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I'd like to receive the latest health and fitness research and studies from ACE. Browse ACE exercise science courses. Thus, patients with proprioceptive deficits are likely to develop adolescent idiopathic scoliosis in their second decade of life, suggesting that the proprioceptive information may not only provide dynamic control of spine alignment but also prevent progressive spinal deformation [ 13 , 15 ].
Moreover, after spinal cord injury, proprioceptive feedback is essential for locomotor recovery and facilitates circuit reorganization [ 16 ]. Ablation of this feedback after behavioral recovery permanently reverts functional improvements, demonstrating the essential role of proprioception also for maintaining regained locomotor function [ 17 ]. Thus, proprioceptive information has functions that extend far beyond motor control and includes non-conscious regulation of skeletal development and function as well as recovery after spinal cord injury [ 4 , 18 ].
Although Golgi tendon organs, joint receptors and other sensory systems also contribute to proprioception, muscle spindles are the most important proprioceptors [ 19 , 20 ]. Muscle spindles are the most frequently found sense organs in skeletal muscles and present in almost every muscle. The density of muscle spindles within the large muscle mass, however, is low so that they are rather difficult to detect. Rough estimates have suggested approximately 50, muscle spindles in the entire human body [ 21 ].
Interestingly, in humans, muscle spindles are mostly absent in facial muscles [ 22 ] and extraocular muscles have unusual muscle spindles and additional unique sensory structures named palisade endings, which might also provide proprioceptive information [ 23 , 24 , 25 ]. Muscle spindles are encapsulated sensory receptors which inform the brain about changes in the length of muscles [ 3 , 20 ]. They consist of specialized muscle fibers so called intrafusal fibers that are multiply innervated and named according to the arrangement of their nuclei as nuclear bag or nuclear chain fibers a schematic representation of a muscle spindle is shown in Fig.
Each muscle spindle contains on average 3—5 mouse [ 28 ] or 8—20 human [ 29 ] intrafusal fibers. Contractile filaments are found in intrafusal fibers predominantly in the polar regions with only a small ring of sarcomeres underneath the sarcoplasmic membrane in the central equatorial region Fig. However, muscle spindles do not contribute significantly to the force generated by the muscle [ 31 , 32 ].
Nuclear bag fibers often extend beyond the fluid-filled fusiform capsule and are attached to intramuscular connective tissue [ 33 ]. Nuclear chain fibers are attached to the polar regions of the thicker and longer nuclear bag fibers [ 33 ]. Structure of muscle spindles and distribution of the DGC.
Panel a shows a schematic representation of the sensory and fusimotor innervation of intrafusal fibers. The connective tissue capsule is indicated in orange. Muscle spindles contain three types of intrafusal fibers: nuclear bag1, nuclear bag2, and nuclear chain fibers. The polar regions of intrafusal fibers contain most of the contractile elements sarcomeres are indicated in blue in panel a. However, interspecies differences exist.
For example, mouse muscle spindles might not have a group II innervation [ 26 ], and in humans, the sensory nerve terminal does not form annulospiral endings and the secondary ending innervates nuclear bag as well as nuclear chain muscle fibers [ 27 ]. Panel b shows a confocal section of the central part of a mouse muscle spindle stained with anti-neurofilament antibodies.
Note the annulospiral endings of the Ia afferents in the central region. Functionally, muscle spindles are stretch detectors, i. Accordingly, when a muscle is stretched, this change in length is transmitted to the spindles and their intrafusal fibers which are subsequently similarly stretched. To respond appropriately to changes in muscle fiber length, intrafusal fibers are innervated by two kinds of neurons: afferent sensory neurons and efferent motoneurons Fig.
In humans, the sensory innervation of the muscle spindle arises from both group Ia and group II afferent fibers also sometimes called type Ia or type II fibers, respectively , which differ in their axonal conduction velocity [ 34 ]. In contrast, in mice an innervation by group II fibers has so far not been detected by histological or functional assays [ 26 , 35 ].
However, transcriptome analysis of DRG proprioceptive neurons has recently suggested the existence of group II fibers also in mice [ 36 ]. There is usually only a single Ia afferent fiber per spindle, and every intrafusal muscle fiber within that spindle receives innervation from that sensory neuron.
In cat, rat and mice and probably many other species , the axon terminals of this sensory afferent fiber coil around the central equatorial part of both nuclear bag and nuclear chain fibers, forming the primary endings also called annulospiral endings [ 37 , 38 ] Fig.
In humans, sensory terminals form irregular coils with branches and varicose swellings [ 39 ]. When present, the smaller group II fiber terminals flank the primary annulospiral endings in the equatorial region Fig. There may be several group II fibers innervating each human spindle [ 40 ].
They can be classified and distinguished from other dorsal root ganglion neurons as a unique neuronal population using single cell transcriptome analysis [ 36 , 41 , 42 ]. Afferent sensory neurons generate action potentials with frequencies that correspond to the size of the stretch and to the rate of stretching [ 43 ] Fig.
Sensory neurons innervating bag1 fibers respond maximally to the velocity of changes in muscle fiber length dynamic sensitivity and those innervating bag2 fibers as well as nuclear chain fibers respond maximally to the amount of stretch static sensitivity. For a recent review on the mechanotransduction processes within the sensory nerve terminal, see [ 45 ].
Typical responses of a muscle spindle to stretch. The responses of an individual muscle spindle from the mouse extensor digitorum longus muscle to ramp and hold stretches applied to the tendon were recorded with an extracellular electrode. Single unit action potentials are shown in a and d. The ramp speed in e was 3-fold higher compared to that in b. In panel f , three different parameters that are usually analyzed to describe muscle spindle function are illustrated: resting discharge RD , dynamic peak DP , and static response SR.
For more information on these parameters, see [ 32 , 33 , 44 ]. Note that the dynamic peak and the static response is higher in f , compared in c due to the higher ramp speed and the longer length change.
Since the fusimotor innervation was cut during the dissection of the muscle, no action potentials can be observed directly after the end of the ramp and hold stretch spindle pause. Sensory neuron activity from muscle spindles can be electrophysiologically recorded and characterized in a number of different ways.
In mice, single unit muscle spindle afferent responses to ramp-and-hold stretches and sinusoidal vibratory stimuli have been well characterized in an ex vivo adult mouse extensor digitorum longus preparation dissected with the innervating nerve attached [ 26 , 46 ]. A typical example for a single unit muscle spindle response to two different ramp-and-hold stretches in the adult mouse extensor digitorum longus muscle is shown in Fig.
In many species, muscle spindles exhibit a resting discharge that is related to the degree of muscle stretch but the frequency of the mean firing rate differs between species. Muscle spindle afferents encode muscle length in their frequency of firing, i. In addition to the static encoding of length changes, spindle afferents, especially primary afferents, can respond to dynamic length changes, i.
In addition to sensory neurons, intrafusal muscle fibers are also innervated by efferent motoneurons fusimotor innervation; Fig.
Axons of motoneurons usually enter the spindle together with the sensory fibers in the central region but innervate intrafusal muscle fibers exclusively in the polar regions. Moreover, both synapses require the extracellular matrix synapse organizer agrin and its receptor complex consisting of the low-density lipoprotein receptor-like protein 4 and the tyrosine kinase MuSK for their formation, suggesting a common molecular basis for their synaptogenesis [ 49 ].
Gamma-motoneurons induce contractions of sarcomeres in the polar region to exert tension on the central region of intrafusal fibers [ 47 , 50 ]. This prevents the slackening of intrafusal fibers during muscle shortenings and allows for continuous adjustment of the mechanical sensitivity of spindles over the wide range of muscle lengths and stretch velocities that occur during normal motor behaviors. Muscle spindle development starts during embryonic stages but continues well into adult life [ 51 ].
Human muscle spindles can be recognized in fetal tissue around the 11th week of gestation [ 52 , 53 ], but little is known about the molecular basis of human muscle spindle development. Fusimotor innervation develops a few days later and is present in mice at E19 [ 54 ]. In rodents and humans, immature myotubes are induced to differentiate into intrafusal fibers when sensory afferent axons contact the primary myotubes [ 55 , 56 , 57 ].
Apparently, nuclear bag fibers differentiate before nuclear chain fibers in rats [ 58 , 59 ]. There is the possibility of a hyperinnervation of intrafusal fibers with subsequent pruning of the terminals for the fusimotor innervation [ 60 ] as well as for the sensory innervation [ 61 ] of rat muscle spindles.
Human muscle spindles are functional at birth, but their response to stretch is immature [ 30 ]. Moreover, with the postnatal increase in muscle mass and mobility, sensory nerve terminals in mice and humans undergo a number of anatomical and physiological changes [ 62 , 63 , 64 ]. By postnatal day 18, muscle spindle afferent firing is indistinguishable from the firing in adult rats suggesting that muscle spindle maturation continues into postnatal life and that muscle spindles are capable of responding to stretch, even at an age when their morphological and ultrastructural maturation is not yet fully accomplished [ 65 ].
Postnatal development of mouse muscle spindles. Muscle spindles from postnatal day 0: P0 a , P8 b , and P40 c. Only the central equatorial region is shown. After the establishment of a physical contact between the sensory axon and the primary myotube, both cells exchange inductive signals ensuring the differentiation of intrafusal fiber and the survival of the sensory neuron.
This reciprocal signaling is essential for muscle spindle differentiation and intrafusal fiber development. Accordingly, elimination of the sensory input but not of the fusimotor input in embryonic and adult muscle spindles results in a rapid degeneration of the intrafusal fibers [ 66 , 67 , 68 ]; for review, see [ 55 ].
The key inductive factor for the sensory neuron-mediated muscle spindle differentiation is the immunoglobulin form of neuregulin-1 Ig-Nrg1. Ig-Nrg1 is expressed by proprioceptive neurons [ 69 , 70 ], and its release from sensory neurons and subsequent binding to the ErbB2 receptor expressed by immature muscle fibers [ 71 ] induces their differentiation into intrafusal muscle fibers.
Accordingly, Nrg1- or ErbB2-deficient mice do not initiate muscle spindle differentiation, do not elaborate Ia afferent terminals and have an ataxic behavior as well as abnormal hind limb reflexes, consistent with severe proprioceptive deficits [ 69 , 70 , 71 , 72 ]. Nrg1—ErbB2 signaling activates downstream targets such as the transcription factor early growth response protein 3 Egr3 [ 73 , 74 , 75 ], and the Ets transcription factors Pea3 , Erm and Er81 as well as the Grb2-associated binder 1 protein, a scaffolding mediator of receptor tyrosine kinase signaling [ 69 , 76 , 77 ].
Although muscle spindles are initially generated in Egr3 -deficient mice [ 75 ], subsequently most of them degenerate, resulting in ataxic behavior [ 73 , 74 ]. Overexpression of Egr3 in primary myotubes on the other hand leads to their differentiation into intrafusal fibers [ 78 ], suggesting that this transcription factor is necessary and sufficient for muscle spindle maintenance. Cleavage of Ig-Nrg1 is required for Ig-Nrg1 function and, accordingly, in the absence of Bace1, muscle spindle numbers are reduced and spindle maturation is impaired.
Moreover, a graded reduction in Ig-Nrg1 signal strength in vivo induced by pharmacological Bace1 inhibition results in increasingly severe deficits in the formation and maturation of muscle spindles in combination with a reduced motor coordination [ 70 ].
The continuous presence of Bace1 and Ig-Nrg1 is essential to maintain muscle spindles in adult muscle, since either pharmacological inhibition of Bace1 or induced Bace1 deficiency in adult proprioceptive neurons also leads to a decline of muscle spindle number [ 70 ].
In summary, the sensory neuron induces the differentiation of muscle spindles from immature myotubes via Ig-Nrg1, Bace1 and ErbB2-mediated activation of Egr3. On the other hand, muscle fibers release neurotrophin-3 NT3 , which activates the tropomyosin receptor kinase C TrkC receptor on proprioceptive sensory neurons and by this secures the survival of the sensory neuron [ 79 , 80 , 81 ]. Muscle-specific overexpression of NT3 results in an increase in the number of proprioceptive afferents and muscle spindles [ 83 , 84 , 85 ].
Interestingly, the survival of proprioceptive sensory neurons supplying distinct skeletal muscles differ in their dependence on Etv1 for their survival and differentiation [ 87 ]. As in the musculoskeletal system in general, various elements of the proprioceptive system decline during ageing [ 90 , 91 ].
These changes might contribute to the frequent falls and motor control problems observed in older adults. On the structural level, muscle spindles in aged humans possess fewer intrafusal fibers, an increased capsular thickness and some spindles which show signs of denervation [ 92 , 93 ]. In old rats, primary endings are less spiral or non-spiral in appearance, but secondary endings appeared unchanged [ 94 , 95 ].
Likewise, in old mice, there is a significant increase in the number of Ia afferents with large swellings that fail to properly wrap around intrafusal muscle fibers. There is also a degeneration of proprioceptive sensory neuron cell bodies in the dorsal root ganglion but no change in the morphology and number of intrafusal muscle fibers [ 96 ].
In addition, electrophysiological studies showed that mature rat muscle spindles display a lower dynamic response of primary endings compared with those of young animals [ 94 ]. Taken together, the proprioceptive system undergoes significant structural and functional changes with advancing age and the changes are consistent with a gradual decline in proprioceptive function in elderly individuals and animals.
An impaired proprioception, in some cases associated with an altered muscle spindle morphology, has been documented as a secondary effect in many diseases. They accumulate misfolded SOD1 protein and the annulospiral endings degenerate, leading to ataxia and motor control problems [ , ]. Recently, a number of studies have analyzed proprioception and muscle spindle function in patients with muscular dystrophy and in dystrophic mouse models.
Muscular dystrophies are a heterogeneous group of more than 30 different mostly inherited diseases characterized by muscular weakness and atrophy in combination with degeneration of the musculoskeletal system [ ].
The molecular basis of many muscular dystrophies are mutations that directly or indirectly influence the function of the dystrophin-associated glycoprotein complex DGC [ , ]. The most common form of muscle dystrophy in humans is Duchenne muscular dystrophy DMD which affects approximately 1 in boys [ ].
DMD is caused by mutations in the DMD gene, which codes for the large cytoskeletal protein dystrophin [ ]. In skeletal muscle, dystrophin links subsarcolemmal F-actin filaments to the extracellular matrix via the DGC [ , ].
This link mechanically stabilizes the sarcolemmal membrane particularly during muscle contraction. While regeneration of damaged muscle fibers occurs initially, it cannot compensate for the prolonged degenerative loss of muscle tissue [ ], leading over time to a reduction of muscle mass, loss of contractile force and, in the case of DMD, to premature death of the affected person due to respiratory or cardiac muscle failure [ ].
Many muscular dystrophy patients suffer from postural instability, sudden spontaneous falls and poor manual dexterity [ , , , ], suggesting that their proprioceptive system might be impaired. However, only minor morphological changes in muscle spindles were detected in human dystrophic muscles.
These changes primarily affect the connective tissue surrounding intrafusal fibers. Likewise, analyses of biopsy specimens from patients with muscular dystrophy and with congenital dystrophy revealed an increased thickness of the spindle capsule and a slight decrease of the intrafusal fiber diameter [ ]. An autopsy study of seven DMD patients aged 15 to 17 years reported more severe pathological changes including degenerative changes, atrophy and loss of intrafusal muscle fibers [ ], but it is unclear if these more extensive changes were caused by the disease or due to postmortem tissue degeneration.
This possibility has to be considered, since proprioceptive functions of muscle spindles in DMD patients appear rather normal see below and since a recent study analyzing muscle spindles from a year-old severely affected DMD patient described that spindle size and number as well as the size of intrafusal myofibers and capsule thickness were in the normal range [ ].
Interestingly, the extrafusal fibers directly surrounding the muscle spindles were also less affected by the degenerative events compared to fibers further away from the spindle, suggesting the possibility of a more protective environment directly around muscle spindles. Likewise, murine models for several muscular dystrophies display only minor changes in muscle spindle structure compared to wildtype control mice.
But, as in the corresponding patients, intrafusal fibers and sensory terminals appeared mostly spared from degeneration [ 44 , ].
Similarly, the DMD mdx mouse line [ ], a widely used model system for muscular dystrophy of the Duchenne type [ ], revealed no reduction of the total number of muscle spindles and no change in the structure of muscle spindles and their sensory innervation [ , ]. Thus, compared to extrafusal muscle fibers, the morphology of intrafusal muscle fibers and of muscle spindles generally appear much less affected by the degenerative processes in humans and in mice with Duchenne-type muscular dystrophy.
The mechanism s , which protect intrafusal myofibers from degeneration and wasting, are unknown. Capsular thickening in the equatorial region may be an adaptive response, preventing the intrafusal fibers from undergoing atrophy. Another explanation for the sparing of muscle spindles in DMD patients could be a better maintenance of the intracellular calcium homeostasis similar to what has been described for extraocular muscles [ ].
Furthermore, the mild phenotypic effect of the dystrophin mutations might be due to the different surface-to-volume ratio, compared to extrafusal fibers. Intrafusal fibers are thinner compared to extrafusal fibers, have a much smaller mechanical burden, and generate considerably less contractile force. They are therefore less likely to suffer from mechanical damage [ ].
Immunohistochemical analysis showed that dystrophin is present in the sarcolemma of the polar regions of intrafusal fibers [ ]. In contrast, in the equatorial region, dystrophin is absent from that part of the intrafusal fiber, which is in contact with the sensory nerve terminal but concentrated in parts without sensory nerve contact [ , ] Fig.
Other proteins of the DGC including alpha-dystrobrevin1; Fig. The area, where the DGC is concentrated, also corresponds to the region where the intrafusal fiber has direct contact to the basal lamina. The interaction of DGC components with basal lamina proteins might stabilize and help to maintain the subcellular concentration of the DGC in this region of the intrafusal fiber.
In any case, the unusual distribution of DGC components indicates a molecular specialization in particular regions of the intrafusal fiber plasma membrane. Distribution of the dystrophin glycoprotein complex in mouse intrafusal fibers. Panel a shows two intrafusal fibers labeled by anti-dystrophin antibodies red channel and by antibodies against the vesicular glutamate transporter 1 vGluT1; white channel.
Panels b — d show the boxed area in panel c at a higher magnification. Note that dystrophin is concentrated in the intrafusal fiber plasma membrane in areas that are not in contact with the sensory neuron. Panels e—j show the distribution of utrophin red channel in the central region of muscle spindles from wildtype e—g and from DMD mdx mice h—j. Anti-vGluT1 antibodies green channel in panels e—j were used to label the sensory nerve terminal.
Panels d , g and j show the merged channels. Utrophin is not detectable in the equatorial region of muscle fibers from wildtype mice e but severely upregulated in intrafusal fibers from DMD mdx mice h.
Note the absence of utrophin in the contact area between intrafusal fiber and sensory nerve terminal. Below is an image of a muscle spindle. When muscles lengthen, the spindles are stretched. This stretch activates the muscle spindle which in turn sends an impulse to the spinal cord. This impulse results in the activation of more motor neurons at spinal level that send an impulse back to the muscle. This impulse tells the muscle to contract with greater force in order to decrease the speed at which the muscle is being stretched.
This is known as the stretch reflex and is shown on the following diagram;. The strength or degree of the muscles response is determined by the speed at which the stretch occurs; where the stretch occurs more rapidly, the spindle stimulates a greater firing frequency of the motor neuron, and the more forceful the contraction of the muscle is in response.
This response is primarily protective, to avoid the potential damage that could occur when a muscle is rapidly stretched beyond its limit. For example, when you accidentally walk into a pothole and roll your ankle — there is a rapid stretch of the ankle and spindles within the stretched muscle s.
Because of the speed of stretch the spindles fire rapid impulses to the nervous system causing a rapid contraction in the stretched muscles.
This response protects you from a completely torn muscle or broken ankle, and usually results in nothing worse than a minor sprain.
As this response needs to occur rapidly virtually instantaneously , the impulses from the spindles only go as far as the spinal cord. Much of the brain and nervous system is devoted to the processing of sensory input, in order to construct detailed representations of the external environment. Through vision, audition, somatosensation, and the other senses, we perceive the world and our relationship to it.
In some cases the relationship between the sensory input and the motor output are simple and direct; for example, touching a hot stove elicits an immediate withdrawal of the hand Figure 1.
Usually, however, our conscious actions require not only sensory input but a host of other cognitive processes that allow us to choose the most appropriate motor output for the given circumstances.
In each case, the final output is a set of commands to certain muscles in the body to exert force against some other object or forces e. This entire process falls under the subject of motor control. These are some of the many components of the motor system that allow us to perform complex movements in a seemingly effortless way. One of the major principles of the motor system is that motor control requires sensory input to accurately plan and execute movements.
This principle applies to low levels of the hierarchy, such as spinal reflexes, and to higher levels. As we shall see throughout this material on the motor system, our abilities to make movements that are accurate, properly timed, and with proper force depend critically on the sensory input that is ubiquitous at all levels of the motor system hierarchy.
The ease with which we make most of our movements belies the enormous sophistication and complexity of the motor system. Engineers have spent decades trying to make machines perform simple tasks that we take for granted, yet the most advanced robotic systems do not come close to emulating the precision and smoothness of movement, under all types of conditions, that we achieve effortlessly and automatically.
How does the brain do it? Although many of the details are not understood, two broad principles appear to be key concepts toward understanding motor control:. The motor system hierarchy consists of 4 levels Figure 1. It also contains two side loops: the basal ganglia and the cerebellum, which interact with the hierarchy through connections with the thalamus.
The brain figure on the left is a schematic version of an idealized brain section that contains the major structures of the motor system hierarchy for illustrative purposes; no actual brain section would contain all of these structures.
Tap on each box on the right to highlight the inputs blue and outputs red of each region. The spinal cord is the first level of the motor hierarchy. It is the site where motor neurons are located. These circuits execute the low-level commands that generate the proper forces on individual muscles and muscle groups to enable adaptive movements. The spinal cord also contains complex circuitry for such rhythmic behaviors as walking. Because this low level of the hierarchy takes care of these basic functions, higher levels such as the motor cortex can process information related to the planning of movements, the construction of adaptive sequences of movements, and the coordination of whole-body movements, without having to encode the precise details of each muscle contraction.
Alpha motor neurons also called lower motor neurons innervate skeletal muscle and cause the muscle contractions that generate movement. Motor neurons release the neurotransmitter acetylcholine at a synapse called the neuromuscular junction. When the acetylcholine binds to acetylcholine receptors on the muscle fiber, an action potential is propagated along the muscle fiber in both directions see Chapter 4 of Section I for review.
The action potential triggers the contraction of the muscle. If the ends of the muscle are fixed, keeping the muscle at the same length, then the contraction results on an increased force on the supports i sometric contraction. If the muscle shortens against no resistance, the contraction results in constant force isotonic contraction. The motor neurons that control limb and body movements are located in the anterior horn of the spinal cord, and the motor neurons that control head and facial movements are located in the motor nuclei of the brainstem.
Even though the motor system is composed of many different types of neurons scattered throughout the CNS, the motor neuron is the only way in which the motor system can communicate with the muscles. Thus, all movements ultimately depend on the activity of lower motor neurons. Motor neurons are not merely the conduits of motor commands generated from higher levels of the hierarchy.
They are themselves components of complex circuits that perform sophisticated information processing. As shown in Figure 1. Two terms are used to describe the anatomical relationship between motor neurons and muscles: the motor neuron pool and the motor unit.
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