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Motor Control, Peripheral
Motor Control, Peripheral N Goyal, University of California Irvine, Orange, CA, USA DA Chad, Harvard Medical School, Boston, MA, USA; and Massachusetts General Hospital, Boston, MA, USA r 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by David A Chad, volume 3, pp 219–226, r 2003, Elsevier Inc.
In a normal human skeletal muscle, the individual muscle fiber components are organized into functional groups called motor units. The term motor unit was first used by Liddell and Sherrington in 1929 and refers to a single alpha motor neuron and the muscle fibers it innervates by way of its motor axon (Figure 1). Alpha motor neurons are the most common among a population of motor neurons in the anterior gray matter of the spinal cord, and they are the principal neurons innervating the muscle fibers (the muscle fibers that move joints, also called extrafusal muscle fibers). Medium- (beta) and small-sized (gamma) motor neurons also innervate muscle, but the latter supply specialized muscle fibers, socalled intrafusal fibers, that are found in tiny structures called muscle spindles whose function is to regulate muscle tone and reflex activity. One alpha motor neuron innervates multiple muscle fibers, but each muscle fiber is innervated by only one motor neuron. The average number of muscle fibers in a motor unit determines the innervation ratio (muscle fibers per motor neuron) of the muscle. This ratio varies greatly from one muscle to another and is related to the degree of dexterity required of that muscle. For instance, the external ocular muscles requiring very fine motor control have an innervation ratio of 10:1; the ratio for a small hand muscle is approximately 100:1. In muscles in which precise control is not needed, the ratios are higher: the ratio for a muscle in the upper arm (biceps) is 500:1, whereas in a leg muscle (gastrocnemius) the ratio is 2000:1. The muscle fibers belonging to a single motor unit are not grouped together but rather are dispersed over a limited area in the skeletal muscle. This area is known as the motor unit territory and in the biceps, for example, reaches a span of 20 mm2. This overlapping arrangement of the territories of
Peripheral nerve
Motor neuron
Muscle fiber Neuromuscular junction
Figure 1 The motor unit. Note the motor neuron, its axon, and the many muscle fibers that are innervated by it. Reproduced from Layzer R (1975) Remediable neuromuscular disorders. Primary Care 2: 235, with permission from Xerox.
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many motor units within a muscle allows the muscle to contract smoothly and evenly.
Histology and Connections of the Peripheral Nervous System Alpha Motor Neurons As noted previously, motor axons are extensions of alpha motor neurons that reside in the anterior horn gray matter of the spinal cord. These anterior horn cells are clustered in nuclei or motor neuron pools, forming longitudinal columns extending from one to four spinal segments. Alpha motor neurons are influenced directly by motor neuron projections from the motor cortex via descending corticospinal fibers and by spinal interneurons. (In an analogous fashion, brainstem motor neurons are influenced by projections from the motor cortex via descending corticobulbar fibers and by brainstem interneurons.) Accordingly, alpha motor neurons are the lowest in the hierarchy of motor control and are thereby designated lower motor neurons. The alpha motor neuron is among the largest in the nervous system. It has a single axon extending to its innervated muscle fibers and a number of large dendrites that sometimes are more than 1 mm in width and extend well into the white matter of the spinal cord, providing an extensive receptive field. Many synaptic endings or boutons (approximately 10 000) contact the dendritic surface (Figure 2). Excitatory inputs are located at the proximal portion of the dendrites or at the cell body or soma; inhibitory synapses are found along the proximal portion of the axon. Acetylcholine is the excitatory transmitter released by the alpha motor neuron’s axon at the junction between the nerve terminal and the muscle fiber (neuromuscular junction). The anterior horn cell determines the characteristic physiology of muscle contraction in the motor unit and the biochemical characteristics of muscle fibers belonging to that motor unit. Functionally, there are three types of motor units: slow fatigable, fast fatigable, and intermediate; the last category describing a population of muscle fibers whose metabolic character is composite of the first two types (see below). Proximal and axial muscles that sustain posture contain predominantly slow-twitch, nonfatigable motor units. Their slowtwitch, fatigue-resistant muscle fibers are known as Type 1 fibers. Owing to a high concentration of myoglobin, these fibers appear red (in animals); such muscle fibers are rich in oxidative enzymes and poor in glycolytic enzyme activity. Extremity muscles involved in fast phasic or ballistic contractions that generate large forces quickly possess mainly fast fatigable motor units. Their fast fatigable muscle fibers are known as Type 2 fibers. They are low in myoglobin and appear white (in animals); such muscle fibers have abundant
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Myelin Axon Endoneurium Schwann cell Endomysium
Naked axon
(a)
Schwann cell
Sole plate
Nucleus Sarcolemma
Endoneurium Endomysium Basement membrane Sarcolemma Naked axon
Presynaptic vesicles
Synaptic cleft
(b)
Figure 2 Alpha motor neuron. This is a transverse section of the spinal cord showing the extensive dendritic system, some of which extends into the white matter. The thick dotted line indicates an axon arising from the cell body. A gray-and-white matter junction is shown by the thin, dashed line. Reproduced from Brown AG (1981) Organization in the Spinal Cord, p. 199. Berlin: Springer-Verlag, with permission from Springer.
Junctional folds
Figure 4 (a) A skeletal muscle neuromuscular junction. (b) Enlarged view of muscle fiber showing the terminal axon lying in the surface groove of muscle fiber. Reproduced with permission from Snell RS (1992) Clinical Neuroanatomy for Medical Students, 3rd edn., 135 pp. Boston: Little, Brown.
approximately equal number of fibers belonging to Types 1, Type 2A, and Type 2B fibers.)
Motor Axon and Neuromuscular Junction
Figure 3 Normal muscle cross section stained with myosin ATPase (pH 9.4) demonstrating the normal arrangement of light (Type 1) and dark (Type 2) fibers.
glycolytic enzyme activity but little oxidative enzyme activity. With a specific histochemical stain, myosin ATPase (at pH 9.4), these muscle fibers may be visualized using light microscopy (Figure 3): Type 1 fibers stain lightly and Type 2 fibers appear dark. (As noted, Type 2 fibers are specialized for glycolytic metabolism, and there are two different types of Type 2 fibers: Type 2B are rather purely glycolytic, having very little oxidative capacity, whereas Type 2A fibers have a metabolic profile that allows for both glycolytic and oxidative metabolism and therefore they are relatively fatigue resistant compared to Type 2B fibers; they are in fact the intermediate fibers mentioned earlier. In most human muscles, there are an
The motor axons of the motor unit are heavily myelinated. As a myelinated motor fiber enters a muscle, it breaks into a number of solitary branches that lose their myelin sheaths. Each branch ends as a naked axon, expanded slightly at its terminal portion that comes to lie in a groove on the surface of a muscle fiber (Figure 4). The axon terminal-muscle fiber association is known as the neuromuscular junction. The plasma membrane of the axon is separated from the plasma membrane of the muscle fiber by 20–50 nm. Thus, the neuromuscular junction consists of pre- and post-synaptic components. Within the former, the axon terminal, there are abundant vesicles and mitochondria. The vesicles, filled with molecules of acetylcholine (ACh), congregate at the presynaptic membrane around structures called dense bars corresponding in their placement to junctional peaks of the postsynaptic membrane. The postsynaptic membrane is highly folded, with ACh receptors concentrated at the peaks. The sarcoplasm immediately beneath the membrane is filled with numerous mitochondria. Acetylcholine esterase, an enzyme that degrades ACh and thereby terminates its physiological action, is present in the gap between axon and muscle fiber.
Muscle Fibers Muscle fibers in adults are approximately 50 mm in diameter. They are polygonal in shape and are bundled into fascicles (Figure 5). Individual fibers are invested by connective tissue, which forms the boundary of the endomysial compartment,
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Trabeculae (of perimysium)
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Muscle fibers Perimysium Epimysium
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Figure 5 Schematic diagram of the connective tissue sheaths of muscle. Muscle fibers are bundled into fascicles bordered by perimysial connective tissue. Reproduced from DeGirolami U and Smith TW (1982) Pathology of skeletal muscle. American Journal of Pathology 107: 235–276.
Muscle fiber (50 microns)
Myofibril (1 micron) A
Filaments (5−10 N M)
I Z Myosin Actin
Figure 6 Ultrastructure of muscle fiber. Each fiber is made up of many myofibrils containing filaments of actin and myosin organized in bands A, I, and Z. NM, nanometers. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
and are bordered by capillaries. Denser perimysial connective tissue and blood vessels separate fascicles. Groups of fascicles are surrounded by adipose tissue, blood vessels, and loose connective tissue forming the epimysium. Nuclei number in hundreds per muscle cell and are positioned eccentrically. Satellite cells capable of aiding in regeneration are also present at the periphery of the cell beneath the basement membrane. The cytoplasm or sarcoplasm contains the contractile apparatus, lipid and glycogen stores, and organelles such as mitochondria. Each fascicle contains approximately 20–60 muscle fibers and each muscle fiber consists of 50–100 myofibrils (Figure 6). Each myofibril is longitudinally divided into sarcomeres, which are the smallest contractile units (Figure 7). The sarcomere is that portion of the myofibril that extends from Z band to Z band. The sarcomere consists of two filaments – thick (myosin) filaments alternating with thin (actin)
Myosin M Substance Actin Tropomyosin Troponin -Actinin
Thick filament Thin filament Z Band
(c)
Figure 7 Organization of protein filaments in a myofibril. (a) Longitudinal section through one sarcomere (Z disk to Z disk) showing the overlap of actin and myosin. (b) Cross section through the A band, where the thin actin filaments interdigitate with the thick myosin filaments in a hexagonal formation. (c) Location of specific proteins in the sarcomere. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
filaments. The four major contractile proteins that are present in a myofilament are actin, myosin, troponin, and tropomyosin. Within the sarcomere, thick myosin alternates with thin actin filaments. Thin filaments attach at the Z band and form the I (lighter or isotropic) band. The thick filaments are located within the A (darker or anisotropic) band, and thin filaments also extend into this region except at the H zone, where there is no overlap of thick and thin filaments. The transverse or T tubules are located near the junction of the A and I bands and transmit the initial depolarization at the motor end plate (Figure 8). On either side of the T tubule is a terminal cistern of the sarcoplasmic reticulum. The terminal cisterns act as the storage space for calcium ions. This sarcoplasmic reticulum–T tubule–sarcoplasmic reticulum complex is called the triad and is responsible for converting electrical signals (membrane action potentials) to chemical signals (calcium release).
Gamma Motor Neurons and Intrafusal Muscle Fibers Among the motor axons contained in peripheral nerve are those derived from the gamma motor neurons, also known as fusimotor neurons, and they constitute up to one-third of the lower motor neurons of the spinal cord. These fusimotor neurons innervate the intrafusal muscle fibers by way of thinly myelinated axons. Intrafusal muscle fibers are contained within muscle spindles, which are structures that are 1–4 mm in length and surrounded by a fusiform capsule of connective tissue. Approximately 6–14 intrafusal muscle fibers reside inside this capsule. (Muscle fibers discussed previously that are innervated by alpha motor neurons are termed as extrafusal because they are situated outside the muscle spindles.) Muscle spindles are numerous in any given muscle but are especially
Motor Control, Peripheral
Large myelinated fibers Gamma motor fibers Small myelinated fibers
Capsule
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Extrafusal muscle fiber
Sarcolemma Motor end-plate
Annulospiral endings
Mitochondrion Nuclear bag
Myofibril Figure 8 Structure of a single muscle fiber cut both horizontally and longitudinally. Individual myofibrils are surrounded and separated by sarcoplasmic reticulum. T tubules are continuous with extracellular fluid and interdigitate with sarcoplasmic reticulum. Note the regular association of the T tubule with the sarcoplasmic reticulum to form membranous triads. Also note the location of myonuclei at the periphery of the muscle fiber and the presence of many mitochondria. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
Neurotendinous spindles
Afferent neuron
Neuromuscular spindles
Lower motor neuron
Alpha anterior horn cell
Motor end-plate Motor end-plate Muscle fiber
Figure 9 Schematic overview of the peripheral motor control system. To the right of the spinal cord section, note the alpha motor neuron innervating seven muscle fibers, representing a motor unit. Also to the right of the spinal cord section, note the sensory afferents from the muscle spindles (designated neuromuscular spindles) and the Golgi tendon organs (neurotendinous spindles). The afferent fiber (originating in the muscle spindle) makes a monosynaptic connection with the alpha motor neuron, which in turn projects to the muscle ending as the motor end plate. Reproduced with permission from Snell RS (1992) Clinical Neuroanatomy for Medical Students, 3rd edn., 130 pp. Boston: Little, Brown.
abundant toward the tendinous attachment of the muscle (Figure 9). Intrafusal fibers are of two types – nuclear bag and nuclear chain fibers (Figure 10). In the former, numerous muscle nuclei are present in an expanded equatorial region of the fiber where cross-striations are absent. In the latter, the muscle nuclei form a row or chain in the center of each fiber at
Intrafusal muscle fibers
Motor end-plates Flower spray endings
Figure 10 A neuromuscular spindle showing two types of intrafusal fibers: the nuclear bag fiber and the nuclear chain fiber (to the right of the nuclear bag fiber and characterized by a longitudinal row of nuclei in the shape of a chain). The extrafusal fiber (shown on the left of the intrafusal fibers) is innervated by a heavily myelinated fiber (from an anterior horn cell) terminating in a motor end plate. The intrafusal fibers are innervated by the gamma motor fibers. Large afferent myelinated fibers originate in annulospiral endings on the nuclear bag fiber. Reproduced with permission from Snell RS (1992) Clinical Neuroanatomy for Medical Students, 3rd edn., 130 pp. Boston: Little, Brown.
the equatorial region. Nuclear bag fibers are larger in diameter than chain fibers, and they extend beyond the capsule at each end to attach to the endomysium of the extrafusal fibers. Intrafusal fibers are innervated by the gamma motor neurons via small end plates (neuromuscular junctions) situated at both ends of the muscle fibers. Westmoreland et al. noted that an important role of the gamma motor neurons is to ‘‘activate the intrafusal fibers leading to contraction and shortening of these fibers on either end of the central noncontractile region.’’ The result is to stretch the central region of the intrafusal fibers and activate sensory receptors and the afferent nerve terminals (vide infra). The functional role of the spindles is discussed later.
Sensory Neurons and the Simple Reflex Arc The alpha motor neurons are influenced not only by upper motor neurons in the motor cortex and motor control neurons in the brainstem but also by sensory inputs from the periphery. In fact, the peripheral pathway that serves as the foundation for the generation of spontaneous muscle contraction in the resting state (also known as muscle tone) is the simple reflex arc. It is composed of a sensory or afferent limb (the heavily myelinated axon originating in the muscle spindle (known as Ia afferent fiber, the largest among all nerve fibers) whose unipolar cell body resides in the sensory or dorsal root
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ganglia); and a motor or efferent limb (the myelinated axon extending from the lower motor neuron). The afferent limb directly stimulates the efferent lower motor neuron via a single synapse; hence, the reflex arc is designated monosynaptic (Figure 9). The specialized unipolar structure of the sensory neuron cell body allows for its axon to bifurcate after leaving the cell body: one process passes to the muscle spindle in the periphery, whereas the other travels into the spinal cord to make its monosynaptic contact with the lower motor neuron. With regard to the sensory innervation of the muscle spindle, the large-diameter myelinated axon (Ia) pierces the capsule of the spindle, loses its myelin sheath, and becomes a naked axon that winds spirally around the equatorial regions of the nuclear bag or chain portions of the intrafusal fibers (Figure 10). A slightly smaller diameter myelinated axon, arising from a smaller dorsal root ganglion neuron, also pierces the muscle spindle capsule, loses its myelin sheath, and forms a naked axon that branches terminally and ends as varicosities, resembling a spray of flowers. These endings are situated mainly on the nuclear chain fibers and some distance away from the equatorial region.
Golgi Tendon Organs These are neurotendinous spindles that are located in tendons at the junction of the tendon and the muscle (Figure 9). They consist of fibrous capsules that surround bundles of collagen fibers. Like the sensory innervation of the muscle spindle described previously, myelinated sensory fibers pierce the capsule and end in club-shaped endings. These fibers are less thickly myelinated and are designated Ib fibers.
Renshaw cell
−
+
Alpha motor neuron
Figure 11 Note the recurrent collateral branch of the alpha motor neuron making an excitatory synaptic contact with a Renshaw cell. Excitation of the Renshaw cell in turn produces inhibition of the alpha motor neuron. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
activation of the Renshaw cells causes inhibition of anterior horn cells (the chemical inhibitory neurotransmitter is amino acid in nature – glycine or taurine). This ‘recurrent inhibition’ or negative feedback serves to stabilize the discharge frequency of pools of anterior horn cells and prevent them from discharging at excessive rates.
Physiological Events Leading to Muscle Contraction Neuromuscular Transmission
Interneurons The interneurons are distributed in the anterior horn of the spinal cord and the brainstem and play a major role in determining the final common output of the motor neurons. Inputs to the interneurons derive from descending tracts originating in the brainstem, motor cortex, and limbic motor system. Additionally, interneurons receive direct or indirect information from peripheral sensory fibers. These inputs comprise both excitatory and inhibitory influences that in turn modulate the overall excitability of the motor neurons, whose motor axons form the final common pathways for innervation of skeletal muscle. Interneurons form intricate neuronal circuits that form the anatomical substrate for a variety of neurophysiological functions, including automatic and stereotyped spinal reflexes that continue to function even when the spinal cord has been separated from the brain and protective and postural reflexes triggered by unpleasant cutaneous stimuli. The interneuronal circuitry also coordinates timing for the integrated activation of synergist muscles and inhibition of antagonist muscles to allow for highly skilled voluntary movements. Among the interneurons is the Renshaw cell. When anterior horn cells are activated and initiate action potentials along their motor axons, collateral branches terminate on Renshaw cells, which in turn send axonal projections to connect with anterior horn cells (Figure 11). The result is that
Muscle contraction occurs as a result of a series of steps beginning with activation of the lower motor neuron (Figure 12). The process starts with an action potential traveling along its axon toward the muscle to be activated. The arrival of an action potential at the axon terminal triggers an influx of calcium ions and the release of hundreds of quanta of acetylcholine simultaneously, producing an end plate potential (EPP) in the muscle. If the EPP reaches sufficient amplitude (threshold response), it leads to further muscle membrane depolarization that opens another class of channels – the voltage-gated sodium channels in the muscle cell – resulting in the current needed to generate a muscle fiber action potential (Figure 13). In the resting state, small fluctuations in membrane potential occur at the end plate region of a given muscle fiber and are called miniature end plate potentials (MEPPs). The MEPPs are produced by the spontaneous release of quanta of acetylcholine from the motor nerve ending and are not of sufficient amplitude to produce a muscle fiber action potential.
Muscle Fiber Excitation Contraction Coupling The muscle fiber action potential propagates at a rate of 3–5 m/s along the muscle membrane (the sarcolemma) and into the T tubules (located at the junction of the A and I bands) (Figure 8). The latter, flanked by the sarcoplasmic
Motor Control, Peripheral
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Nerve terminal action potential
Acetylcholine release
End-plate potential +
K
Muscle fiber action potential
ACh receptor −
Nerve impulse
Sarcoplasmic reticulum calcium release
+
Na
Na
Inhibition of tropomyosin-troponin
Actin-myosin interaction
+
ACh
Voltage-gated Na+ channel
Muscle contraction Figure 12 Sequence of events leading to muscle contraction. Reproduced from Daube JR, Reagan TJ, Sandok BA, and Westmoreland BE (1986) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
reticulum and forming a triad complex, transmits the action potential inside the muscle fiber; this action potential causes signal transduction through ryanodine receptors releasing calcium ions. The calcium ions then bind to the troponin subunits, causing a conformational change in the tropomyosin and the actin helix configuration. In another calciumdependent process that requires ATP, cross-bridges are formed between thick and thin filaments. Sliding of the thin actin filaments over the thick myosin filaments produces muscle contraction. The shortening of the sarcomeres and the I band during contraction is not due to a change in the absolute length of the filaments but rather to the sliding of the filaments. Contraction ceases when calcium is removed from the sarcoplasmic reticulum by active transport.
Spinal Control Mechanisms for Muscle Contraction In this section, it is examined how the muscle spindles and the motor neuron and interneuron populations of the spinal cord provide the substrate for anatomical connections and physiological interrelationships that allow for the integrated activation of agonist and antagonist muscles. The role of the component parts of the peripheral motor control system is described and the sequence of physiological events that follow the stretch of a flexor muscle (e.g., the activation of the biceps
Figure 13 The binding of acetylcholine (ACh) at transmitter-gated channels opens channels permeable to both Na þ and K þ . The flow of these ions in and out of the cell depolarizes the cell membrane, producing the end plate potential. This depolarization opens neighboring voltage-gated Na þ channels. To elicit an action potential, the depolarization produced by the end plate potential must open sufficient Na þ channels to reach the threshold for initiating the action potential. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
muscle by tapping on the biceps tendon to elicit a reflex biceps contraction) is examined. First, following the tendon tap, excitatory signals are transmitted from the annulospiral endings of the nuclear bag intrafusal fibers – that are stretched by the tendon tap – along the Ia afferents to activate the motor neurons, which in turn activate the extrafusal muscle fibers and lead to the biceps monosynaptic muscle contraction (Figure 14), so that the biceps may contract without resistance, the motor neurons innervating the antagonist triceps muscle are inhibited (designated reciprocal inhibition). This inhibition is brought about by these same Ia afferents that simultaneously stimulate inhibitory interneurons that inhibit the alpha motor neurons for the antagonist extensor, the triceps. The biceps alpha motor neurons that have been excited also send collateral impulses to the inhibitory interneurons (the Renshaw cells), thereby regulating their own excitation. The mechanical contraction (flexion) of the biceps exerts tension on the IIb
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Inhibitory interneuron
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C-7 + −
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Flexor muscle
sensory fibers of the Golgi tendon organ that project to the spinal cord. These Golgi tendon organ afferents have an inhibitory effect on alpha motor neurons (via inhibitory interneurons), thereby preventing too much tension from being generated by the biceps, and they stimulate excitatory interneurons that activate alpha motor neurons innervating the antagonist triceps muscle. This antagonist contraction inhibits further flexor contraction and restores the flexor muscle (biceps) to its original position. Finally, biceps contraction loosens the intrafusal fibers, which stimulates a feedback system that activates the gamma motor neurons to contract the intrafusal fibers. In effect, the gamma motor neurons cause the intrafusal fibers to shorten (or adjust) and this stretches the equatorial region of the fibers, thereby stimulating the annulospiral and flower spray endings and once again restoring the stretch sensitivity of the muscle spindle.
See also: Motor System; Overview. Motor Unit Potential. Muscle Contraction; Overview. Neurons, Overview
Further Reading Figure 14 Pathways for the monosynaptic reflex and for reciprocal inhibition. An Ia afferent fiber is shown making monosynaptic contact with a flexor (biceps) motor neuron and an inhibitory interneuron. The latter sends a projection to an extensor (triceps) motor neuron, providing the pathway for reciprocal inhibition. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
Dubowitz V and Sewry CA (2007) Muscle Biopsy: A Practical Approach, 3rd edn. Philadelphia: Saunders Elsevier. Fitzgerald MJT, Gruener G, and Mtui E (2007) Clinical Neuroanatomy and Neuroscience, 5th edn. Philadelphia: Saunders Elsevier. Snell RS (2010) Clinical Neuroanatomy for Medical Students, 7th edn. Philadelphia: Lippincott Williams and Wilkins.
In a normal human skeletal muscle, the individual muscle fiber components are organized into functional groups called motor units. The term motor unit was first used by Liddell and Sherrington in 1929 and refers to a single alpha motor neuron and the muscle fibers it innervates by way of its motor axon (Figure 1). Alpha motor neurons are the most common among a population of motor neurons in the anterior gray matter of the spinal cord, and they are the principal neurons innervating the muscle fibers (the muscle fibers that move joints, also called extrafusal muscle fibers). Medium- (beta) and small-sized (gamma) motor neurons also innervate muscle, but the latter supply specialized muscle fibers, socalled intrafusal fibers, that are found in tiny structures called muscle spindles whose function is to regulate muscle tone and reflex activity. One alpha motor neuron innervates multiple muscle fibers, but each muscle fiber is innervated by only one motor neuron. The average number of muscle fibers in a motor unit determines the innervation ratio (muscle fibers per motor neuron) of the muscle. This ratio varies greatly from one muscle to another and is related to the degree of dexterity required of that muscle. For instance, the external ocular muscles requiring very fine motor control have an innervation ratio of 10:1; the ratio for a small hand muscle is approximately 100:1. In muscles in which precise control is not needed, the ratios are higher: the ratio for a muscle in the upper arm (biceps) is 500:1, whereas in a leg muscle (gastrocnemius) the ratio is 2000:1. The muscle fibers belonging to a single motor unit are not grouped together but rather are dispersed over a limited area in the skeletal muscle. This area is known as the motor unit territory and in the biceps, for example, reaches a span of 20 mm2. This overlapping arrangement of the territories of
Peripheral nerve
Motor neuron
Muscle fiber Neuromuscular junction
Figure 1 The motor unit. Note the motor neuron, its axon, and the many muscle fibers that are innervated by it. Reproduced from Layzer R (1975) Remediable neuromuscular disorders. Primary Care 2: 235, with permission from Xerox.
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many motor units within a muscle allows the muscle to contract smoothly and evenly.
Histology and Connections of the Peripheral Nervous System Alpha Motor Neurons As noted previously, motor axons are extensions of alpha motor neurons that reside in the anterior horn gray matter of the spinal cord. These anterior horn cells are clustered in nuclei or motor neuron pools, forming longitudinal columns extending from one to four spinal segments. Alpha motor neurons are influenced directly by motor neuron projections from the motor cortex via descending corticospinal fibers and by spinal interneurons. (In an analogous fashion, brainstem motor neurons are influenced by projections from the motor cortex via descending corticobulbar fibers and by brainstem interneurons.) Accordingly, alpha motor neurons are the lowest in the hierarchy of motor control and are thereby designated lower motor neurons. The alpha motor neuron is among the largest in the nervous system. It has a single axon extending to its innervated muscle fibers and a number of large dendrites that sometimes are more than 1 mm in width and extend well into the white matter of the spinal cord, providing an extensive receptive field. Many synaptic endings or boutons (approximately 10 000) contact the dendritic surface (Figure 2). Excitatory inputs are located at the proximal portion of the dendrites or at the cell body or soma; inhibitory synapses are found along the proximal portion of the axon. Acetylcholine is the excitatory transmitter released by the alpha motor neuron’s axon at the junction between the nerve terminal and the muscle fiber (neuromuscular junction). The anterior horn cell determines the characteristic physiology of muscle contraction in the motor unit and the biochemical characteristics of muscle fibers belonging to that motor unit. Functionally, there are three types of motor units: slow fatigable, fast fatigable, and intermediate; the last category describing a population of muscle fibers whose metabolic character is composite of the first two types (see below). Proximal and axial muscles that sustain posture contain predominantly slow-twitch, nonfatigable motor units. Their slowtwitch, fatigue-resistant muscle fibers are known as Type 1 fibers. Owing to a high concentration of myoglobin, these fibers appear red (in animals); such muscle fibers are rich in oxidative enzymes and poor in glycolytic enzyme activity. Extremity muscles involved in fast phasic or ballistic contractions that generate large forces quickly possess mainly fast fatigable motor units. Their fast fatigable muscle fibers are known as Type 2 fibers. They are low in myoglobin and appear white (in animals); such muscle fibers have abundant
Encyclopedia of the Neurological Sciences, Volume 3
doi:10.1016/B978-0-12-385157-4.00618-7
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Myelin Axon Endoneurium Schwann cell Endomysium
Naked axon
(a)
Schwann cell
Sole plate
Nucleus Sarcolemma
Endoneurium Endomysium Basement membrane Sarcolemma Naked axon
Presynaptic vesicles
Synaptic cleft
(b)
Figure 2 Alpha motor neuron. This is a transverse section of the spinal cord showing the extensive dendritic system, some of which extends into the white matter. The thick dotted line indicates an axon arising from the cell body. A gray-and-white matter junction is shown by the thin, dashed line. Reproduced from Brown AG (1981) Organization in the Spinal Cord, p. 199. Berlin: Springer-Verlag, with permission from Springer.
Junctional folds
Figure 4 (a) A skeletal muscle neuromuscular junction. (b) Enlarged view of muscle fiber showing the terminal axon lying in the surface groove of muscle fiber. Reproduced with permission from Snell RS (1992) Clinical Neuroanatomy for Medical Students, 3rd edn., 135 pp. Boston: Little, Brown.
approximately equal number of fibers belonging to Types 1, Type 2A, and Type 2B fibers.)
Motor Axon and Neuromuscular Junction
Figure 3 Normal muscle cross section stained with myosin ATPase (pH 9.4) demonstrating the normal arrangement of light (Type 1) and dark (Type 2) fibers.
glycolytic enzyme activity but little oxidative enzyme activity. With a specific histochemical stain, myosin ATPase (at pH 9.4), these muscle fibers may be visualized using light microscopy (Figure 3): Type 1 fibers stain lightly and Type 2 fibers appear dark. (As noted, Type 2 fibers are specialized for glycolytic metabolism, and there are two different types of Type 2 fibers: Type 2B are rather purely glycolytic, having very little oxidative capacity, whereas Type 2A fibers have a metabolic profile that allows for both glycolytic and oxidative metabolism and therefore they are relatively fatigue resistant compared to Type 2B fibers; they are in fact the intermediate fibers mentioned earlier. In most human muscles, there are an
The motor axons of the motor unit are heavily myelinated. As a myelinated motor fiber enters a muscle, it breaks into a number of solitary branches that lose their myelin sheaths. Each branch ends as a naked axon, expanded slightly at its terminal portion that comes to lie in a groove on the surface of a muscle fiber (Figure 4). The axon terminal-muscle fiber association is known as the neuromuscular junction. The plasma membrane of the axon is separated from the plasma membrane of the muscle fiber by 20–50 nm. Thus, the neuromuscular junction consists of pre- and post-synaptic components. Within the former, the axon terminal, there are abundant vesicles and mitochondria. The vesicles, filled with molecules of acetylcholine (ACh), congregate at the presynaptic membrane around structures called dense bars corresponding in their placement to junctional peaks of the postsynaptic membrane. The postsynaptic membrane is highly folded, with ACh receptors concentrated at the peaks. The sarcoplasm immediately beneath the membrane is filled with numerous mitochondria. Acetylcholine esterase, an enzyme that degrades ACh and thereby terminates its physiological action, is present in the gap between axon and muscle fiber.
Muscle Fibers Muscle fibers in adults are approximately 50 mm in diameter. They are polygonal in shape and are bundled into fascicles (Figure 5). Individual fibers are invested by connective tissue, which forms the boundary of the endomysial compartment,
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Trabeculae (of perimysium)
Blood vessels
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I
A
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Muscle fibers Perimysium Epimysium
Perimysium
Figure 5 Schematic diagram of the connective tissue sheaths of muscle. Muscle fibers are bundled into fascicles bordered by perimysial connective tissue. Reproduced from DeGirolami U and Smith TW (1982) Pathology of skeletal muscle. American Journal of Pathology 107: 235–276.
Muscle fiber (50 microns)
Myofibril (1 micron) A
Filaments (5−10 N M)
I Z Myosin Actin
Figure 6 Ultrastructure of muscle fiber. Each fiber is made up of many myofibrils containing filaments of actin and myosin organized in bands A, I, and Z. NM, nanometers. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
and are bordered by capillaries. Denser perimysial connective tissue and blood vessels separate fascicles. Groups of fascicles are surrounded by adipose tissue, blood vessels, and loose connective tissue forming the epimysium. Nuclei number in hundreds per muscle cell and are positioned eccentrically. Satellite cells capable of aiding in regeneration are also present at the periphery of the cell beneath the basement membrane. The cytoplasm or sarcoplasm contains the contractile apparatus, lipid and glycogen stores, and organelles such as mitochondria. Each fascicle contains approximately 20–60 muscle fibers and each muscle fiber consists of 50–100 myofibrils (Figure 6). Each myofibril is longitudinally divided into sarcomeres, which are the smallest contractile units (Figure 7). The sarcomere is that portion of the myofibril that extends from Z band to Z band. The sarcomere consists of two filaments – thick (myosin) filaments alternating with thin (actin)
Myosin M Substance Actin Tropomyosin Troponin -Actinin
Thick filament Thin filament Z Band
(c)
Figure 7 Organization of protein filaments in a myofibril. (a) Longitudinal section through one sarcomere (Z disk to Z disk) showing the overlap of actin and myosin. (b) Cross section through the A band, where the thin actin filaments interdigitate with the thick myosin filaments in a hexagonal formation. (c) Location of specific proteins in the sarcomere. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
filaments. The four major contractile proteins that are present in a myofilament are actin, myosin, troponin, and tropomyosin. Within the sarcomere, thick myosin alternates with thin actin filaments. Thin filaments attach at the Z band and form the I (lighter or isotropic) band. The thick filaments are located within the A (darker or anisotropic) band, and thin filaments also extend into this region except at the H zone, where there is no overlap of thick and thin filaments. The transverse or T tubules are located near the junction of the A and I bands and transmit the initial depolarization at the motor end plate (Figure 8). On either side of the T tubule is a terminal cistern of the sarcoplasmic reticulum. The terminal cisterns act as the storage space for calcium ions. This sarcoplasmic reticulum–T tubule–sarcoplasmic reticulum complex is called the triad and is responsible for converting electrical signals (membrane action potentials) to chemical signals (calcium release).
Gamma Motor Neurons and Intrafusal Muscle Fibers Among the motor axons contained in peripheral nerve are those derived from the gamma motor neurons, also known as fusimotor neurons, and they constitute up to one-third of the lower motor neurons of the spinal cord. These fusimotor neurons innervate the intrafusal muscle fibers by way of thinly myelinated axons. Intrafusal muscle fibers are contained within muscle spindles, which are structures that are 1–4 mm in length and surrounded by a fusiform capsule of connective tissue. Approximately 6–14 intrafusal muscle fibers reside inside this capsule. (Muscle fibers discussed previously that are innervated by alpha motor neurons are termed as extrafusal because they are situated outside the muscle spindles.) Muscle spindles are numerous in any given muscle but are especially
Motor Control, Peripheral
Large myelinated fibers Gamma motor fibers Small myelinated fibers
Capsule
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Extrafusal muscle fiber
Sarcolemma Motor end-plate
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Mitochondrion Nuclear bag
Myofibril Figure 8 Structure of a single muscle fiber cut both horizontally and longitudinally. Individual myofibrils are surrounded and separated by sarcoplasmic reticulum. T tubules are continuous with extracellular fluid and interdigitate with sarcoplasmic reticulum. Note the regular association of the T tubule with the sarcoplasmic reticulum to form membranous triads. Also note the location of myonuclei at the periphery of the muscle fiber and the presence of many mitochondria. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
Neurotendinous spindles
Afferent neuron
Neuromuscular spindles
Lower motor neuron
Alpha anterior horn cell
Motor end-plate Motor end-plate Muscle fiber
Figure 9 Schematic overview of the peripheral motor control system. To the right of the spinal cord section, note the alpha motor neuron innervating seven muscle fibers, representing a motor unit. Also to the right of the spinal cord section, note the sensory afferents from the muscle spindles (designated neuromuscular spindles) and the Golgi tendon organs (neurotendinous spindles). The afferent fiber (originating in the muscle spindle) makes a monosynaptic connection with the alpha motor neuron, which in turn projects to the muscle ending as the motor end plate. Reproduced with permission from Snell RS (1992) Clinical Neuroanatomy for Medical Students, 3rd edn., 130 pp. Boston: Little, Brown.
abundant toward the tendinous attachment of the muscle (Figure 9). Intrafusal fibers are of two types – nuclear bag and nuclear chain fibers (Figure 10). In the former, numerous muscle nuclei are present in an expanded equatorial region of the fiber where cross-striations are absent. In the latter, the muscle nuclei form a row or chain in the center of each fiber at
Intrafusal muscle fibers
Motor end-plates Flower spray endings
Figure 10 A neuromuscular spindle showing two types of intrafusal fibers: the nuclear bag fiber and the nuclear chain fiber (to the right of the nuclear bag fiber and characterized by a longitudinal row of nuclei in the shape of a chain). The extrafusal fiber (shown on the left of the intrafusal fibers) is innervated by a heavily myelinated fiber (from an anterior horn cell) terminating in a motor end plate. The intrafusal fibers are innervated by the gamma motor fibers. Large afferent myelinated fibers originate in annulospiral endings on the nuclear bag fiber. Reproduced with permission from Snell RS (1992) Clinical Neuroanatomy for Medical Students, 3rd edn., 130 pp. Boston: Little, Brown.
the equatorial region. Nuclear bag fibers are larger in diameter than chain fibers, and they extend beyond the capsule at each end to attach to the endomysium of the extrafusal fibers. Intrafusal fibers are innervated by the gamma motor neurons via small end plates (neuromuscular junctions) situated at both ends of the muscle fibers. Westmoreland et al. noted that an important role of the gamma motor neurons is to ‘‘activate the intrafusal fibers leading to contraction and shortening of these fibers on either end of the central noncontractile region.’’ The result is to stretch the central region of the intrafusal fibers and activate sensory receptors and the afferent nerve terminals (vide infra). The functional role of the spindles is discussed later.
Sensory Neurons and the Simple Reflex Arc The alpha motor neurons are influenced not only by upper motor neurons in the motor cortex and motor control neurons in the brainstem but also by sensory inputs from the periphery. In fact, the peripheral pathway that serves as the foundation for the generation of spontaneous muscle contraction in the resting state (also known as muscle tone) is the simple reflex arc. It is composed of a sensory or afferent limb (the heavily myelinated axon originating in the muscle spindle (known as Ia afferent fiber, the largest among all nerve fibers) whose unipolar cell body resides in the sensory or dorsal root
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ganglia); and a motor or efferent limb (the myelinated axon extending from the lower motor neuron). The afferent limb directly stimulates the efferent lower motor neuron via a single synapse; hence, the reflex arc is designated monosynaptic (Figure 9). The specialized unipolar structure of the sensory neuron cell body allows for its axon to bifurcate after leaving the cell body: one process passes to the muscle spindle in the periphery, whereas the other travels into the spinal cord to make its monosynaptic contact with the lower motor neuron. With regard to the sensory innervation of the muscle spindle, the large-diameter myelinated axon (Ia) pierces the capsule of the spindle, loses its myelin sheath, and becomes a naked axon that winds spirally around the equatorial regions of the nuclear bag or chain portions of the intrafusal fibers (Figure 10). A slightly smaller diameter myelinated axon, arising from a smaller dorsal root ganglion neuron, also pierces the muscle spindle capsule, loses its myelin sheath, and forms a naked axon that branches terminally and ends as varicosities, resembling a spray of flowers. These endings are situated mainly on the nuclear chain fibers and some distance away from the equatorial region.
Golgi Tendon Organs These are neurotendinous spindles that are located in tendons at the junction of the tendon and the muscle (Figure 9). They consist of fibrous capsules that surround bundles of collagen fibers. Like the sensory innervation of the muscle spindle described previously, myelinated sensory fibers pierce the capsule and end in club-shaped endings. These fibers are less thickly myelinated and are designated Ib fibers.
Renshaw cell
−
+
Alpha motor neuron
Figure 11 Note the recurrent collateral branch of the alpha motor neuron making an excitatory synaptic contact with a Renshaw cell. Excitation of the Renshaw cell in turn produces inhibition of the alpha motor neuron. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
activation of the Renshaw cells causes inhibition of anterior horn cells (the chemical inhibitory neurotransmitter is amino acid in nature – glycine or taurine). This ‘recurrent inhibition’ or negative feedback serves to stabilize the discharge frequency of pools of anterior horn cells and prevent them from discharging at excessive rates.
Physiological Events Leading to Muscle Contraction Neuromuscular Transmission
Interneurons The interneurons are distributed in the anterior horn of the spinal cord and the brainstem and play a major role in determining the final common output of the motor neurons. Inputs to the interneurons derive from descending tracts originating in the brainstem, motor cortex, and limbic motor system. Additionally, interneurons receive direct or indirect information from peripheral sensory fibers. These inputs comprise both excitatory and inhibitory influences that in turn modulate the overall excitability of the motor neurons, whose motor axons form the final common pathways for innervation of skeletal muscle. Interneurons form intricate neuronal circuits that form the anatomical substrate for a variety of neurophysiological functions, including automatic and stereotyped spinal reflexes that continue to function even when the spinal cord has been separated from the brain and protective and postural reflexes triggered by unpleasant cutaneous stimuli. The interneuronal circuitry also coordinates timing for the integrated activation of synergist muscles and inhibition of antagonist muscles to allow for highly skilled voluntary movements. Among the interneurons is the Renshaw cell. When anterior horn cells are activated and initiate action potentials along their motor axons, collateral branches terminate on Renshaw cells, which in turn send axonal projections to connect with anterior horn cells (Figure 11). The result is that
Muscle contraction occurs as a result of a series of steps beginning with activation of the lower motor neuron (Figure 12). The process starts with an action potential traveling along its axon toward the muscle to be activated. The arrival of an action potential at the axon terminal triggers an influx of calcium ions and the release of hundreds of quanta of acetylcholine simultaneously, producing an end plate potential (EPP) in the muscle. If the EPP reaches sufficient amplitude (threshold response), it leads to further muscle membrane depolarization that opens another class of channels – the voltage-gated sodium channels in the muscle cell – resulting in the current needed to generate a muscle fiber action potential (Figure 13). In the resting state, small fluctuations in membrane potential occur at the end plate region of a given muscle fiber and are called miniature end plate potentials (MEPPs). The MEPPs are produced by the spontaneous release of quanta of acetylcholine from the motor nerve ending and are not of sufficient amplitude to produce a muscle fiber action potential.
Muscle Fiber Excitation Contraction Coupling The muscle fiber action potential propagates at a rate of 3–5 m/s along the muscle membrane (the sarcolemma) and into the T tubules (located at the junction of the A and I bands) (Figure 8). The latter, flanked by the sarcoplasmic
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Nerve terminal action potential
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Muscle contraction Figure 12 Sequence of events leading to muscle contraction. Reproduced from Daube JR, Reagan TJ, Sandok BA, and Westmoreland BE (1986) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
reticulum and forming a triad complex, transmits the action potential inside the muscle fiber; this action potential causes signal transduction through ryanodine receptors releasing calcium ions. The calcium ions then bind to the troponin subunits, causing a conformational change in the tropomyosin and the actin helix configuration. In another calciumdependent process that requires ATP, cross-bridges are formed between thick and thin filaments. Sliding of the thin actin filaments over the thick myosin filaments produces muscle contraction. The shortening of the sarcomeres and the I band during contraction is not due to a change in the absolute length of the filaments but rather to the sliding of the filaments. Contraction ceases when calcium is removed from the sarcoplasmic reticulum by active transport.
Spinal Control Mechanisms for Muscle Contraction In this section, it is examined how the muscle spindles and the motor neuron and interneuron populations of the spinal cord provide the substrate for anatomical connections and physiological interrelationships that allow for the integrated activation of agonist and antagonist muscles. The role of the component parts of the peripheral motor control system is described and the sequence of physiological events that follow the stretch of a flexor muscle (e.g., the activation of the biceps
Figure 13 The binding of acetylcholine (ACh) at transmitter-gated channels opens channels permeable to both Na þ and K þ . The flow of these ions in and out of the cell depolarizes the cell membrane, producing the end plate potential. This depolarization opens neighboring voltage-gated Na þ channels. To elicit an action potential, the depolarization produced by the end plate potential must open sufficient Na þ channels to reach the threshold for initiating the action potential. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
muscle by tapping on the biceps tendon to elicit a reflex biceps contraction) is examined. First, following the tendon tap, excitatory signals are transmitted from the annulospiral endings of the nuclear bag intrafusal fibers – that are stretched by the tendon tap – along the Ia afferents to activate the motor neurons, which in turn activate the extrafusal muscle fibers and lead to the biceps monosynaptic muscle contraction (Figure 14), so that the biceps may contract without resistance, the motor neurons innervating the antagonist triceps muscle are inhibited (designated reciprocal inhibition). This inhibition is brought about by these same Ia afferents that simultaneously stimulate inhibitory interneurons that inhibit the alpha motor neurons for the antagonist extensor, the triceps. The biceps alpha motor neurons that have been excited also send collateral impulses to the inhibitory interneurons (the Renshaw cells), thereby regulating their own excitation. The mechanical contraction (flexion) of the biceps exerts tension on the IIb
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Extensor muscle
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sensory fibers of the Golgi tendon organ that project to the spinal cord. These Golgi tendon organ afferents have an inhibitory effect on alpha motor neurons (via inhibitory interneurons), thereby preventing too much tension from being generated by the biceps, and they stimulate excitatory interneurons that activate alpha motor neurons innervating the antagonist triceps muscle. This antagonist contraction inhibits further flexor contraction and restores the flexor muscle (biceps) to its original position. Finally, biceps contraction loosens the intrafusal fibers, which stimulates a feedback system that activates the gamma motor neurons to contract the intrafusal fibers. In effect, the gamma motor neurons cause the intrafusal fibers to shorten (or adjust) and this stretches the equatorial region of the fibers, thereby stimulating the annulospiral and flower spray endings and once again restoring the stretch sensitivity of the muscle spindle.
See also: Motor System; Overview. Motor Unit Potential. Muscle Contraction; Overview. Neurons, Overview
Further Reading Figure 14 Pathways for the monosynaptic reflex and for reciprocal inhibition. An Ia afferent fiber is shown making monosynaptic contact with a flexor (biceps) motor neuron and an inhibitory interneuron. The latter sends a projection to an extensor (triceps) motor neuron, providing the pathway for reciprocal inhibition. Reproduced from Westmoreland BE, Benarroch EE, Daube JR, et al. (1994) Medical Neurosciences. An Approach to Anatomy, Pathology and Physiology by Systems and Levels. Boston: Little, Brown, with permission from LWW.
Dubowitz V and Sewry CA (2007) Muscle Biopsy: A Practical Approach, 3rd edn. Philadelphia: Saunders Elsevier. Fitzgerald MJT, Gruener G, and Mtui E (2007) Clinical Neuroanatomy and Neuroscience, 5th edn. Philadelphia: Saunders Elsevier. Snell RS (2010) Clinical Neuroanatomy for Medical Students, 7th edn. Philadelphia: Lippincott Williams and Wilkins.