Neural Control of Force - Different Force Requests PDF

PHYSIO 13 – Neural control of force - different force requests 1.​ Regulation of muscular force recruitment by CNS Force is exerted by muscles, which are acting on tendons, which are acting on bones, which are moving the joints. Movements are therefore the result of joint movements. The body m...

PHYSIO 13 – Neural control of force - different force requests 1.​ Regulation of muscular force recruitment by CNS Force is exerted by muscles, which are acting on tendons, which are acting on bones, which are moving the joints. Movements are therefore the result of joint movements. The body must make the muscular force adequate to the task performed. The force exerted by a muscle depends on two factors: ​ mechanical properties of the muscle itself (elasticity of the muscle) ​ the control exerted by the nervous system on muscle motoneurons In order to be able to exert the perfect amount of force, the brain should be aware of the mechanical properties of the muscles. This lecture is about how the nervous system drives the muscle machine controlling the force recruitment, also by taking into account the structural properties of the muscle. 2.​ The motor unit The fundamental unit of the motor system, formed by one spinal motor neuron and the number of muscle fibers innervated by its axon. A single motor axon may branch to innervate several muscle fibers that function together as a group. Although each muscle fiber is innervated by a single motor neuron, an entire muscle may receive input from hundreds of different motor neurons. 3.​ The structure of a motor unit The myofibrils are tubular structures made by sarcomeres connected in series. The arrangement of the sarcoplasmic reticulum cisternae is in parallel with respect to the sarcomeres and in relation with the T tubules. T tubules are invaginations of the sarcoplasm. They are are coincident with the Z disk. The sarcoplasmic reticulum, which is particularly developed and has a precise structure in muscle cells. It has an important relationship with the T tubules: on both sides of the T tubule, there are structures called terminal cisternae, which are enlargements of the sarcoplasmic reticulum. This geometrical organization of the sarcomeres, that are building up the myofibrils, is perfectly arranged with the T tubules and the cisternae. 4.​ The sarcomere The sarcomere is the functional unit of the myofibril. It is delimited on each side by a Z disk, which is the site where the actin filaments attach. Actin filaments extend towards the midline of the sarcomere, but never actually meet it. In fact, in the midline, there is a zone where there is the myosin, which goes in the opposite direction, towards the periphery. The sarcomere is characterized by -​ a most peripheral zone, where there is only actin, -​ a central zone, where there is only myosin, -​ an intermediate zone, where actin and myosin overlap. Myosin, which is characterized by a head, and actin are available in 360 degrees; in fact, the Z disk is a “disk” and not a “line”. Titin and nebulin filaments are kept inside to maintain the perfect geometrical structure and to stabilize the structure.  5.​ The neuromuscular junction When the muscle is switched on, an electrical event, the action potential, is needed in order to have a mechanical reaction. The action potential, which is transmitted to the muscle fibre by the motor neuron. The axons of the motor neuron, located in the lamina IX of the anterior horn, come from the spinal cord, exit through the spinal anterior roots and then enter the spinal nerves to innervate muscles below the neck. Above the neck, the motor nuclei of the cranial nerves are used. There are two important motor nuclei, which are in the brainstem: -​ trigeminal (V) motor nucleus, which innervates the masticatory muscles, -​ VIIth nerve motor nucleus, which innervates the mimic muscles. On each muscle, the endplate has a very huge and extensive synaptic contact, that is paired with the postsynaptic organization of the nicotinic receptors (which is abundant). This allows the transduction of an action potential in the muscle. (1)​ The action potential opens calcium voltage-gated channels, which allow the transport of calcium. (2)​ Exocytosis of vesicles, that contain Ach, a neurotransmitter, takes place. (3)​ Acetylcholine binds to the nicotinic receptors located in the postsynaptic membrane and opens a channel for Na+ and K+. The electrochemical gradient favours the entrance of Na+, which results in depolarization. In the graph below, the endplate potential, which occurs in the synaptic membrane, is represented with a dashed line. Just outside the synaptic membrane, on the sarcolemma, there are the voltage-gated sodium channels. The dimensions of the endplate (it is very big) bring the membrane to the threshold and trigger an action potential.  6.​ Mechanism of contraction and importance of Ca2+ The action potential is generated by the membrane, but the sarcomere is inside, and between these two structures there is the cytoplasm. There should be an intermediate step that links the action potential with the mechanical event happening inside the cell. This link is represented by the calcium, which is stored in the sarcoplasmic reticulum (SR) and is barely detectable in the cytoplasm. A great amount of calcium is essential to induce the release of the sites for the binding between myosin and actin, by involving troponin and tropomyosin. This action potential is able to signal an intracellular response that makes the fibers contract, this happens by means of Ca2+ ions released by the sarcoplasmic reticulum. To reach this structure we need 2 proteins on the T tubules: -​ DHPR or dihydropyridine, a transmembrane T tubule p° on the sarcolemma. It is linked to a sarcoplasmic reticulum channel. -​ RyR or ryanodine, a ca2+ channel located on the sarcoplasmic reticulum. They are a transmembrane T tubule protein (so on the sarcolemma) linked to a sarcoplasmic reticulum channel, respectively. The arrival of the action potential on the T tubule changes the conformation of DHPR (sort of voltage sensitive) and consequently opens the RyR channel for calcium that goes out of the sarcoplasmic reticulum in the sarcoplasm (cytoplasm), reaching all the myofibrils simultaneously, even the deep ones because the T tubule goes very deep inside the cell (super efficient this way, very important for the homogeneous contraction of the muscle fibers). Meantime, the pumps, along all the sarcoplasmic reticulum start working to replace the calcium in the sarcoplasmic reticulum. Of course, the velocity of the pump with respect to the velocity of diffusion of calcium outside is much slower. The concentration of calcium in the cytoplasm increases. As calcium binds to troponin, the structure of tropomyosin changes. Finally, tropomyosin gets out from the binding site of myosin and myosin is able to bind to actin. Muscle contraction usually stops when also the signaling from the motor neuron ends: this leads to the repolarization of the sarcolemma and T tubules and to the closure of the calcium channels in the SR. Ca2+ ions are then pumped back into the SR and the tropomyosin is able to re-cover the binding sites on the actin. In the graphs , When the membrane depolarizes, there is a huge increase of calcium until a limit is reached: this corresponds simultaneously to the muscle force generated by the cell (the increase of force parallels the time course of the free calcium concentration) this means that the force of the muscle depends on calcium concentration. The amount of calcium is the determinant in the amount of force he higher is the calcium concentration, the higher is the force exerted.. “Rigor mortis” is the rigidity of the body after death: it is due to the fact that the body does not have any ATP and, for this reason, myosin molecules adhere to actin filaments, because actin and myosin cannot detach. As a result, the muscles become rigid. After a while, the bridges get detached and rigor mortis ends. The cross-bridge (which is the binding between actin and myosin) and the movement of the head pulling the actin are fundamental for muscle contraction: in fact, the head of the myosin moves 45 degrees towards the midline, changing the angular arrangement, pulling the sarcomere towards the midline. This results in muscle shortening and changing in length. To move an object, referred to as a load, the muscle fibres of a skeletal muscle must shorten, and this contraction generates a force called muscle tension. Muscle tension can also be generated when the muscle is contracting against a load that does not move, resulting in two main types of skeletal muscle contractions: -​ isotonic contractions: tension is the same and length shortens mouvements (dumbbell) -​ isometric contractions: tension increases and length stays the same antigravity muscles When the load applied to the muscle overcomes the maximal force of the muscle, there is the production of force. Force can be produced in isometric conditions without the shortening of the muscle, meaning that the bridges are continuously formed but without changing the length. An isometric contraction occurs when a muscle produces tension without a change in muscle length. Isometric contractions involve sarcomere shortening and increasing muscle tension, but do not move a load, as the force produced cannot overcome the resistance provided by the load. For example, if a person attempts to lift a hand weight that is too heavy, there will be sarcomere activation and shortening to a point, and ever-increasing muscle tension, but no change in the position of the hand weight. In everyday life, isometric contractions are active in maintaining posture and keeping bone and joint stability. In isotonic contraction, however, as there is a constant load, muscles can shorten. The muscle shortening and velocity of shortening depend on the load. Another important aspect is the length of the muscle: as the length of the muscle changes, the mechanical properties of the muscle change, and this results in a change of force. 7.​ Single twitch and tetanic contraction A single muscle twitch includes -​ a latent period, -​ a contraction phase (when tension increases) -​ a relaxation phase (when tension decreases). During the latent period, the action potential is propagated along the sarcolemma. During the contraction phase, Ca2+ ions in the sarcoplasm bind to troponin, tropomyosin moves from actin-binding sites, cross-bridges form and sarcomeres shorten. During the relaxation phase, tension decreases as Ca2+ ions are pumped out of the sarcoplasm and cross-bridge cycling stops. a.​ The single twitch A single twitch is the force exerted by a muscle fiber excited by 1 action potential. When an action potential arrives at the level of the neuromuscular junction, it stimulates the muscle. In the graph above, there is at first a steady rate before the gradual increase. This is due to the electromechanical coupling taking a certain amount of time. The time corresponds to the moment where the excitation and contraction are coupled, but contraction has not occurred yet. Then, as the muscle generates increasing levels of tension, the force rises to a peak: the Ca2+ ions in the sarcoplasm have bound to troponin, tropomyosin has shifted away from actin-binding sites, cross-bridges have formed and sarcomeres are actively shortening. Following this, there is a decline, which continues until the end of the twitch when the muscle is not developing any force (that is measured with a dynamometer). Tension decreases as Ca2+ ions are pumped out of the sarcoplasm back into the sarcoplasmic reticulum and, consequently, the muscle fibres return to their resting state. The whole muscle twitch takes 70 milliseconds. The more the bridges are built up, the higher is the force. Then, at a certain time, the pumps work high to replace calcium in the reticulum and to decrease the probability to make bridges. When the action potential has finished and membrane potential is at resting state, dihydropiritin and Ryr return back to their resting position, and force declines. b.​ tetanic force Single twitch is a stereotyped process, because the mechanisms that occur in the cells (such as the amount of sodium released) are always the same. In the second, third and fourth lines of the graph above (counting from below), the second action potential is given before the first is finished. -​ The third line has a higher peak of force than the second, -​ the second has a higher peak than the first line This is due to the increased frequency of stimulation. In the highest line, which is the one with highest frequency of stimulation, no fluctuations can be seen. Only the maximum value that is exerted can be seen: this is because the second action potential is given when calcium has already declined and there are less actin-myosin bridges. However, the value of force cannot be higher than that, and this is called the tetanic summation, which is the maximum tetanic force exerted by the muscle. When muscle fibers respond to multiple action potentials with increasing frequency, the muscle twitches sum up one over the other (the subsequent stimulus comes in the rising phase of the previous one, summing to it): this phenomenon is called tetanic force, this is a mechanism through which we can increase the muscle force. The action potentials are so frequent that the calcium cannot be sequestered in time by the pumps. The tetanic force corresponds to the maximum force that can be exerted by a muscle. The tetanic summation is possible because the action potential lasts less (5ms) than the mechanical event created by it (70ms) In conclusion, the frequency of the charge of the motor neuron matters for the force. The higher is the frequency of discharge, the higher will be the tetanic force exerted by the muscle, until maximal force, which is the plateau, is reached. 8.​ Tetanic summation Going from A to E, it is evident that when the frequency of discharge increases, there is a progressive summation of the concentration of calcium until the maximal possible release of calcium, and so, the maximal possibility to form the bridges, is reached. The tetanic summation is possible only because the action potential duration is shorter than the one of the single twitch. If the action potential duration corresponded to the duration of the single twitch, there wouldn’t have never been summation. This is due to the fact that if that was the case, there could not have been another action potential. The diagram above represents the duration of action potential in the myocardial cells. Black line is the action potential of myocardial cells and the red line is the twitch of muscle cells responding to this event in the heart. Can there be a tetanic summation in the heart? The answer is no and this is a very brilliant property of the heart. In the heart, there can never be a tetanic summation and this is due to the 200 milliseconds long action potential of the heart. In fact, by looking at the length of the plateau of different parts of the heart (the endocardium, epicardium) it can be proven that none of them can have a tetanic summation or contraction that is not driven by an action potential. 9.​ Motor neurons location and motor nuclei Lower motor neurons can be found in the lamina IX of the anterior horn of the spinal cord. The motor neurons are clustered in motor pools/nuclei that are distributed along the ≠ neuromeres of the spinal cord, forming the innervation of one muscle. Motor pools for the soleus and gastrocnemius, which are muscles of the leg, can be seen in the picture above: the black dots represent motor neurons arranged -​ from L6 to S2 for gastrocnemius -​ L5,L6,L7 for the soleus. Motor nuclei are organized in more than one segment. As in the sensory system, the arrangement of motor neurons has a somatotopic distribution (see the above picture): -​ the motor neurons that control the proximal muscles and the epiaxial muscles are located in the ventromedial portion of the anterior horn (lamina IX). -​ the motor neurons that control the distal muscles (e.g. one of the legs, feet, and hands) are located in the dorsolateral portion of the anterior horn (lamina IX). 10.​Innervation ratio The muscle fibers innervated by a single motor neuron are not clustered inside the muscle but are homogenously distributed. This allows the harmonic contraction of the muscle. The innervation ratio is a very important aspect in muscles. A given motor neuron can either innervate a few fiber (extraocular muscles) or many fibers (gastrocnemius, 2000:1). The innervation ratio is not dependent on the dimension of the muscle but on the precision of movement of the nervous system. A high number of motor units gives a more precise movement whereas fewer motor units gives a more powerful but less precise movement. The precision of movement is therefore dependant on: -​ the number of muscle fibers connected to the neuron -​ the frequency of action potential that each motor neurons can drive towards the muscle 11.​Functional and biochemical properties of muscle fibers The functional properties of muscle fibers are -​ the velocity of contraction: measured on the time taken for the single twitch to peak -​ the maximal force of contraction: measured by the amplitude of the tetanic contractions -​ the fatiguability: measured through high frequency electrical stimulation going on and observing the percentage of force decreasing after a certain time (some last an hour, some a few minutes) In the following picture, 3 types of fibers of the same length (this allows to avoid the mechanical properties) are represented and the 3 diagrams on the top show their single twitch: it can be observed that the 3 fibers have a different single twitch (2g-10g-50g). So, in a muscle there can be different types of fibers: -​ slow resistant (SR), -​ fast resistant (FR), -​ fast fatiguing (FF) motor units. Each muscle has a different relative proportion of these fibers, depending on its function. Biochemical properties of muscles are: -​ ATPases: The fibers express different ATPases, enzymes necessary for the hydrolysis of ATP. The ATPases influence the way the myosin processes the ATP and this is responsible for the velocity of the twitch by influencing the velocity of formation of cross-bridges -​ Myofibrils: The fast fibers (both types) are characterized by 9,4 type of myofibril, which are very fast compared to the 4,3 type found in the slow fibers -​ Glycolysis: Enzymes involved in glycolysis – like phosphorylase and lactic dehydrogenase – are found more in the fast fibers -​ Oxidative phosphorylation: Enzymes found in the mitochondria involved in the oxidative reaction – like: NADH dehydrogenase, hexokinase and cytochrome C – are found in the more resisting fiber (the slow and the fast resistant: the fatigue depends on the metabolism of the fibers, using aerobic or anaerobic respiration). -​ Storage of substrates needed for energy production – like glycogen, lipids, myoglobin – are more abundant in the resisting fibers. The fast fatiguing uses glycogen which is a fast energy source, but the gain in term of energy production is very low. The resistance of a muscle is dependant on the metabolism: a resistance fiber needs a high storage of energy. The energy can be obtained by oxidative phosphorylation (slow fibers) or by glycolysis (fast fibers). The resistance is also dependant on the vascularization: slow and fast resistant fibers are vascularized by a lot of capillary vessels, because they need a lot of nutrients for the oxidative pathway, while fast fibers do not need many nutrients because they use glycolysis. The different types of fibers are mixed in different rations among the muscles, according to their function (postural muscles, muscles used for lifts...) For example, the following graph shows the maximal tetanic force of the medial gastrocnemius and the soleus plotted on the time to peak: it can be seen that all the types of fibers are present, but the relative proportion is different (e.g. in anti-gravitary muscles there are more slow resistant fibers than in other muscles). 12.​Functional and biochemical properties of motor neurons There are 2 types of motor neurons: -​ ⍺, which innervate the skeletal muscle fibers -​ γ, which innervate the intrafusal fibers of the muscle spindle (so they are not considered now). Tetanic summation is based on the principle that the tetanic force is regulated by the frequency of discharge. This frequency depends both on the intensity (how fast the force is recruited) and time (how long the movement will last). The current-to-frequency coding in the sensory system is also applicable in motor neurons: the intensity of the stimulus causes a deflection of modulation of the membrane potential (receptor potential), which leads to a high frequency of discharge (because the intensity is increasing). When increasing the intensity of stimulation, the neuron responds with a higher frequency of discharge with a linear relationship. The maximal frequency of discharge is reached when the action potential is generated right after the absolute refractory period. In the beginning there is the square pulse, the response to the stimulus recalls the slow adapting fibers, apart from the beginning where the neuron seems to respond to the velocity of variation of the intensity. For example, the following graph shows the frequency of discharge in relation with the current intensity (the stimulating current is a square pulse): it can be seen that, at a steady state (red square), there is a linear correlation between frequency and intensity, in fact when the intensity of the stimulus is increased, also the frequency of discharge increases (as in the sensory system). Another feature that has to be observed is the first interval of the spike (green square): in the graph, it can be seen that the first interval of spike changes depending on the different velocity of increasing intensity. This means that the neuron reacts to the velocity of stimulation by adapting (there is not a linear correlation). To understand this concept, another experiment has to be done. To verify the current-to-frequency coding, the neuron is submitted to different ramps of current (with different velocities): -​ higher the change in the current, the higher is the frequency of discharge. -​ When the current is constant, the frequency of firing remains at a steady state. Therefore, the motor neuron is both slow and fast adapting. They are: -​ Static: they are able to react to the stimulating current, with a frequency of discharge related to the intensity. -​ Dynamic: they are able to react to changes in velocity of the stimulating current. 13.​Dynamic sensitivity of motor neurons Muscle force is very dependent on motor neurons firing, as tetanic summation depends on the action potentials. Despite that, muscles have different properties compared to neurons as they: -​ have an inertia -​ are slow changing compared to motor neurons. This is useful to change the amount of force to be recruited fast! The motor neuron needs to fire very high frequency at the very beginning in order to overcome the inertia of the muscle and change the motor command, preparing the muscle to undergo a tetanic summation, once the inertia is overcome, the motor neuron fires with a constant frequency. To understand how much this is important we compare the profile of a muscle unit with respect to a model with no dynamic sensitivity: -​ in the muscle driven by a neuron with a dynamic sensitivity, the muscle response behaves faithfully to the neural request (faster or slower depending on the motor command, with the same final strength) -​ in the muscle driven by a model without dynamic sensitivity, the muscle does not behave faithfully because no matter how fast or slow the motor neuron fires, the muscle reacts with the same speed (which is slow). Functional properties of motoneurons are optimally coupled with the functional properties of the muscle units it innervates: -​ the fast fibers are connected with a motor neuron having a short hyperpolarization phase, close to the one of a single twitch -​ slow fibers connected with a motor neuron with a longer hyperpolarization phase that is coincident with the muscle twitch. These types of neurons are called big and small, connecting respectively with fast and slow fibers. Comparing two motoneurons with their muscle fibers: -​ at threshold, both neuron discharge at the minimal frequency corresponding to the frequency needed to start summation. -​ From the minimal frequency the neuron can only increase the frequency of discharge resulting in the progressive summation of the twitches into tetanic force. So the big and small motor neurons have a different minimal frequency of discharge which corresponds to the onset of the tetanic summation in the fibers. The mechanism of activation of the motor neurons follows the size principle: first the small neurons are activated, then only if we need more force the big neurons are recruited (spatial summation). In the single units, also the frequency of discharge is of course increased to have a greater force (temporal summation) 14.​Clinical point – AS or Lou Gehrig disease Lou Gehrig's disease, also called amyotrophic lateral sclerosis (ALS), causes the nerve cells in certain regions of the brain and spinal cord to gradually die. Eventually, people who have Lou Gehrig's disease (ALS) lose the ability to move their limbs and the muscles needed to move, eat, speak and breathe.