
The enzyme myokinase catalyses the transfer of a phosphate group from one ADP molecule to another to form ATP and the by-product adenosine monophosphate (AMP).
This is known as the ‘last gasp’ of short-term energy stores.
oxidative phosphorylation
- occurs in which types of fibres
- what is it
- how much ATP
- how fast
- Occurs in slow twitch and intermediate type of fibres.
- Reduction of O2 into H20 using electrons from NADH and FADH2.
- Occurs on the inner mitochondrial membrane.
- Explained by the principle of the chemiosmotic theory.
- Involves a series of “downhill” electron transfers – exergonic.
- Energy used to drive protons through the inner membrane.
- Transmembrane chemical + electrical difference drives ATP synthesis.
- 38 ATP molecules produced per molecules of glucose
- But quite a slow process – plentiful but slow
substrate-level phosphorylation
- occurs in which types of fibres
- what is it
- how much ATP
- how fast
- Occurs in fast twitch type of fibres.
- Direct formation of ATP by phosphorylation of ADP.
- Produced by reaction with high free energy.
- These reactions do not require oxygen, therefore, it is important in tissues short of oxygen (e.g. skeletal muscles).
- Produces 2 ATP molecules
- Limited supply of ATP but fast
what happens in normal and intense muscular contraction? - what converted to what, requiring ATP via what, how much ATP, how fast is process?
- In normal muscular contraction, glucose is converted into pyruvate and then CO2.
- This requires ATP via oxidative phosphorylation.
- There is plentiful ATP but the process is slow.
- In intense muscular contraction, glycogen in converted into glucose and then lactate.
- This requires ATP via substrate level phosphorylation.
- There is limited ATP but the process is fast.
- Oxygen and nutrient supply is rate limiting.
• Muscle glycogen reserves are finite and lactate is a problem.
Oxygen is used by liver to produce glucose from lactate – Cori Cycle.
• But muscle still needs a rapid method to produce ATP from ADP.
ATP and creatine are produced from ADP and Phosphocreatine via the enzyme creatine kinase.
what is fibre hypertrophy?
muscle hypertrophy results from an increase in the number of actin and myosin filaments in each muscle fibre
increase in size of fibres?
• Along with the increasing size of myofibrils, the enzyme systems that provide energy also increase. This is especially true of the enzymes for glycolysis, allowing rapid supply of energy during short-term forceful muscle contraction.
what is fibre aplasia?
The rate of synthesis of muscle contractile proteins is far greater when hypertrophy is developing. In turn, some of the myofibrils themselves have been observed to split within hypertrophying muscle to form new myofibrils.
hyperplasia = increase in number of fibres
when does muscle atrophy occur? what is the pathway?
When a muscle remains unused for many weeks, the rate of degradation of the contractile proteins is more rapid than the rate of replacement.
Therefore, muscle atrophy occurs.
The pathway that appears to account for much of the protein degradation in a muscle undergoing atrophy is the ATP-dependent ubiquitin-proteasome pathway.
Proteasomes degrade damaged or unneeded proteins by proteolysis.
Ubiquitin is a regulatory protein that labels which cells will be targeted for proteasomal degradation.
describe the adjustment of muscle length
When muscles are stretched to greater than normal length, new sarcomeres are eventually added at the ends of the muscle fibres, where they attach to the tendons.
This increases the length of muscles.
muscle denervation
- what does loss of innervation to a muscle result in
- what happens after about 2 months
- what happens if the muscle is once again innervated
- what happens in the final stage of denervation atrophy
- what are the fibres that remain like
- Loss of innervation to a muscle results in atrophy.
- After about 2 months, proteasome degradation begins to occur, causing further muscle wastage.
- If the muscle is once again innervated, then there can be full recovery within 3 months.
• In the final stage of denervation atrophy, most of muscle fibres are destroyed and replaced by fibrous and fatty tissue.
This fibrous tissue has a tendency to continue shortening for many months, which is called contracture.
• The fibres that do remain are composed of a long cell membrane with many muscle cell nuclei but with few or no contractile properties and little or no capability of regenerating myofibrils if a nerve does regrow.
when do macromotor units form? what do they effect?
- When some but not all nerve fibres to a muscle are destroyed, the remaining nerve fibres branch off to form new axons that then innervate many of the paralyzed muscle fibres.
- This causes large motor units called Macromotor units.
- This decreases the fineness of control one has over the muscles but does allow the muscles to regain varying degrees of strength.
what can exercise increase (cellular level)?
Exercise can increase muscle mitochondrial biogenesis (i.e. gives more mitochondria per muscle cell).
This is probably via Ca2+ signalling pathways in the cell as well as via a chronic imbalance of ATP demand versus ATP production by mitochondria which causes activation of signalling protein kinases.
- Acute exercise initiates higher levels of mRNA, as observed during the recovery period following exercise
- The protein products of the mRNA are imported into pre-existing mitochondria, or be incorporated into multi-subunit complexes of the respiratory electron transfer chain
- The result is the expansion of the mitochondrial network within muscle cells and the capacity for aerobic ATP provision
- The chain of events becomes impaired with chronic inactivity and aging, which leads to a reduced muscle aerobic capacity and an increased tendency for apoptosis (driven by cytochrome-c leakage from the mitochondria)
- The resumption or retention of an active lifestyle can ameliorate this, improve endurance, and help maintain muscle mass in older age
AMPK - what does it do?
AMPK – adenosine monophosphate-activated protein kinase:
This enzyme plays a role in cellular energy homeostasis.
This is the ‘fuel gauge of the cell’.
During a bout of exercise, AMPK activity increases while the muscle cell experiences metabolic stress brought about by an extreme cellular demand for ATP.
Upon activation, AMPK increases cellular energy levels by inhibiting anabolic energy consuming pathways (fatty acid synthesis, protein synthesis, etc.) and stimulating energy producing, catabolic pathways (fatty acid oxidation, glucose transport, etc.).
AMPK + AMP -> AMPK-P = important in slow twitch muscle
AMP -> IMP +NH3 = important in fast twitch muscle
what can lack of exercise lead to?
Skeletal muscle atrophy causes a drop in:
Protein levels, fibre diameter, force production, and fatigue resistance.
A reduction in protein synthesis coupled with increased protein degradation pathways contribute to muscle loss due to disuse.
Proteolytic pathways (ubiquitin-proteasome, lysosomal, and calpain) are involved in muscle atrophy.
Transcription factor NF-κB and myostatin are important cell signallers for muscle cell atrophy. Lack of exercise leads to increase in these factors in muscle.
what does the gait cycle consist of?
one cycle of swing and stance by one limb
describe the stance phase. which muscles are involved with each part of phase?
- Heel strike (initial contact) – Gluteus maximus and Tibialis anterior
- Loading response (foot flat) – Quadriceps femoris
- Midstance – Soleus and gastrocnemius (together known as Triceps surae)
- Terminal stance (heel off) – Soleus and gastrocnemius (Triceps surae)
describe the swing phase. which muscles are involved?
The swing phase begins after push off when the toes leave the ground and ends when the heel strikes the ground.
- Preswing (toe off) – Rectus femoris
- Initial and Midswing – Iliopsoas and rectus femoris
- Terminal swing – Hamstrings, Tibialis anterior and Ankle dorsiflexers
how much of the gait cycle does each phase occupy?
- Terminal swing – Hamstrings, Tibialis anterior and Ankle dorsiflexers
• The swing phase occupies approximately 40% of the walking cycle and the stance phase, 60%.
• The stance phase is longer because it features a period of double support as the weight is being transferred from one leg to the other.
In running, there is no period of double support.
most of the change in gait cycle time is due to shortening of what?
Most of the change in cycle time is due to shortening the stance phase; the swing phase remains relatively constant over a wide range of locomotor speeds.
what is controls the timing and coordination of complex patterns of movement and adjusts them in response to altered circumstances?
local circuits in the spinal cord called central pattern generators
what are different abnormal gaits?
- apraxic gait
- waddling gait
- crossing over/scissoring gait
- parkinsonian
- hemiplegic
- cerebellar ataxia
- sensory ataxia
describe apraxic gait
- Problem with cortical integration – frontal lobe damage (e.g. hydrocephalus, infarction).
- Acquired walking skills become disorganized.
- Shuffling small steps (marche a petit pas) may be seen here.
- Patient usually has small-stepping, broad-based gait.
- Patient almost seems to have forgotten how to walk.
