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Lecture 8: Excitation-Contraction Coupling. Summary From Last Lecture. Summary: Contraction Cycle. Ca 2+ is a Trigger For Contraction. F12-9. Troponin and tropomyosin (associated with actin filaments) prevent myosin heads from compleating the power stroke; like a safety latch on a gun.
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Ca2+ is a Trigger For Contraction F12-9 • Troponin and tropomyosin (associated with actin filaments) prevent myosin heads from compleating the power stroke; like a safety latch on a gun. • Tropomyosin partially blocks the binding site for myosin during rest. Contraction is initiated when Ca2+ binds to troponin causing tropomyosin to change its shape and expose the rest of the myosin binding site to complete the power stroke.
For relaxation to occur, calcium concentrations within the cytosol need to drop, and calcium needs to unbind from troponin C. • The unbinding of calcium from troponin C causes troponin (a complex of three molecules including troponin C) and tropomyosin to return to their ‘off’ positions; ie. tropomyosin partially blocking the myosin binding site on G-actin, and troponin C becoming unbounded from calcium. • During the relaxation phase, actin and myosin are not bound together, and the thick and thin filaments of the sarcomere slide back to their original position with the aid of elastic molecules (eg. titin).
Sources of Energy For Contraction ATP • Muscle cells are unusual in the they require modest levels of ATP when at rest, and substantial amounts of ATP during intense contraction. The ATP present in muscle fibres during rest can only power the muscle for a few seconds. 3 ways to generate ATP: • ATP from creatine phosphate. • Anaerobic metabolism of glucose is not efficient and makes cells acidic through the production of lactic acid. • Aerobic metabolism is very efficient but requires an adequate supply of oxygen to the muscles.
Fibre-Type Composition of Muscles Affects Their Speed of Contraction and Resistance to Fatigue • Skeletal muscle fibres can be classified into three groups, based on their speed of contraction, and their resistance to fatigue during intense stimulation: • A) Fast-twitch glycolytic fibres. • B) Fast-twitch oxidative fibres. • C) Slow-twitch (oxidative) fibres. • The speed of contraction with repeated stimulation is determined by the isoforms of myosin present in the thick filaments. Different isoforms have different ATPase activity. Fast fibres split ATP more rapidly and complete more contraction cycles than slow fibres. This speed translates into fast tension development. Fast twitch muscle fibres develop tension approx. 3x faster than slow twitch fibres. • Contraction duration is determined according to the fibre-type. Twitch duration is dependent on the rate at which Ca2+ is removed from the cytosol by the SR. Contractions of slow twitch fibres last 10X longer than in fast twitch fibres. • Resistance to fatigue with repeated stimulation is thought to result from preventing buildup of lactic acid. Fast twitch fibres fatigue more easily than slow twitch fibres.
Tension Developed in a Muscle is a Function of Sarcomere Length • The force created by a contracting muscle is termed tension. • The load is the weight (or force) that opposes the contraction of the muscle. • The resting length of the muscle needs to be optimum to produce maximal tension. • Sarcomere has to form optimum number of crossbridges to generate maximal force. The sarcomere length reflects the extent of overlap between thin and thick filaments.
Exciting-Contraction (E-C) Coupling F12-10 • APs resulting from transmitter release triggers muscle contraction. • The combination of electrical and mechanical events in the muscle fibre is called excitation-contraction coupling.
Muscle APs in the t-tubules activates dihydropyridine (DHP) receptors, which open Ca2+ channels. Ca2+ binds to troponin to initiate the power stroke.
Muscle Fatigue • Muscle fatigue is a condition in which the muscle is no longer able to generate or sustain the expected power output. • Its thought to mainly arise from failure in excitation-contraction coupling within the muscle than from presynaptic factors. • Central fatigue include subjective feelings of tiredness and a desire to cease activity. Its thought that central fatigue precedes physiological fatigue in the muscle. Acidosis of lactic acid dumped into the bloodstream may influence the sensation of fatigue perceived in the brain.
However, other factors which may contribute to fatigue may arise from: • A) Depletion of glycogen stores within the muscle. • B) Accumilation of H+ from the buildup of lactic acid and the increased production of inorganic phosphate from ATP breakdown. Both H+ and inorganic phosphates interfere with crossbridge function. • C) Increased production of extracellular K+ production with maximal exercise depolarizes the membrane potential and decreases release of Ca2+ from the SR. • D) Neuronal causes result from failure of transmission at the neuromuscular junction.
Temporal Sequence of E-C Coupling F12-11 • A single contraction- relaxation cycle in the muscle is known as a twitch. • Latent period is the time needed for Ca2+ to diffuse from the SR to initiation of the power stroke. • During relaxation, the SR removes Ca2+ from the cytosol and sarcomeres return to resting length.
Summation of Twitches Produces a Tetanus • The summation of twitches upon repeated stimulation causes an increase in tension up to a state of maximal contraction known as a tetanus. Fatigue produces a drop in tension eventhough the stimuli continues. • An unfused (or incomplete) tetanus results when the muscle has a chance to slightly relax between stimuli, although maximal tension is achieved. F12-15
The Somatic Motor Neuron and the Muscle Fibres it Innervates is Called a Motor Unit F12-16 • An AP in the motor neuron causes all the muscle fibres it innervates to contract. • The number of fibres in a motor unit varies (e.g. small number of fibres in motor units which exert fine control, like in eye muscles) , but the fibre-type composition of the motor unit remains the same. • Inheritance in part determines the fibre-type composition, however it can also be changed by altering the fibre’s metabolic characteristics.
A Muscle is Composed of Many Motor Units • A motor unit contracts in an all-or-none manner. • In a muscle, the tension and its duration can be varied by: • (a) Changing the number of motor units responding at one time. • (b) Changing the type of motor unit which is active. • Tension could be increased by recruitment of additional motor units. Recruitment is controlled by the nervous system and proceeds in a fixed order. F12-17
Nervous Control of Recruitment • Order of recruitment is highly correlated with the diameter and conduction velocity of the axon, the size of the motor neuron cell body and the size and strength of the muscle fibres in the motor unit. • Small motor neurons fire first and the largest fire last. This is the size principle of motor neuron recruitment.
The size principle serves two purposes: A) allows the most fatigue-resistant fibres to be recruited first and keeps the most fatigable fibres in reserve until higher forces need to be generated. B) the increment of force generated by successively activated motor units will be roughly proportional to the level of force at which each individual unit is recruited. • As the highest threshold for motor neurons are recruited, the muscle contractions are reaching a maximum. Motor units drop out in the order opposite from their recruitment. • Slow-twitch oxidative fibres have the lowest threshold for recruitment. • Fast-oxidative fibres have a medium threshold for recruitment. • Fast-twitch glycolytic fibres have a high threshold for recruitment. • Small cell bodies have a high transmembrane resistance (Rhigh)because they have a smaller surface area and fewer channels. Thus, according to Ohm’s law (V= IRhigh), the synaptic currents produce large excitatory graded potentials (EPSPs) which readily fire APs. However, the velocity of the APs as they travel towards the axon terminals are slow because of the small diameter axons. • In contrast, in large motor neurons, the cell bodies have a larger surface area and more channels; thus, a lower transmembrane resistance (Rlow). The synaptic currents therefore produce subthreshold EPSPs (V= IRlow), making it harder to trigger APs. However, if triggered, they travel down the large diameter axons faster.
Asynchronous Recruitment • The nervous system recruits different motor units at different times to maintain muscle tension. This allows the motor neurons to rest between contractions. • This avoids muscle fatigue in a sustained contraction.
Muscle Disorders • Could result from failure in signaling in the nervous system, failure of synaptic transmission and problems with the muscle itself. • Muscle cramps are caused by hyperexcitability of the somatic motor neuron controlling the muscle. Stretching the muscle relieves muscle cramps by sending sensory information back to the CNS to inhibit the motor neurons. • Muscle overuse resulting in muscle fatigue. Trauma may also cause tearing of the tissue. • Muscle disuse could be just as bad as overuse, resulting in muscle atropy. E.g. muscle immobilized in a cast for long periods. The blood supply to the muscle diminishes and muscle fibres get smaller. Atropy longer than an year is permanent. • Acquired disorders, such as weakness resulting from infectious diseases, such as, influenza, poisoning by toxins such as that producing botulism (botulinum toxin) and tetanus (tetanus toxin). • Inherited disorders are the hardest to treat. E.g. muscular dystrophy as well as biochemical defects in glycogen and lipid storage.
Duchenne muscular dystrophy is due to the absence of a cytoskeletal protein known as dystrophin. These muscle fibres have tiny tears which allow Ca2+ ions to enter them and activate enzymes that break down fibre components. Patients usually die before 30.
Summary • Calcium binding to troponin C is required to initiate the power stroke. • ATP for muscle contraction can be derived from three sources. • There are three types of skeletal muscle fibres in our body sub serving different contractile requirements. • Sarcomeres need to be of optimum length to generate maximum tension during contraction. This results from the formation of maximum number of crossbridges. • E-C coupling refers to the combination of events where a nerve AP evokes a muscle AP leading to contraction. The muscle AP activates voltage-gated DHP receptors in t-tubules, causing calcium channels (mechanically linked to DHP receptors) to open in the SR. Thus providing the calcium to trigger contraction. • Muscle fatigue results when the muscle cannot generate the maximum power output. Its influenced by a number of factors. • The basic unit of muscle contraction is the motor unit. The force of contraction can be increased by recruiting additional motor units. Asynchronous recruitment of motor units ensures that muscles do not fatigue during sustained contraction. • The size principle ensures that the smallest motor neurons are recruited first; these normally innervating slow-twitch oxidative fibres.
