Musculoskeletal Physiology

Skeletal muscles:

• Sarcomere: the basic unit of contraction and consists of thick filaments interdigitated with thin filaments attached to the Z disks.
• T-tubules: invagination of the sarcolemma that transmit action potential to the terminal cisternae of the sarcoplasmic reticulum to induce calcium release
• Sarcoplasmic reticulum: a location of calcium store and is released during stimulation to begin muscle contraction
• Calcium regulation of contractile process:
- Concentration of Ca2+ is low in relaxed state by the action of Ca2+ pump (which have a high affinity for calcium)
- At rest the tropomysin molecules lies across the binding site of the G-actin molecule and prevent interaction of myosin
- During contraction stimulation, intracellular Ca2+ levels increases transiently, and four Ca2+ bind to the troponin C causing a conformation change of the tropnin-tropomysin complex. This then shift the tropomyosin molecule to remove steric interference to crossbridge interaction.
- Ca2+ pumps on the move calcium back into the sarcoplasmic reticulum
• Cross bridge cycling:
- ATP binds to the detached myosin head and is hydrolyzed into ADP and Pi by ATPase
- The new myosin complex have a high affinity for actin and attaches to the filament at a 90o angle
- Release of the inorganic phosphate initiates the power stroke and myosin head rotate on its hinge to 45o pushing the associated actin filament past
- The cycle ends with the release of ADP and the myosin resumes a rigor state
- Binding again of ATP re-start the cycle as the myosin loses affinity for actin and detaches
• Excitation-Contraction Coupling:
- Action potential is propagated sarcolemma and conducted into the T-tubules
- Depolarization is detected by the voltage sensitive DHPR (L-type calcium channel) and the receptor undergoes conformational change that interact with the cytoplasmic domain of the ryanodine receptors (calcium channels), thereby triggering it
- A calcium spark is initiated with the opening of groups of RyR1 receptor and release of stored Ca2+
- Ryanodine receptors is further stimulated by cystolic Ca2+ through a positive feedback called calcium induced calcium release and this coupled with intracellular protein action such as phospholipase C (activate inositol receptors) produces the calcium transient
• Role of mitochondria:
- Accumulate Ca2+
- Produces reactive oxygen species
- Ca2+ buffer to suppress CICR
- Suppress mitochondria function lead to Ca2+ signal increase
• Time course of contraction: a single twitch last 50-200ms following that of the stimulant AP which last only 2-3ms. Removal of Ca2+ causes the offset of force development
- Tetanus: continued stimulation and multiple sequential action potential will produced a summation of “twitches” through a maintained and increased Ca2+ concentration, hence an elongated action of maximum force.
• Types of contraction:
- Isometric: contraction with no external shortening as the load on the muscle exceeds the tension generated by the contracting muscle
- Isotonic: contraction with movement due to an in balance of load and force generated. Concentric contraction occurs when muscle shortens and eccentric contraction occurs when muscle elongates.
• Eccentric contraction: in this type of contraction, the force generated is smaller than the load and hence the muscle lengthens. The myosin power stroke is only adequate to slow the opposing movement (possibly filament slips during unattached myosin heads)
- Most muscle damage occurs with this contraction producing delayed onset muscle soreness
- Best for muscle strengthening as there is a release of cytokine with the damage
• Force Length relationship:
- At extreme short lengths, the actin are compressed together and buckling diminishes force development
- Increasing length, exposes more actin to overlap with myosin hence increasing force production
- Optimum length occurs at around 2.2 micrometer for the length of sarcomere
- Further increase in length will cause loss of overlap of actin and myosin, less crossbridge formation and decreasing force production
- After optimum length, passive force begins to act to demonstrate the elastic properties of the connective tissue and cytoskeleton.
• Contraction injury hypothesis: believed to be initiated by weaker sarcomere. It can be measured indirectly by calcium influx into muscles, level of CK in blood and decreased isometric force produced.
- Popping sarcomere: the theory of DOMS which explains that during eccentric contraction, not all sarcomeres lengthen evenly. The weakest sarcomere will always lengthen first and becomes massively stretches leading to injury. The soreness felt is the process of reinforcement of sarcomere in series and consequently each sarcomere can operate at a shorter length overall.
• Force velocity relationship: for equilibrium contraction
- With increased load, the velocity decreases
- At point of maximum force, the velocity is zero and isometric contraction occurs
- Once the load exceeds the force, the acceleration of negative velocity increases rapidly
• Muscle fiber types: muscles types are categorized by their metabolic properties, colour, ability to split ATP etc, based on function and structure. The difference is due to their protein, i.e. different isoforms of actin and myosin
- Type 1 slow oxidative fibers: slow rate of ATP turnover and plentiful mitochondria and myoglobin but undergoes slow oxidative metabolism to generate force
- Type 2 A fast oxidative glycolytic fibers: high rate of ATP turnover and energy phosphate stores. Undergoes rapid anaerobic glycolytic metabolism
- Type 2 B fast glycolytc fibers
• Force regulation:
- Motor unit: a group of the same type muscles fibers innervated by a single motor neuron
- Recruitment of motor unit: progressive increase in excitatory input produces a graded contractile response through recruitment of motor units of different nature. To ensure efficiency, small oxidative motor units are always recruited first and if work load is too high, large glycolytic motor units are recruited last.
• Neuromuscular transmission:
- Synapse: pre-synaptic axon branches are closely related to the membrane or end plate of the post-synaptic neuron by a 20-50nm synaptic cleft. Pre-synaptic terminal contains hundreds of synaptic vesicles with the neurotransmitter chemical acetylcholine while post-synaptic end plate is packed with Ach receptors.
- Transmitter inactivation and recycling: The synaptic cleft is a basement membrane composed of collagen and the enzyme acetylcholinesterase is anchored to the collagen fibrils. The enzyme is made in the muscle and deposited in the ECM and its action is to rapidly hydrolyze acetylcholine into choline and stop inhibition. AchE is a primary target for insecticides.
- Role of calcium channels: using red conotoxin which binds to Ca2+ channels and alpha-bungarotoxin which binds to postsynaptic receptors, it can be observed that the Ca2+ channel is distributed entirely across the presynaptic junction and postsynaptic receptors is scattered over the postsynaptic membrane. During transmission, action potential reaches the nerve terminal and depolarization of the voltage-gated calcium channel result in a calcium influx and lead to exocytosis of the acetylcholine-containing vesicles.
- Postsynaptic events: released acetylcholine bind to the acetylcholine receptors and the ion channel is opened allowing flow of non-specific ionic particles (Na+ inflow, K+ outflow). This event causes depolarization of the motor endplate which in turn triggers the Na+ channels to open and hence produces a new propagating AP.
• End plate potential: the voltage state of the end plate of the postsynaptic nerve.
- experiments: using alpha-toxin to reduce the number of acetylcholine receptors so threshold is not reached or decrease calcium supply to prevent vesicle fusing can help examine the activity of EPP.
- features: EPP in muscle are always supra-threshold. Unlike EPC, the rise of EPP is progressive as the charge separation and electrochemical gradient diminishes but the drop is similar.
• End plate current: measurement of the current through the voltage channel.
- features: EPC rises sharply at the start with the synchronous opening of the acetylcholine receptors. As the channel closes with the removal of the binding ligand, the ECR slowly decreases and this duration is determined by the stochastic closure of the individual channels. Thus the overall acting period of EPC is the mean opening time of the acetylcholine receptors.
• Presynaptic cycling:
- budding of vesicle from endosome
- docking of the vesicle to the membrane
- priming of the vesicle to the membrane (attachment)
- fusion of the vesicles into the membrane
- endocytosis of the choline into vesicles of the cell and integrates into the endosome
• Abnormal neurotransmission: key symptom of muscle disorders is weakness and caused by defects in the nervous control of the muscle.
- pre-synaptic: Lamber-Eaton syndrome, diabete, some naturally occurring Toxins
- post-synaptic: myasthenia gravis, alpha-toxins such as Curare
• Lambert-Eaton syndrome: disorder in which the antibodies is produced against the Ca2+ channel and thus requires repeated stimulation to release acetylcholine. There is a loss of active zone.
• Toxin:
• Myasthenia gravis: an autoimmune disorder in which antibodies is produces against the acetycholine receptors. Acetylcholine release is still normal but insufficient receptors for EPP to reach threshold and produce action potential. This is commonly characterized by weakness and fatigue (especially face muscles). Postsynaptic junctional folds is also greatly reduced.
• Muscular dystrophies: progressive and degenerative disorder caused by mutations of genes encoding the dystrophin-glycoprotion complex and inheritance can be autosomal or X-linked.
- Duchenne muscular dystrophy: rapid degeneration of muscle caused by X chromosome mutation causing dystrophin in the patient to be lost. Dystrophin is used inside muscle cells for structural support and is though to strength muscle cells by anchoring elements of the internal cytoskeletons to the surface membrane. Large pseudohypertrophy of muscles is produced and patients died generally between 15-25 due to respiratory and cardiac failure.
• Muscle fatigue: failure to maintain the require or expected power output leading to lowered muscle performance.
- causes: not clearly established by potential sites include pathways between brain and contractile protein interaction.
- Sites of muscle fatigue: excitatory input to higher motor center, excitatory drive to lower motor neurons motor neuron excitability,. neuromuscular transmission, contractile mechanism, metabolic energy supply.
- central fatigue: decreases activation of CNS and number of motor units recruited
- peripheral fatigue: an afferent on the cellular mechanisms that control force such as smaller calcium transient, slower crossbridge cycling. Main proposed cause is the accumulation of metabolite (lactic acid etc) and depletion of energy resources.
• Exhausive exercise: increased ADP and Pi depletes free energy in the cell and eventually may lead to dysfunction of ATPase so decreased active transport and detachment of X-bridge.
• ROS: can damage intracellular proteins and denature one or more key proteins associated with Ca2+ release. ROS production is increased in intensive muscle activity due to oxidation of the mitochondria.
• Aging: loss of skeletal muscle strength and mass can be explained with motor unit remodeling. The decreased physical activity are due to instrinsic irreversible age-related changes in the muscle fibers with the denervation of fast fatigue fibers and increase proportion of type I slow oxidative fibers. Furthermore there is a decrease in the capillary to fibre ratio.

Smooth muscle

• Smooth muscle: non-striated muscles in which its contractile network are arranged in multiple direction, i.e. intermediate filaments are not parallel to cell axis.
- gastrointestinal
- vascular
- ocular
- urinary
- respiratory
- reproductive
• Structure:
- no T tubule and troponin complex but has sparse sarcoplasmic reticulum.
- Its actin and tropomyosin component is greater in smooth muscles but has significantly less myosin
- dense bodies acting like Z disk providing mechanical coupling- between cells
- cells joined by gap junction allowing electrical and chemical communication
• Function: smooth muscle plays major role in hollow organs such as the blood, lymph organs, digestive tract etc. as the component of the muscular wall. Its ability to contract in multiple directions over a great angle is important in the regulation of luminal space and tubule movement such as peristalsis.
• Activation of smooth muscle:
- smooth muscle is controlled by an array of neural and hormonal inputs. Neurotransmitter may be located in varicosities in the autonomic or instrinsic nerve and diffuse to muscles while hormone are carried in capillaries
- multiple units are activated by nerves innervation and each unit independently controlled while single units are activated through electrical conduction.
- some types relies on excitatory action potential, some requires slow wave of depolarization and some are myogenic
- contraction initiated by calcium transient through SR and ECM influx
• Contact between cells:
- mechanical: simple apposition (close to each other), intermediate contacts and anchoring desmosomes
- electrical: gap junctions which are cytoplasmic continuity between the cells. This allows the smooth muscle cells to contract in synchrony while being sparsely innervated.
• Pattern of activity;
- slow wave potential: slow progressive increase in membrane potential to threshold
- pacemaker: spontaneous depolarization
- pharmacological coupling: adding or removing drugs can affect membrane potential by changing calcium concentration
• Contractile process:
- contraction of smooth muscle is regulated by cystolic calcium concentration (at rest is 120 nmole) which is linked to myosin regulated instead of actin regulation as in striated muscles. Calcium source are extracellular or SR stores.
- large electrochemical gradient exist between cystolic and SR
• Electrical contraction coupling
- depolarization of the muscles is brought about by the activation of voltage dependent calcium channel (VDCC) and influx of Ca2+ instead of Na+. L-type Ca2+ channels such as the dihydropyridine receptors also allow influx of Ca2+ ions and initiate calcium induced calcium release through the RyR1receptors of the SR.
- non-selective cation channels also plays important roles. These include G-protein coupled receptors, ligands gated, stretch activated, tonically activated.
- Calcium sparks also occurs as localized spontaneous transients in Ca2+ release events at the periphery of the cell (not uniform throughout cytoplasm). Results is activated channels such as Ca2+-activated K+ channel causing spontaneous transient outward current (STOC) – hyperpolarization. Ca2+-activated Cl- channel however causing spontaneous transient inward current (STIC) – depolarization
• Regulation of contraction:
- smooth muscle contains a unique myosin light chain sub-unit called p-light chain which can exist in phosphorylated or non-phosphorylated states.
- Phosphorylation is determined by activity of the Ca2+ calmodulin dependent protein known as myosin light chain kinase (MLCK). 4 calcium ion binds to calmodulin and the complex then binds to MLCK and thereby forming an activated calmodulin-myosin kinase complex.
- the enzyme complex phosphorylates a serine residue on the myosin light chain using one ATP molecule and so activate one myosin head. Crossbridge cycle proceeds once a second ATP binds to the myosin head.
- phosphotases cleaves the phosphate group from the myosin light chain and inactivate the myosin
• Caldesmon: a CaCM binding protein that regulate thin filament interaction by acting analogously as troponin in smooth muscles. increased cytoplasmic calcium level, increase active CaCM and so greater number of caldeson bound to the CaCM.
• Crossbridge cycling: activity of crossbridge can be graded depending on the ratio of MCLK and phosphotase C. Multiple crosslink can occur.
• Slow crossbridge cycling: when the myosin light chain is dephosphorylated., myosin ATPase activity decreases and the myosin is attached to the actin in a state of rigor and can maintain tone and hold force with minimal expenditure of energy. This confers a great physiological advantage to smooth muscles.
• SM efficiency: efficiency is low in smooth muscle. ATP required for both light chain phosphorylation (control) and crossbridge cycling during shortening. The mechanical work produced per ATP hydrolyze is only 20% for smooth muscles as compared to the 40% of skeletal muscles
• SM economy: economy is high in smooth muscle as smooth muscle has a very slow detachment rate and all crossbridges develop force. ATP use is low while force is maintained in the absence of external work, i.e. during the rigor states.
• Force modulation of smooth muscle:
- number of cells innervated
- effect of neurotransmitters, hormone or peptides on the MLCK and phosphotase C via membrane potential, enzyme phosphorylation and second messenger production
• Force length relationship: the range of the relationship between force and length is much greater than that of the skeletal muscles as smooth muscle is able to operate for a greater range of lengths.

Control of movement:

• Disorder of movement: movement disorder are most common symptom in patient with neurological disease, such as stroke, Parkinson, spinal cord injuries, myasthenia gravis etc
• Three classes of movement:
- voluntary: controlled by the motor nerves in the brain stem
- reflexes: somatic responses such as vestibular, withdrawal reflex
- rhythmic motor patterns: unconscious repeated motor functions such as breathing, locomotion and chewing. Reflex may override voluntary action, i.e. chemoreceptor reflex means can’t stop breathing.
• Motoneuron: upper motor neurons located in the motor nuclei of spinal cords (anterior horn) and motor nuclei in the brainstem (III, IV, V, VI, VII, IX, X, XI, XII). Both alpha and gamma motoneurons always activate together.
- alpha motoneuron: innervate the extrasfual muscle fibres that is directly responsible for generation of force by muscles. It can either by a fast firing type II B motor unit or slow firing type I motor unit.
- gamma motoneuron: nerve that innervate intrafusal muscle fibers at the periphery of the muscle spindles and control the excitability of stretch receptors in the muscle spindles. Does not directly affect contraction
• Motor unit: anatomical and functional elements of the motor systems consisting of a single alpha motoneuron innervating all its muscle fibers through the neuromuscular junctions. Each motoneuron can innervate from 5 – 2000 muscle fibers.
• Types of motor units:
- fast fatigue: large muscle fibers with short twitch time producing large forces of contraction but “tires out” easily, e.g. gastrocnemius
- slow: small muscle fibers with long twitch durations producing weak forces of contract but does not tire out easily, e.g. soleus
- cross innervation of muscle fibers types also causes exchange of the type of the contraction and biochemistry
• Size principle: S type motor units are always recruited first and some is firing AP almost constantly. They are used in relatively weak contractions and best for carrying small loads. However in heavy exercise, the FF type units are then also recruited. Exercise is needed to prevent atrophy of FF units. Slow muscles have much greater precision than strong contraction.
• Intrafusal motor units: muscle spindles located in the muscle but contains no actin or myosin. Contraction of the muscle causes the periphery to contract and hence middle section to lengthen and the spiral neural ending detect amount of stretch. Activation of gamma motoneuron along with the motor nerve allows brain to know what’s happening.
• Co-activation of alpha and gamma motoneurons: stimulation of alpha motoneuron causes contraction of extrafusal fibers while stimulation of gamma motoneuron proceed the contraction the intrafusal fibers. This is required to keep muscle spindle contracts at the right length and maintain its sensitivity.
• Alpha motoneuron pathway: derived from descending motor tracts (pyramidal tract), spinal interneuron and propriospinal neurons (co-ordinates upper and lower limb)
• Receptors of movement:
- muscle spindles: monitor the length of fibers and their speed of change
- golgi tendon organs: monitor muscle tension
- nociceptive receptors: detects pain in the skin
- joint receptor: monitor joint
• Role of receptor in control of movement:
- understanding about the current position of the part of the body and the length of the muscles controlling it
- as muscle acts, obtain continuous information about the state of the muscle, position and velocity of changing and delivered to the brain, e.g. stretch reflexes and feedback to the brain
- to initiate reflex action or inhibit muscle action
• Spinal reflexes: involves a series of events mediated by 5 elements
- stimulation of the receptor
- action potential through the afferent sensory fibers
- central synaptic relay to efferent motor fibers
- initiation of AP in the efferent fibers
- action of the effector muscle
• Stretch reflex: myotactic or monosynaptic reflex – knee jerk. A response to maintain upright posture.
- striking the quadriceps tendon causes a stretch or vibration in the muscles which is detected by the muscle spindles
- Ia afferent (sensory neurons responding to change in length and its rate) conducts action potential directly to alpha motoneurons (only one synapse) in the corresponding lumbar vertebrate
- potential is relayed through glutamatergic excitatory synapse using glutamate as neurotransmitter
- axons of the alpha motoneurons act as the efferent fibers
- the quadriceps muscle contract synergistically (can be homonymous) to produce reflex
• Reciprocal inhibition: a reflex between flexor and extensor of a muscle
- as part of a reflex to contract a muscle such as biceps brachii, the Ia afferent may also synapse with an Ia inhibitory interneuron which contacts the alpha motoneuron of the antagonist muscle, in this case triceps, and inhibit its action by releasing glycine (neuron-inhibitor)
• Common reflexes: bicep reflex (C5, C6) and knee jerk (L3, L4)
• Reverse myotactic reflex: this is important reflex which protect the muscle during extreme conditions of overworking and maintain muscle tension in optimal range
- mediated by the golgi tendon organs which is in series with the muscle. Contraction of muscle against a load puts tension in the tendon (stretches it)
- action potential is sent along the Ib afferent
- in the spinal cord, the Ib afferent synapses with the Ib inhibitory interneuron which suppress stimulation of the efferent fibers
- the inhibited alpha motoneuron will no longer affect the muscle
• Flexion withdrawal reflex:
- pain detected by nociceptors
- signal is propagated along the type III and IV fibers to the spinal cord
- the sensory nerve synapses with excitatory interneurons for flexor muscles at several different spinal segments and inhibitory interneuron for extensor muscles
- consequential stimulation and inhibition of the alpha motoneuron to the corresponding muscle effectively produce a rapid withdrawal reflex of the limb away from the pain stimulus
• Cross extension reflex along with flexion withdrawal: an important reflex to help maintain balance and posture after elevating one limb from the pain stimulus
- sensory neuron forms further association with interneurons of the muscles of the other leg (contralateral nerves) and excitatory interneuron to the extensor muscle and inhibitory interneuron to the flexor muscle allows extension of the leg to maintain balance.

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