Muscle Contraction Mechanism Lecture 1 PDF

NEUR3101 Muscle and Motor control Lecture 1 Muscle contraction (assumed knowledge + more) A/Prof Ingvars Birznieks  Sliding filament and cross-bridge theory Kenney et al., Physiology of sport and exercise (6th Ed) Chapter 1, Structure and functi...

NEUR3101 Muscle and Motor control Lecture 1 Muscle contraction (assumed knowledge + more) A/Prof Ingvars Birznieks  Sliding filament and cross-bridge theory Kenney et al., Physiology of sport and exercise (6th Ed) Chapter 1, Structure and function of exercising muscle Pages 28-37 Martini et al., Visual anatomy and physiology (2nd Ed) Module 9, Skeletal muscle tissue The structure of a muscle  The structure of a muscle fibre Myofibril Nuclei Sarcolemma Sarcoplasm Skeletal muscle fibre A section of a muscle fibre, revealing its myofibrils, each of which is composed of myofilaments Sarcolemma Myofibril Thin filament Thick filament Mitochondria Sarcomeres, the repeating functional units of myofilaments Arrangement of filaments in zone of overlap A band I band Myofibril M line Sarcomere Z line H band The transverse tubules and the sarcoplasmic reticulum Myofibril T tubule encircling sarcomere Sarcoplasmic Transverse tubules (T tubules) at zone of overlap reticulum (SR) Sarcolemma Transverse tubule Terminal cisternae Position of M line Triad The structure of a neuromuscular junction, and the events that occur in the generation and propagation of an action potential Motor end plate Synaptic terminal Sarcoplasmic reticulum Myofibril Motor neuron Path of electrical impulse (action potential) Note: not a muscle, but only Axon one muscle fibre Neuromuscular junction Myofibril Motor end plate  The structure of a neuromuscular junction, and the events that occur in the generation and propagation of an action potential Vesicles containing Arriving action Sarcolemma of ACh Synaptic cleft ACh (red) potential motor end plate receptor site Motor end plate Na+ AChE Na+ Junctional fold Junctional Na+ fold The locations of ACh and The action potential, Release of ACh into ACh binds to receptors AChE in a resting Leads to ACh release the synaptic cleft on the motor end plate neuro-muscular junction T tubule Action Sarcoplasm Sarcoplasmic potential reticulum (SR) Ca2+ Ca2+ AChE Excitation-contraction coupling, the dumping of calcium ions onto sarcomeres as a result of the Propagation of the movement of an action potential action potential across Generation of an action potential, down the T tubule the entire membrane surface and the removal of Ach by AChE  The structure of a sarcomere A sarcomere is the basic unit of striated muscle tissue. It is the repeating unit between two Z lines. Not to be confused with Tintin A longitudinal section of a sarcomere Titin (connectin) Myofibril Z line Thin filament Thick filament  The structure of thin filaments α-actinin Z line G-actin (globular actin) F-actin (filamentous actin) is a twisted strand composed of The attachment of thin filaments to two rows of 300–400 individual the Z line at either end of a sarcomere molecules of G-actin Active site F-actin Troponin Nebulin G-actin Tropomyosin (holds the F-actin strand together) A thin filament, which is primarily composed of actin associated with other interacting proteins  The structure of thick filaments Core of titin M line Thick filament Myosin molecule Free head Tail Hinge-like connection between head and tail that allows pivoting A thick filament contains about 300 myosin molecules, each made up of a pair of myosin subunits twisted around one another. The myosin heads are arranged in a spiral, each facing one of the surrounding thin filaments. Each thick filament has a core of titin. From either end of the thick filament, a strand of titin continues across the I band to the Z line on that side.  Muscle fibre contraction Step 2: Active sites exposed Step 1: Contraction cycle begins Calcium ions bind to troponin, weakening The contraction cycle is a series of the bond between actin and the troponin– interrelated steps that begins with the tropomyosin complex. arrival of calcium ions within the zone of The troponin molecule then changes shape overlap in a sarcomere. and position, rolling the tropomyosin molecule away and exposing the active binding sites on actin allowing interaction with the energized myosin heads.  Muscle fibre contraction Step 3: Cross-bridge formation Step 4: Myosine head pivoting Once the active sites are exposed, the After the cross-bridges form, the energy energized myosin heads bind to them, that was stored in the resting state is forming cross-bridges. released as the myosin heads pivot toward the M line. This action is called the power stroke; when it occurs, the bound ADP and phosphate group are released.  Muscle fibre contraction Step 5: Cross-bridge detachment Step 6: Myosine reactivation When another ATP binds to the myosin Myosin reactivates when the free myosin head, the link between the myosin head head splits ATP into ADP and P. and the active site on the actin molecule is broken. The energy released is used to extend the myosin head. The active site on actin is now exposed and able to form another cross-bridge.  Muscle fibre contraction The entire cycle repeats several times each second, as long as Ca2+ concentrations remain elevated and ATP reserves are sufficient. Calcium ion levels will remain elevated only as long as action potentials continue to pass along the T tubules and stimulate the terminal cisternae. Once that stimulus is removed, the calcium channels in the SR close and calcium ion pumps pull Ca2+ from the cytosol and store it within the terminal cisternae. Troponin molecules then shift position, swinging the tropomyosin strands over the active sites and preventing further cross-bridge formation. How sarcomere length affects muscle tension Sarcomeres produce tension most efficiently within an optimal range of lengths. When A decrease in the resting resting sarcomere length is sarcomere length reduces within this range, the maximum tension because stimulated number of cross-bridges can sarcomeres cannot shorten form, producing the greatest very much before the thin tension. filaments extend across the An increase in sarcomere length center of the sarcomere and reduces the tension produced by collide with or overlap the thin reducing the size of the zone of overlap filaments of the opposite side. and the number of potential cross-bridge interactions. Tension (percent of maximum) Tension production When the zone of overlap is reduced to falls to zero when zero, thin and thick filaments cannot the thick filaments interact at all. The muscle fiber cannot are jammed against Normal produce any active tension, and a the Z lines and the range contraction cannot occur. Such sarcomere cannot extreme stretching of a muscle fiber is shorten further. normally prevented by titin filaments (which tie the thick filaments to the Z lines) and by the surrounding Decreased length Increased sarcomere length connective tissues. Tension production is greatest when a muscle is stimulated at its optimal length The tension a muscle fibre produces is related to sarcomere length. When sarcomeres are either stretched or compressed compared to optimal resting length, tension production declines. The arrangement of skeletal muscles, connective tissues, joints and bones normally prevents too much compression or stretching. During walking, for example, leg muscle fibres are stretched very close to “ideal length” before contractions occur.  Rigor mortis ATP drives both muscle contraction (hydrolysis) and release cross-bridges between myosin and actin. At death, ATP production stops and muscle stiffing sets in, reaching a maximum within 12 h, because there are no ATP molecules available to break the myosin-actin bridges. Rigor mortis disappears after 24 - 48 h because of muscle tissue degradation.  Summary: muscle fibre structures Thin filaments G-actin globular actin F-actin filamentous actin – a polymer consisting of g-actin molecules Nebulin is a very large protein which length is proportional to thin filament length, thus suggested to be acting as a "ruler" and regulating thin filament length Troponin is a regulatory protein, binding Ca2+ and changing shape of tropomyosin Tropomyosin is a two-stranded alpha-helical coiled protein which covers actin binding sites until troponin binds Ca2+ ion Thick filaments Myosin consists of two myosin subunits twisted around one another A bundle of 300 myosin molecules makes up thick filament Titin makes up core of the myosin and spans through the sarcomere attaching to a Z-disk α-actinin what z-lines are mostly made of  Summary: skeletal muscle contraction Neural Control A skeletal muscle fiber contracts when stimulated by a motor neuron at a neuromuscular junction. The stimulus arrives in the form of an action potential at the synaptic terminal. Excitation–contraction coupling At the synaptic terminal, the action potential causes the release of Ach into the synaptic cleft. The Ach diffuses to the motor end plate, binds to receptors, and opens sodium ion channels, which leads to the production of an action potential in the sarcolemma. Excitation The action potential in the sarcolemma travels along the T tubules to the triads, where it triggers the release of calcium ions Calcium from the terminal cisternae of the release sarcoplasmic reticulum. triggers Thick-thin The contraction cycle then begins, and filament interaction it will continue as long as ATP is available and action potentials are still produced at the motor end plate. As the thick and thin filaments interact, the Muscle fiber sarcomeres shorten, pulling the ends of the contraction muscle fiber closer together. leads to During the contraction, the entire skeletal Muscle muscle shortens and produces a pull, or contraction tension, on the tendons at either end.  Watch videos: Events at the neuromuscular junction https://www.youtube.com/watch?v=CLS84OoHJnQ Cross Bridge Cycle https://www.youtube.com/watch?v=7O_ZHyPeIIA Thank you for your attention NEUR3101 Motor control Lecture 2 Motor units, motoneuron recruitment and control The size principle A/Prof Ingvars Birznieks  Lower motor neuron circuits Chapter 16 Purves et. al, Neuroscience (6th Ed)  Neural centres responsible for movement control Lower motor neurons are neurons which send their axons directly to skeletal muscles. Upper motor neurons control the local circuit neurons and α-motor neurons. Local circuit neurons located in the spinal cord or in the motor nuclei of the brainstem cranial nerves they regulate activity of the lower motor neurons. Cerebellum and basal ganglia regulate activity of the upper motor neurons without direct access to either the local circuit neurons or lower motor neurons.  Lower motor neurons (LMNs) Lower motor neurons are neurons which send their axons directly to skeletal muscles usually meant α-motor neurons however γ-motor neurons controlling muscle spindle sensitivity are also lower motor neurons axons from motor neurons located in the spinal cord travel to muscles via the ventral roots and peripheral nerves lower motor neurons in the brainstem are located in the motor nuclei and axons travel via cranial nerves Note that the upper motor neurons also could be located in the brainstem! all commands for movement (reflexive or voluntary) are ultimately conveyed to muscles only by lower motor neurons Charles Sherrington introduced term “final common path”, because no other cells have direct access to muscles – the path has to involve the lower motor neurons!  Upper motor neurons (UMNs) cell bodies located in the cerebral cortex or brainstem upper motor neurons in the cortex are essential for initiation of voluntary movements essential for complex spatiotemporal sequences of skilled movements axons synapse with the local circuit neurons and in rare cases (mostly for distal muscles) directly with lower motor neurons upper motor neurons in the brainstem are involved in regulation of muscle tone, control of posture and balance in response to vestibular, auditory, visual and somatic sensory inputs  Local circuit neurons are interneurons, which are responsible for activation of α-motor neurons located close to where corresponding α-motor neurons are (in spinal cord or in motor nuclei of brainstem cranial nerves) receive descending projections from higher centres mediate sensory-motor reflexes maintain interconnections for rhythmical and stereotyped behaviour Even without inputs from the brain the local circuit neurons can control involuntary highly coordinated limb movements like walking (has been demonstrated in animals, some success has been seen using electrical stimulation in humans).  Cerebellum and basal ganglia Cerebellum and basal ganglia are called complex circuits and they do not contain any type of motor neurons do not have direct access to either local circuit neurons or lower motor neurons regulate activity of upper motor neurons cerebellum largest subsystem detecting and attenuating the difference between expected and actual movement - “motor error” mediates real-time ongoing error correction (feedback control) responsible for long term reduction of errors (motor learning) basal ganglia supress unwanted movements prepare upper motor neuron circuits for initiation of movement malfunction can lead to Parkinson’s and Huntington’s disease Hierarchical organisation of movement control Figure 16.1  Motor neuron – muscle relationship Each lower motor neuron innervates muscle fibres within a single muscle. Individual motor axons branch within muscles to synapse on many muscle fibres. Each muscle fibre is innervated only by one single α-motor neuron. An action potential generated in the axon bring to the threshold and activate all muscle fibres it innervates.  Motor unit A motor unit is made up of a motor neuron and the skeletal muscle fibres innervated by that axon (Sherrington). Fibres are typically distributed over a relatively wide area within the muscle to ensure that the contractile force is spread evenly, to ensure that local damage to motor neurons or their axons will not have significant effect on muscle contraction. Activation of one motor unit corresponds to the smallest amount of force the muscle can produce. Figure 16.5  Motor neuron – muscle relationship All motor neurons innervating a single muscle are called motor neuron pool for that muscle and are grouped together in one cluster. The motor neuron pools that innervate distal parts of the extremities (fingers and toes) lie farthest from the midline (lateral motor neuron pool). Figure 16.3  Types of motor units Motor units vary in size – both in regard to cell body size of motor neuron and number of fibres it innervates. Small α-motor neurons innervate relatively few muscle fibres to form motor units that generate small forces. Large α-motor neurons innervate larger number of more powerful muscle fibres. Motor units differ in the types of muscle fibres that they innervate. Small α-motor neurons have lowest activation thresholds and thus are first to be recruited.  Types of motor units There are three major motor unit types: Slow (S) motor units – small cell bodies, small number of muscle fibres low activation threshold high endurance - muscle fibres rich in myoglobin, mitochondria, dense capillary network important for activities that require sustained muscular contraction (e.g., posture) connect to Slow Oxidative (SO) type I muscle fibres containing myosin heavy chain MyHC-I isoform Fast fatigue-resistant (FR) motor units – intermediate size generate twice the force of a slow motor unit fatigue resistant connect to Fast Oxidative/Glycolytic (FOG) type IIa muscle fibres with MyHC-IIa Fast fatigable (FF) motor units – largest motor units generate highest level of force in brief contractions such during jumping easily fatigable, sparse mitochondria high activation threshold, nevertheless capable of high firing rates connect to type IIb Fast Glycolytic (FG) muscle fibres with MyHC-IIb and/or MyHC-IIx Note that humans have only type MyHC-IIx isoform  Mapping fibre types to MyHC types Muscle fibre type classification could be done by means of two different methodological approaches ATPase histochemistry and SDS-PAGE electrophoresis. ATPase histochemistry determines fibre type. It is the classical method based on muscle tissue staining and muscle fibre examination under microscope. It has distinguished three fibre types type I, type IIa and type IIb. Electrophoretic SDS-PAGE method determines MyHC protein type. It is based on protein separation by mass. It uses sodium dodecyl sulfate (SDS) molecules to bind to proteins (different MyHC types in this case) to move them in electric field and polyacrylamide gel. There are 4 main MyHC isoforms identified using similar nomenclature: type I, IIa, IIb, but introducing additional type IIx to be placed between IIa and IIb types. The mapping between MyHC isoforms and ATPase histochemistry could be confusing and means that type IIb muscle fibre types may correspond to two different MyHC isoforms IIx or IIb. Force and fatigability of motor units Figure 16.6  Types of motor units Soleus muscle involved in postural control, has predominantly small motor units and average innervation ratio is 180 muscle fibres per motor neuron. Gastrocnemius muscle innervation ratio is 1000-2000 muscle fibres per motor neuron and can generate forces needed for sudden changes in body position. In extraocular muscles average innervation ratio is 3 fibres per unit.  Use dependant motor unit plasticity Pattern of neural activity in a motor nerve provides instructive signal which can influence the expression of muscle fibre phenotype. Following 56 days of chronic electrical nerve stimulation, nearly all fibres acquired the histochemical phenotype of slow oxidative fibres. Implications for FES (functional electrical stimulation) in paralysed patients. Changes in fibre type after chronic electrical stimulation in cats  Star – S (slow) type I muscle fibres  Square – FR (fast fatigue-resistant) type IIa muscle fibres  Circle – FF (fast fatigable) type IIb muscle fibres Box 16A  Neuromuscular matching Experimentally switching a nerve innervating a fast muscle to innervate a slow muscle instead has lead to a slow muscle transition to contractile and histochemical properties of a fast muscle (i.e. a change in muscle phenotype). Alpha motoneurone type: Muscle name: Dominant fibre type: Figure 13.9 p431 Bear, Neuroscience: Exploring the Brain, 2007.  Regulation of muscle force Muscle force could be increased by increasing discharge rate (number of spikes per unit of time) number of active motor units  Effects of firing rate on muscle tension Under normal conditions the maximum firing rate of motor neurons is less than that required for fused tetanus. The asynchronous firing at different lower motor neurons provides a steady level of input to the muscle, which averages out the changes in tension due to contractions and relaxations of individual motor units and achieves apparently smooth overall muscle contraction. Figure 16.8 Henneman’s size principle of motor unit recruitment In 1960s Elwood Henneman from Harvard Medical School observed that gradual increase in muscle tension results from the recruitment of motor units in a fixed order according to their size. During a weak contraction only low threshold small size S motor units are activated. As synaptic activity driving a motor neuron pool increases, the FR units are recruited. To reach the maximum force finally the largest size FF units are recruited last. This systematic relationship between motor neuron size and recruitment order has come to be known as the size principle. S FR FF Regulation of muscle force Figure 16.7 Biophysical principle underlying motor unit recruitment size principle Ohm’s Law: I = V / R; Current = Voltage / Resistance V = I x R; Voltage = Current x Resistance Threshold voltage is the same regardless same I of neuron’s size. Low R Similar synaptic input is capable inducing small V-change the same current I determined by the Higher R small EPSP amount of released transmitter: greater V-change larger EPSP Ismall=Ilarge For larger neurons R is lower as they have large surface area and volume: Rsmall>Rlarge Vsmall = I x Rsmall Vlarge = I x Rlarge  Vsmall > Vlarge Thus with the same synaptic input small motoneuron will reach threshold for action potential generation while it will Recruited first remain subthreshold for a larger neuron. Kandel et al., Fig. 34-5  Strength of muscle contraction is regulated by means of discharge rate and number of active motor units Motor neurons Action potentials transmitted by axon  Violations of the size principle Electrical stimulation electrical stimulation can alter recruitment order, tending to recruit larger motor units first Cat “paw-shake” response? high threshold units preferentially recruited for maximal velocity repetitive, cyclic movement During fast contractions? it has been suggested that larger motor units may be preferentially recruited during fast forceful contractions in humans... During eccentric contractions? It has been suggested that during eccentric contraction larger motor units are preferentially activated  Motor unit changes with aging On average the motor units of old adults have a higher innervation ratio Because muscle fibres that are abandoned when their parent nerve dies are reinnervated by sprouting collateral branches from remaining motoneurons Muscles undergo atrophy as other abandoned muscle fibres die Old adults have fewer motor units than young adults Apoptosis of motoneurones in the spinal cord from age 60 onwards Muscles of old adults also exhibit a shift towards more slow-twitch properties The consequence of these changes is weaker muscles for old adults Thank you for your attention  Muscle fibre types Part 1 – Classification and methods Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice  The system at a glance Voluntary movement: brain (UMN) > spine (LMN) > nerve > muscle Purves, Neuroscience Boron, Medical Physiology  Basic terminology fibres within fibres within fibres... Stanfield, Principles of Human Physiology  Basic terminology Muscle fibre = 1 cell fibril = chain of sarcomeres filament = proteins (myosin, actin) fibres within fibres within fibres... Stanfield, Principles of Human Physiology  human body: >600 muscles – all of the same type?...probably not! Netter, Atlas of Human Anatomy  Short message: “slow vs. fast fibers” Martini, Fundamentals of Anatomy & Physiology  Histochemistry: mATPase and other single cell (=fiber) enzymes humans: “IIB-like” ATP staining, but no IIB myosin (IIX) Berchtold et al., Physiol Rev 2000  History: two classification schemes Histochemical - staining ATPase activity at different pH values - Slow type = low ATPase activity, unstable at high pH Myosin head (alkaline), stable at low pH = ATPase (acidic) ATP  ADP+Pi - Fast type = high ATPase activity, stable at high pH (alkaline), unstable at low pH (acidic) - Shows fast (type II) and slow (type I) fibre types Berchtold et al., Physiol Rev 2000  History: two classification schemes Histochemical Immunohistochemical - Specific monoclonal - staining ATPase activity at antibodies against different different pH values myosin isoforms - Slow type = low ATPase Myosin head - Showed a new fibre type: 2X activity, unstable at high pH = ATPase - Arabic numbering: 2A, 2B, 2X (alkaline), stable at low pH - Shows more subtypes (acidic) ATP  ADP+Pi - Histochemical type IIB has - Fast type = high ATPase myosin heavy chain (MHC) activity, stable at high pH 2X in humans, MHC 2B in (alkaline), unstable at low pH other mammals (acidic) - Shows fast (type II) and slow Anti-2A antibodies Anti-2B antibodies (type I) fibre types Gorza, J Histochem 1990 Berchtold et al., Physiol Rev 2000  Single fiber protein gel electrophoresis Myosin heavy chains (MHC) – single fibers Boron, Medical Physiology Larsson, J. Physiol, 1993  Single fiber protein gel electrophoresis Myosin heavy chains (MHC) – single fibers Boron, Medical Physiology Larsson, J. Physiol, 1993  Single fiber protein gel electrophoresis Myosin heavy chains (MHC) – single fibers Fibre staining (mATPase) reflected in protein electrophoresis (SDS- PAGE) patterns Boron, Medical Physiology Larsson, J. Physiol, 1993  Single fiber protein gel electrophoresis Myosin heavy chains (MHC) Short message: variability across many proteins (MHC, MLC, others) Myosin light chains (MLC) Sodium Dodecyl Sulfate-PolyAcrylamide Gel Electrophoresis Larsson, J. Physiol, 1993  Myosin genes, heavy chain proteins, occurrences In humans: MYH4 gene but no MyHC-2B protein Schiaffino, Physiol Rev, 2011  Note: many other muscle proteins can be stained Parvalbumin: Ca2+ buffering variability within an EDL muscle note: intermediate fibers Fast (white), PV +++ Slow (red), PV + Berchtold et al., Physiol Rev 2000  Technique: muscle biopsy Small tissue volume ( 2A > Slow] for all loads Force/load Schiaffino, Physiol Rev, 2011  Speed of shortening between species Myosin consider: filaments - hummingbird wings only - running/scratching rodents - hunting predators Single muscle fibres Schiaffino, Physiol Rev, 2011  Mitochondria and capillaries Different contraction types (fast vs slow) require different amounts of mitochondria (oxidative phosphorylation) and capillaries (blood/O2 supply) Slow type (I): more mitochondria, more capillaries  aerobic metabolism Fast type (II A/B/X): fewer mitochondria and capillaries  anaerobic metabolism Stanfield, Principles of Human Physiology Metabolism slow fast aerobic metabolism needs more O2  myoglobin ↑  slow fibres red Schiaffino, Physiol Rev, 2011  Muscle fatigue ATP decline (single fibres) Glycogen depletion (30 km run) Fast fibre (type II) Slow fibre (type I) glycogen preserved glycogen preserved Schiaffino, Physiol Rev, 2011 Kenney, Physiology of Sport and Exercise  Functional properties of human single fibers type I slow type 2A fast type 2X fast Schiaffino, Physiol Rev, 2011  Functional properties of human single fibers type I slow type 2A fast aerobic type 2X fast A, B  (anti-)correlated metabolic profiles anaerobic Schiaffino, Physiol Rev, 2011 anaerobic  Functional properties of human single fibers slow fast C  two clusters with different shortening velocities (slow/fast) Schiaffino, Physiol Rev, 2011  Functional properties of human single fibers twitch contraction time low  fast high  slow max. isometric tension (g) D EDL: fast, variable force rat SOL: slow >> fast, medium force Schiaffino, Physiol Rev, 2011  Summary fiber types (1) Stanfield, Principles of Human Physiology  Summary fiber types (2) Silverthorn, Human Physiology  Summary fiber types (3) Martini, Fundamentals of Anatomy & Physiology  Muscle fibre types Part 3 – Fibre type variations and transitions Dr. Frederic von Wegner WARNING  This material has been reproduced and communicated to you by or on behalf of the University of New South Wales in accordance with section 113P of the Copyright Act 1968 (Act).  The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act.  Do not remove this notice  Sex differences - fiber type (MyHC) ratio in M/F: identical - differences in muscle mass (testosterone, after puberty) - total mass: larger type-2 / type-1 ratio in men selective type-2 hypertrophy due to testosterone (?) - Total fibre type area (Staron et al., 2000): - Female: I > II A > II X - Male: II A > I > II X - different metabolic profiles women: more lipid metabolism during exercise  Alpha-actinin 3 / ACTN3 – the gene for speed - ACTN3 – alpha-actinin 3 - Z-disk protein in fast fibers - frequent mutation leads to a premature stop codon “X” (1 bio. people)  no alpha-actinin 3 (no obvious disease) - elite athletes (sprinters) extremely high proportion of type RR, i.e. 2 alleles without the X mutation 40 m sprint times (s) Moran, Eur J Human Genetics 2006 ACTN3 not only speed Pickering, Front Physiol, 2017 ACTN3 not only speed Pickering, Front Genetics, 2018  Fiber types in athletes Power lifter Marathon High jumper (vastus lat.) 85% 90% Type II Type I Type II hypertrophy Whyte, The Physiology of Traning  Fiber types in athletes Kenney, Physiology of Sport and Exercise Sarcomere proteins slow fast Short message: The whole sarcomere changes, not only myosin Schiaffino, Physiol Rev, 2011  Message: training-specific activation of signaling pathways, signal: metabolism van Wessel, Eur J Physiol, 2010 Fiber type transitions: - a “better” ATPase is not enough - all components have to change - calcium channels - mitochondria - troponin - SERCA (Ca2+ pump) - Z-disk structure - Titin, nebulin - glyocen+lipid storage - lactate transporters... Schiaffino, Physiol Rev, 2011  Fiber type transitions 1. Physiological factors: development, training, aging, hormones 2. Pathological processes: prolonged rest, hypogravity 3. Experiments: cross-reinnervation, electrical stimulation  Fiber type transitions 1. Physiological factors: development, training, aging, hormones 2. Pathological processes: prolonged rest, hypogravity 3. Experiments: cross-reinnervation, electrical stimulation Nearest-neighbour principle: I II A II X II B humans rodents  Slow-to-fast transitions intermediate intermediate types types I II A II X II B humans rodents High-frequency electrical stimulation (like fast-type motor neurons) Muscle unloading (suspension) Microgravity Hyperthyroidism  Fast-to-slow transitions intermediate intermediate types types I II A II X II B humans rodents Low-frequency electrical stimulation (like slow-type motor neurons) Muscle overload (weights) Endurance training Hypothyroidism