Physiology_Levy

Physiology_Levy. The visceral motor fibers in the autonomic nerves are accompanied by visceral afferent fibers. Most of these afferent fibers supply information that originates from sensory receptors in the viscera. The activity of these sensory receptors only rarely reaches the level of consciousness; however, these receptors initiate the afferent limb of reflex arcs. Both viscerovisceral and viscerosomatic reflexes are elicited by these afferent fibers. Even though these visceral reflexes generally operate at a subconscious level, they are very important for homeostatic regulation and adjustment to external stimuli.


Physiology_Levy

Physiology_Levy. The fast-acting neurotransmitters released by visceral afferent fibers are not well documented, although many of these neurons release an excitatory amino acid transmitter such as glutamate. However, visceral afferent fibers also contain many neuropeptides or combinations of neuropeptides, including angiotensin II, arginine vasopressin, bombesin, calcitonin gene–related peptide, cholecystokinin, galanin, substance P, enkephalin, oxytocin, somatostatin, and vasoactive intestinal polypeptide.


Physiology_Levy

Physiology_Levy. Visceral afferent fibers that can mediate conscious sensation include nociceptors that travel in sympathetic nerves, such as the splanchnic nerves. Visceral pain is caused by excessive distention of hollow viscera, contraction against an obstruction, or ischemia. The origin of visceral pain is often difficult to identify because of the diffuse nature of the pain and its tendency to be referred to somatic structures (see ). Visceral nociceptors in sympathetic nerves reach the spinal cord via the sympathetic chain, white rami, and dorsal roots. The terminals of nociceptive afferent fibers project to the dorsal horn and to the region surrounding the central canal. They activate not only local interneurons, which participate in reflex arcs, but also projection cells, which include spinothalamic tract cells that signal pain to the brain.


Physiology_Levy

Physiology_Levy. A major visceral nociceptive pathway from the pelvis involves a relay in the gray matter of the lumbosacral spinal cord. These neurons send axons into the fasciculus gracilis that terminate in the nucleus gracilis. Thus the dorsal columns not only contain primary afferents for somatic sensation (their main component) but also second-order neurons of the visceral pain pathway (recall that second-order axons for somatic pain travel in the lateral funiculus as part of the spinothalamic tract). Visceral nociceptive signals are then transmitted to the ventral posterior lateral nucleus of the thalamus and presumably from there to the cerebral cortex. Interruption of this pathway accounts for the beneficial effects of surgically induced lesions of the dorsal column at lower thoracic levels to relieve pain produced by cancer of the pelvic organs.


Physiology_Levy

Physiology_Levy. Other visceral afferent fibers travel in parasympathetic nerves. These fibers are generally involved in reflexes rather than sensation (except for taste afferent fibers; see ). For example, the baroreceptor afferent fibers that innervate the carotid sinus are in the glossopharyngeal nerve. They enter the brainstem, pass through the solitary tract, and terminate in the nucleus of the solitary tract (see Fig. 4.6E ). These neurons connect with interneurons in the brainstem reticular formation. The interneurons, in turn, project to the autonomic preganglionic neurons that control heart rate and blood pressure (see The nucleus of the solitary tract receives information from all visceral organs, except those in the pelvis. This nucleus is subdivided into several areas that receive information from specific visceral organs. The Enteric Nervous System


Physiology_Levy

Physiology_Levy. The Enteric Nervous System The enteric nervous system, which is located in the wall of the gastrointestinal tract, contains about 100 million neurons. The enteric nervous system is subdivided into the myenteric plexus, which lies between the longitudinal and circular muscle layers of the gut, and the submucosal plexus, which lies in the submucosa of the gut. The neurons of the myenteric plexus primarily control gastrointestinal motility (see ), whereas those in the submucosal plexus primarily regulate body fluid homeostasis (see


Physiology_Levy

Physiology_Levy. The types of neurons found in the myenteric plexus include not only excitatory and inhibitory motor neurons (which can be considered parasympathetic postganglionic neurons) but also interneurons and primary afferent neurons. Afferent neurons supply mechanoreceptors within the wall of the gastrointestinal tract. These mechanoreceptors are the beginning of the afferent limb of reflex arcs within the enteric plexus. Local excitatory and inhibitory interneurons participate in these reflexes, and the output is sent through the motor neurons to smooth muscle cells. Excitatory motor neurons release acetylcholine and substance P; inhibitory motor neurons release dynorphin and vasoactive intestinal polypeptide. The circuitry of the enteric plexus is so extensive that it can coordinate the movements of an intestine that has been completely removed from the body. However, normal function requires innervation by the autonomic preganglionic neurons and regulation by the CNS.


Physiology_Levy

Physiology_Levy. Activity in the enteric nervous system is modulated by the sympathetic nervous system. Sympathetic post-ganglionic neurons that contain norepinephrine inhibit intestinal motility, those that contain norepinephrine and neuropeptide Y regulate blood flow, and those that contain norepinephrine and somatostatin control intestinal secretion. Feedback is provided by intestinofugal neurons that project back from the myenteric plexus to the sympathetic ganglia. The submucosal plexus regulates ion and water transport across the intestinal epithelium and glandular secretion. It also communicates with the myenteric plexus to ensure coordination of the functions of the two components of the enteric nervous system. The neurons and neural circuits of the submucosal plexus are not as well understood as those of the myenteric plexus, but many of the neurons contain neuropeptides, and the neural networks are well organized.


Physiology_Levy

Physiology_Levy. The main type of neuron in autonomic ganglia is the post-ganglionic neuron. These cells receive synaptic connections from preganglionic neurons, and they project to autonomic effector cells. However, many autonomic ganglia also contain interneurons. These interneurons process information within the autonomic ganglia; the enteric plexus can be regarded as an elaborate example of this kind of processing. One type of interneuron found in some autonomic ganglia contains a high concentration of catecholamines; hence, these interneurons have been called small, intensely fluorescent (SIF) cells. SIF cells are believed to be inhibitory.


Physiology_Levy

Physiology_Levy. The classic neurotransmitter of autonomic ganglia, whether sympathetic or parasympathetic, is acetylcholine. The two classes of acetylcholine receptors in autonomic ganglia are nicotinic and muscarinic receptors, so named because of their responses to the plant alkaloids nicotine and muscarine. Nicotinic acetylcholine receptors can be blocked by such agents as curare or hexamethonium, and muscarinic receptors can be blocked by atropine. Nicotinic receptors in autonomic ganglia differ somewhat from those on skeletal muscle cells.


Physiology_Levy

Physiology_Levy. Nicotinic and muscarinic receptors both mediate excitatory postsynaptic potentials (EPSPs), but these potentials have different time courses. Stimulation of preganglionic neurons elicits a fast EPSP, followed by a slow EPSP. The fast EPSP results from activation of nicotinic receptors, which cause ion channels to open. The slow EPSP is mediated by muscarinic receptors (primarily the M2 receptor; see ) that inhibit the M current, a current produced by potassium conductance. Neurons in autonomic ganglia also release neuropeptides that act as neuromodulators. Besides acetylcholine, sympathetic preganglionic neurons may release enkephalin, substance P, luteinizing hormone–releasing hormone, neurotensin, or somatostatin. Catecholamines such as norepinephrine and dopamine serve as the neurotransmitters of SIF cells in autonomic ganglia.


Physiology_Levy

Physiology_Levy. Catecholamines such as norepinephrine and dopamine serve as the neurotransmitters of SIF cells in autonomic ganglia. Sympathetic postganglionic neurons typically release nor-epinephrine, which excites some effector cells but inhibits others. The receptors on target cells may be either α-or β-adrenergic receptors. These receptors are further subdivided into α1, α2, β1, β2, and β3 receptor types on the basis of pharmacological and genetic features. The distribution of these types of receptors and the actions that they mediate when activated by sympathetic postganglionic neurons are listed for various target organs in


Physiology_Levy

Physiology_Levy. Table 11.1 α1 receptors are located postsynaptically, but α2 receptors may be either presynaptic or postsynaptic. Receptors located presynaptically are generally called autoreceptors; they usually inhibit release of transmitter. The effects of agents that excite α1 or α2 receptors can be distinguished through the use of antagonists to block these receptors specifically. For example, prazosin is a selective α1-adrenergic antagonist, and yohimbine is a selective α2-adrenergic antagonist. The effects of α1 receptors are mediated by activation of the inositol triphosphate/diacylglycerol second messenger system (see Chapter 3). In contrast, α2 receptors decrease the rate of synthesis of cyclic adenosine monophosphate (cAMP) through action on a G protein.


Physiology_Levy

Physiology_Levy. Chapter 3). In contrast, α2 receptors decrease the rate of synthesis of cyclic adenosine monophosphate (cAMP) through action on a G protein. β receptors were originally classified on the basis of the ability of antagonists to block them, but this has been supplemented by genetic studies. The β1 and β2 proteins have been much more extensively studied than has β3, but it is thought that the proteins that make up all three types of β receptors are similar, with seven membrane-spanning regions connected by intracellular and extracellular domains (see ). Agonist drugs that work on β receptors activate a G protein that stimulates adenylyl cyclase to increase the cAMP concentration. This action is terminated by the buildup of guanosine diphosphate. Radialmuscle,irisα Contraction(mydriasis)++ —Sphinctermuscle,irisα —Contraction(miosis)+++ Ciliarymuscleβ Relaxationforfarvision+ Contractionfornearvision+++


Physiology_Levy

Physiology_Levy. Radialmuscle,irisα Contraction(mydriasis)++ —Sphinctermuscle,irisα —Contraction(miosis)+++ Ciliarymuscleβ Relaxationforfarvision+ Contractionfornearvision+++ Sinoatrialnodeβ1Increaseinheartrate++ Decreaseinheartrate;vagalarrest+++ Atriaβ1IncreaseincontractilityandconductionDecreaseincontractilityand(usually)velocity++ increaseinconductionvelocity++ Atrioventricular(AV)nodeβ1IncreaseinautomaticityandDecreaseinconductionvelocity;AVblockconductionvelocity++ +++ His-Purkinjesystemβ1IncreaseinautomaticityandLittleeffectconductionvelocity+++ Ventriclesβ1Increaseincontractility,conductionSlightdecreaseincontractilityvelocity,automaticity,andrateofidioventricularpacemakers+++ Coronaryα,β2Constriction+;dilation Skeletalmuscleα,β2Constriction++;dilation c,e Pulmonaryα,β2Constriction+;dilation Abdominalviscera,renalα,β2Constriction+++;dilation + —Salivaryglandsα Constriction+++ Dilation++ Veins (Systemic) α,β2Constriction++;dilation++ —


Physiology_Levy

Physiology_Levy. Pulmonaryα,β2Constriction+;dilation Abdominalviscera,renalα,β2Constriction+++;dilation + —Salivaryglandsα Constriction+++ Dilation++ Veins (Systemic) α,β2Constriction++;dilation++ — Responses of Effector Organs to Autonomic Nerve Impulses—cont’d 11.1 Effector Organs Receptor Type Adrenergic Impulses,a Responsesb Cholinergic Impulses,a Responsesb Bronchialmuscleβ2Relaxation+ Contraction++ Bronchialglands?Inhibition(?)Stimulation+++ Motilityandtoneα2,β2Decrease(usually) + Increase+++ Sphinctersα Contraction(usually)+ Relaxation(usually)+ SecretionInhibition(?)Stimulation+++ Motilityandtoneα2,β2Decrease + Increase+++ Sphinctersα Contraction(usually)+ Relaxation(usually)+ SecretionInhibition(?)Stimulation+++ Gallbladder and Ducts Relaxation+ Contraction+


Physiology_Levy

Physiology_Levy. Motilityandtoneα2,β2Decrease + Increase+++ Sphinctersα Contraction(usually)+ Relaxation(usually)+ SecretionInhibition(?)Stimulation+++ Gallbladder and Ducts Relaxation+ Contraction+ Motilityandtoneα Increase(usually)Increase(?)Uterus α,β2Pregnant:contraction(α);Variable nonpregnant:relaxation(β)Sex Organs, Male α Ejaculation+++ Erection+++ + Generalizedsecretion+++ Spleen Capsule α,β2Contraction+++;relaxation+ — Adrenal Medulla —SecretionofepinephrineandnorepinephrineLiver α,β2Glycogenolysis,gluconeogenesis β2Increasedsecretion+ —Fatcellsα,β1Lipolysis


Physiology_Levy


Physiology_Levy

Physiology_Levy. β receptor activity is controlled in a number of ways. It can be antagonized by the action of α1 receptors. The β receptors can also be desensitized by phosphorylation with prolonged exposure to agonists. Regulation of β receptor numbers represents a third control mechanism. For example, β receptor numbers can be decreased by being internalized. Alternatively, β receptor numbers can be increased (upregulated) in certain circumstances: for example, after denervation. Note that the number of α receptors is likewise regulated. In addition to releasing norepinephrine, sympathetic postganglionic neurons release neuropeptides such as somatostatin and neuropeptide Y. For example, cells that release both norepinephrine and somatostatin supply the mucosa of the gastrointestinal tract, and cells that release both norepinephrine and neuropeptide Y innervate blood vessels in the gut and the limb. Another chemical mediator in sympathetic postganglionic neurons is adenosine triphosphate (ATP).


Physiology_Levy

Physiology_Levy. The endocrine cells of the adrenal medulla are similar in many ways to sympathetic postganglionic neurons (see also ). They receive input from sympathetic preganglionic neurons, are excited by acetylcholine, and release catecholamines. However, the cells of the adrenal medulla differ from sympathetic postganglionic neurons in that they release catecholamines into the circulation rather than into a synapse. Moreover, the main catecholamine released is epinephrine, not norepinephrine. In humans, 80% of the catecholamine released by the adrenal medulla is epinephrine, and 20% is norepinephrine.


Physiology_Levy

Physiology_Levy. Some sympathetic postganglionic neurons release acetylcholine rather than norepinephrine as their neurotransmitter. For example, sympathetic postganglionic neurons that innervate eccrine sweat glands are cholinergic. The acetylcholine receptors involved are muscarinic, and they are therefore blocked by atropine. Similarly, some blood vessels are innervated by cholinergic sympathetic postganglionic neurons. In addition to releasing acetylcholine, the postganglionic neurons that supply the sweat glands also release neuropeptides, including calcitonin gene–related peptide and vasoactive intestinal polypeptide. The neurotransmitter released by parasympathetic postganglionic neurons is acetylcholine. The effects of these neurons on various target organs are listed in


Physiology_Levy

Physiology_Levy. The neurotransmitter released by parasympathetic postganglionic neurons is acetylcholine. The effects of these neurons on various target organs are listed in Table 11.1 . Parasympathetic postganglionic actions are mediated by muscarinic receptors. On the basis of binding studies, the action of selective antagonists, and molecular cloning, five types of muscarinic receptors have been identified (see Chapter 6). Activation of M1 receptors enhances the secretion of gastric acid in the stomach. M2 receptors are the most abundant receptor type in smooth muscle, including smooth muscle in the intestines, uterus, trachea, and bladder. In addition, they are present in autonomic ganglia and in the heart, where they exert negative chronotropic and inotropic actions (see


Physiology_Levy

Physiology_Levy. Chapter 18). M 3 receptors are also present in the smooth muscle of a variety of organs, and although they are less abundant than M2 receptors, normal contractile patterns appear to require an interaction between the two types of receptors. M4 receptors, like M2 receptors, are present in autonomic ganglia and thus play a role in synaptic transmission at these sites. M5 receptors are present in the sphincter muscle of the pupil, in the esophagus, and in the parotid gland, as well as in cerebral blood vessels.


Physiology_Levy

Physiology_Levy. Muscarinic receptors, like adrenergic receptors, have diverse actions. Some of their effects are mediated by specific second messenger systems. For example, cardiac M2 muscarinic receptors may act by way of the inositol triphosphate system, and they may also inhibit adenylyl cyclase and thus cAMP synthesis. Muscarinic receptors also open or close ion channels, particularly K+ or Ca++ channels. This action on ion channels is likely to occur through activation of G proteins. A third action of muscarinic receptors is to relax vascular smooth muscle by an effect on endothelial cells, which produce endothelium-derived relaxing factor (EDRF). EDRF is actually nitric oxide, a gas released when arginine is converted to citrulline by nitric oxide synthase (see ). Nitric oxide relaxes vascular smooth muscle by stimulating guanylate cyclase and thereby increasing levels of cyclic guanosine monophosphate (cGMP), which in turn activates a cGMP-dependent protein kinase (see ). The number of


Physiology_Levy

Physiology_Levy. smooth muscle by stimulating guanylate cyclase and thereby increasing levels of cyclic guanosine monophosphate (cGMP), which in turn activates a cGMP-dependent protein kinase (see ). The number of muscarinic receptors is regulated, and exposure to muscarinic agonists decreases the number of receptors by internalization of the receptors.


Physiology_Levy

Physiology_Levy. Chagas disease istheresultofinfectionbytheparasiteTrypanosoma cruzi.


Physiology_Levy

Physiology_Levy. Central Control of Autonomic Function The discharges of autonomic preganglionic neurons are controlled by pathways that synapse on autonomic preganglionic neurons. The pathways that influence autonomic activity include spinal cord and brainstem reflex pathways, as well as descending control systems originating at higher levels of the nervous system, such as the hypothalamus. Examples of Autonomic Control of Particular Organs The dilator and constrictor muscles of the iris, which are under the control of sympathetic and parasympathetic fibers, respectively, determine the size of the pupil. Activation of sympathetic innervation of the eye, via thoracic white rami and sympathetic trunk ganglia, dilates the pupil, which occurs during emotional excitement and also in response to painful stimulation. The neurotransmitter at the sympathetic postganglionic synapses is norepinephrine, and it acts at α receptors.


Physiology_Levy

Physiology_Levy. The parasympathetic nervous system exerts an action on pupillary size opposite that of the sympathetic nervous system. Whereas the sympathetic system elicits pupillary dilation, the parasympathetic system constricts the pupil. The preganglionic parasympathetic nerves that innervate the pupillary constrictor are in the Edinger-Westphal nucleus, which is in the midbrain, and travel in cranial nerve III, and so damage to this nerve can lead to a dilated pupil (mydriasis).


Physiology_Levy

Physiology_Levy. Pupil size is reduced by the pupillary light reflex and during accommodation for near vision. In the pupillary light reflex, light that strikes the retina is processed by retinal circuits that excite W-type retinal ganglion cells (see Chapter 8). These cells respond to diffuse illumination. The axons of some of the W-type cells project through the optic nerve and tract to the pretectal area, where they synapse in the olivary pretectal nucleus. This nucleus contains neurons that also respond to diffuse illumination. Activity of neurons of the olivary pretectal nucleus causes pupillary constriction by means of bilateral connections with parasympathetic preganglionic neurons in the Edinger-Westphal nuclei. The reflex results in contraction of the pupillary sphincter muscles in both eyes, even when light is shone into only one eye.


Physiology_Levy

Physiology_Levy. The accommodation response, which is important for focusing on near objects, involves pupillary constriction, increasing the curvature of the lens, and convergence of the eyes. This response is triggered by information from M cells of the retina that is transmitted to the striate cortex through the geniculostriate visual pathway (see ). The specific stimuli that trigger accommodation are thought to be a blurred retinal image and disparity of the image between the two eyes. After the information is processed in the visual cortex, signals are transmitted directly or indirectly to the middle temporal cortex, where they activate neurons in a visual area known as MT. Area MT neurons transmit signals to the midbrain that activate parasympathetic preganglionic neurons in the Edinger-Westphal nuclei, which results in pupillary constriction. At the same time, signals are transmitted to the ciliary muscle that cause it to contract. The ciliary muscle contraction allows the lens to round up and


Physiology_Levy

Physiology_Levy. which results in pupillary constriction. At the same time, signals are transmitted to the ciliary muscle that cause it to contract. The ciliary muscle contraction allows the lens to round up and increase its refractile power. (Convergence is a somatic response mediated by neurons in the oculomotor [cranial nerve III] nucleus of the midbrain.)


Physiology_Levy

Physiology_Levy. Thepupillarylightreflexissometimesabsentinpatientswithtertiary(advanced)syphilis,whichaffectstheCNS(i.e.,intheformoftabesdorsalis).Althoughthepupilfailstorespondtolight,ithasanormalaccommodationresponse.ThisconditionisknownastheArgyll Robertson pupil. Theexactmechanismiscontroversial.Oneexplanationrestsonthefactthatsomeoptictractfibersprojecttothepretectalareainthemidbrain.Thesefiberscanbedamagedinsyphiliticmeningitis,possiblybythepresenceofspirochetesinthesubarachnoidspace.NotethatthepretectalareaprojectstotheEdinger-Westphalnucleus,alsointhemidbrain,whosecellsoriginatetheparasympatheticinnervationoftheeye,whichcontrolsthepupillarysphinctermuscle.Althoughinputtotheolivarypretectalnucleusisinterrupted,theoptictractfibersprojectingtothelateralgeniculatenucleusarenotdestroyed,andthusvisionismaintained,asispupillaryconstrictionduringaccommodation. The urinary bladder is controlled by reflex pathways in the spinal cord and also by a supraspinal center (


Physiology_Levy

Physiology_Levy. The urinary bladder is controlled by reflex pathways in the spinal cord and also by a supraspinal center ( Fig. 11.3 ). The sympathetic innervation originates from preganglionic sympathetic neurons in the upper lumbar segments of the spinal cord. Postganglionic sympathetic axons act to inhibit the smooth muscle (detrusor muscle) throughout the body of the bladder, and they also act to excite the smooth muscle of the trigone region and the internal urethral sphincter. •Fig. 11.3 Illustration of Descending and Efferent Pathways for Reflexes That Control the Urinary Bladder. Forclarity,onlysomeofthemajorinvolvedpathwaysareshown.(RedrawnfromdeGroatWC,BoothAM.InDyckPJ,etal[eds].Peripheral Neuropathy. 2nded.Philadelphia:WBSaunders;1984.)


Physiology_Levy

Physiology_Levy. The detrusor muscle is tonically inhibited during filling of the bladder, and such inhibition prevents urine from being voided. Inhibition of the detrusor muscle is mediated by the action of norepinephrine on β receptors, whereas excitation of the trigone and internal urethral sphincter is elicited by the action of norepinephrine on α receptors. The external sphincter of the urethra also helps control voiding. This sphincter is a striated muscle, and it is innervated by motor axons in the pudendal nerves, which are somatic nerves. The motor neurons are located in the Onuf nucleus, in the ventral horn of the sacral spinal cord.


Physiology_Levy

Physiology_Levy. The parasympathetic preganglionic neurons that control the bladder are located in the sacral spinal cord (the S2 and S3 or S3 and S4 segments). These cholinergic neurons project through the pelvic nerves and are distributed to ganglia in the pelvic plexus and the bladder wall. Post-ganglionic parasympathetic neurons in the bladder wall innervate the detrusor muscle, as well as the trigone and sphincter. The parasympathetic activity contracts the detrusor muscle and relaxes the trigone and internal sphincter. These actions result in micturition, or urination. Some of the postganglionic neurons are cholinergic and others are purinergic (they release ATP). Micturition is normally controlled by the micturition reflex (see


Physiology_Levy

Physiology_Levy. Fig. 11.3 ). Mechanoreceptors in the bladder wall are excited by both stretch and contraction of the muscles in the bladder wall. Thus as urine accumulates and distends the bladder, the mechanoreceptor afferents begin to discharge. The pressure in the urinary bladder is low during filling (5 to 10 cm H2O), but it increases abruptly when micturition begins. Micturition can be triggered either reflexively or voluntarily. In reflex micturition, bladder afferent fibers excite neurons that project to the brainstem and activate the micturition center in the rostral pons (Barrington’s nucleus). The descending projections also inhibit sympathetic preganglionic neurons that prevent voiding. When a sufficient level of activity occurs in this ascending pathway, micturition is triggered by the micturition center. Commands reach the sacral spinal cord through a reticulospinal pathway. Activity in the sympathetic projection to the bladder is inhibited, and the parasympathetic projections to the


Physiology_Levy

Physiology_Levy. center. Commands reach the sacral spinal cord through a reticulospinal pathway. Activity in the sympathetic projection to the bladder is inhibited, and the parasympathetic projections to the bladder are activated. Contraction of muscle in the wall of the bladder causes a vigorous discharge of the mechanoreceptors that supply the bladder wall and thereby further activates the supraspinal loop. The result is complete emptying of the bladder.


Physiology_Levy

Physiology_Levy. A spinal reflex pathway also exists for micturition. This pathway is operational in newborn infants. However, with maturation, the supraspinal control pathways take on a dominant role in triggering micturition. After spinal cord injury, human adults lose bladder control during the period of spinal shock (urinary incontinence). As the spinal cord recovers from spinal shock, some degree of bladder function is recovered because of enhancement of the spinal cord micturition reflex. However, the bladder has increased muscle tone and fails to empty completely. These circumstances frequently lead to urinary infections. Autonomic Centers in the Brain


Physiology_Levy

Physiology_Levy. Autonomic Centers in the Brain Influence over autonomic output is maintained by autonomic centers, which consist of local networks of neurons, in a variety of brain regions. The micturition center in the pons, which was just discussed, is one example. Many other autonomic centers with diverse functions exist. Vasomotor and vasodilator centers are in the medulla, and respiratory centers are in the medulla and pons. Perhaps the greatest concentration of autonomic centers is found in the hypothalamus. The Hypothalamus and Preoptic Area The hypothalamus is part of the diencephalon. Some of the nuclei of the hypothalamus are shown in


Physiology_Levy

Physiology_Levy. The Hypothalamus and Preoptic Area The hypothalamus is part of the diencephalon. Some of the nuclei of the hypothalamus are shown in Fig. 11.4 . Located anteriorly from the hypothalamus are telencephalic structures: the preoptic region and septum, both of which help regulate autonomic function. Important fiber tracts that course through the hypothalamus are the fornix, the medial forebrain bundle, and the mammillothalamic tract. The fornix is used as a landmark to divide the hypothalamus into medial and lateral zones.


Physiology_Levy

Physiology_Levy. The hypothalamus has many functions; see for a discussion of hypothalamic control of endocrine function. Its control of autonomic function is emphasized here. In its control of autonomic function, the hypothalamus functions much like a control system that is termed, in •Fig. 11.4 Illustration of Main Nuclei of the Hypothalamus, Viewed From the Third Ventricle. Anterioristotheright.(RedrawnfromNautaWJH,HaymakerW.The Hypothalamus. Springfield,IL:CharlesCThomas;1969.) engineering, a servomechanism: that is, a system in which a particular physiological parameter is controlled through the use of negative feedback loops to maintain the parameter at a particular set point or value. The following examples illustrate this principle for body temperature, body weight and adiposity, and water intake.


Physiology_Levy

Physiology_Levy. Homeothermic animals maintain a relatively constant core body temperature in situations of fluctuating environmental temperatures and differing levels of bodily activity that cause endogenous heat production. This ability rests on information from three main groups of thermoreceptors located in the skin, CNS, and viscera. Information about the external temperature is provided by thermoreceptors in the skin. Core body temperature is monitored by central thermoreceptive neurons in the preoptic area (and possibly the spinal cord), which monitor the temperature of local blood. Thermoreceptors in the viscera monitor the temperature in these organs. All of these receptors provide temperature information to the preoptic area (pathways described later), along with parts of the hypothalamus, in which this information is used to keep core body temperature constant. Thus the preoptic area and hypothalamus act together as a servomechanism with a set point at the normal body temperature.


Physiology_Levy

Physiology_Levy. Although the signals from each of these sources are integrated, their relative importance may shift, depending on the situation. Changes in environmental temperature evoke more rapid and much larger changes in the temperature of the skin than in the body core, and so cutaneous receptors are probably the initial and most often used mechanism for compensating for external changes in temperature. Central thermoreceptors are more important for situations with internal causes of temperature change, such as during exercise, or in which external changes temperature are so severe or prolonged that core body temperature starts to change despite the signals from peripheral thermoreceptors. Last, alteration of body temperature by ingestion of hot or cold food or liquids is detected by the visceral thermoreceptors.


Physiology_Levy

Physiology_Levy. Error signals (i.e., cooling and warming of the body), which represent a deviation from the set point of the servomechanism, evoke responses that tend to restore body temperature toward the set point. These responses are mediated by the autonomic, somatic, and endocrine systems.


Physiology_Levy

Physiology_Levy. Situations involving cooling, for example, trigger a variety of responses that increase heat production (thermogenesis) and minimize heat loss. Heat production is increased by mechanisms that include shivering thermogenesis (asynchronous contractions of skeletal muscle that increases heat production) and brown adipose tissue (BAT) thermogenesis (in BAT thermogenesis, oxidative phosphorylation is uncoupled from ATP synthesis, which allows the energy released by the reaction to be dissipated as heat instead), and increased thyroid hormone levels lead to increased metabolism. Heat loss is reduced by cutaneous vasoconstriction and by piloerection. Piloerection is effective in animals with fur but not in humans; in the latter, the result is only goose bumps. In addition, tachycardia occurs, which may help provide metabolites to be used in thermogenesis to the thermogenic tissues (fat and muscle) and help distribute the heat generated throughout the body. Finally, the perception of being


Physiology_Levy

Physiology_Levy. which may help provide metabolites to be used in thermogenesis to the thermogenic tissues (fat and muscle) and help distribute the heat generated throughout the body. Finally, the perception of being cold influences the decision to initiate voluntary behaviors: in this case, possibly putting on a jacket.


Physiology_Levy

Physiology_Levy. Warming the body generally causes changes in the opposite direction. The activity of the thyroid gland diminishes, which leads to reduced metabolic activity and less heat production. Heat loss is increased by sweating, salivation (in some animals but not humans), and cutaneous vasodilation (because of decreased sympathetic activity). However, again tachycardia occurs, this time presumably to allow optimal perfusion of the cutaneous circulation for heat dissipation.


Physiology_Levy

Physiology_Levy. Early studies identified the preoptic region and anterior hypothalamus as a heat loss center and the posterior hypothalamus as a heat conservation center. For example, lesions in the preoptic region prevent sweating and cutaneous vasodilation, and if an individual with a lesion in this region is placed in a warm environment, hyperthermia occurs. Conversely, electrical stimulation of the heat loss center causes cutaneous vasodilation and inhibits shivering. In contrast, lesions in the area dorsolateral to the mammillary body interfere with heat production and conservation and can cause hypothermia when the person is in a cold environment. Electrical stimulation in this region of the brain evokes shivering.


Physiology_Levy

Physiology_Levy. Many details of the circuitry and physiologic processes underlying the temperature regulation responses are now known, and they indicate that the preoptic area and dorsal medial hypothalamic nucleus are key components in the regulation of body temperature. The preoptic area in particular appears to be the target of the various sources of sensory information. Cutaneous temperature information is conveyed by thermosensitive primary afferents that synapse in the dorsal horn of the spinal cord onto neurons that project up to and excite the parabrachial nucleus in the caudal midbrain. Information from visceral afferents is relayed by the solitary nucleus to the parabrachial nucleus as well. The parabrachial neurons in turn excite neurons within a specific part of the preoptic area, the median nucleus (of the preoptic area). Many median nucleus neurons are also sensitive to local changes in blood temperature and contain prostaglandin E2 (PGE2) receptor 3 (EP3), which mediates fever


Physiology_Levy

Physiology_Levy. median nucleus (of the preoptic area). Many median nucleus neurons are also sensitive to local changes in blood temperature and contain prostaglandin E2 (PGE2) receptor 3 (EP3), which mediates fever responses (see the following “In the Clinic” box).


Physiology_Levy

Physiology_Levy. Thus the median preoptic nucleus is a key component of the thermoregulatory control system in which information from the various types of thermoreceptors is integrated. Output from this nucleus is directed to the neighboring medial preoptic area, which projects to regions of the rostral medulla, both directly and via the dorsal medial hypothalamic nucleus. The rostral medulla has spinally projecting neurons that project to the lateral horn of the spinal cord, where the preganglionic sympathetic neurons are located, and the activity of these neurons regulates BAT thermogenesis and modulates cutaneous vasomotor tone. The rostral medulla also projects to the ventral horn of the spinal cord, which contains the somatic motor neurons that contract skeletal muscle and thus mediate the shivering response.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Regulation of Feeding and Body Weight Energy homeostasis is crucial for the survival of the animal. The challenge is that most cells need a continuous supply of nutrients to function, but most animals do not constantly eat; instead, they have periodic meals. Thus to achieve energy homeostasis, feeding behavior is controlled by many factors, which operate both on a short-term basis to control ingestion and on a long-term basis to control body weight in order to ensure sufficient energy stores. Both hedonic and homeostatic factors are involved; however, in this chapter, the focus is on the latter because of the central role that the hypothalamus plays in energy homeostasis.


Physiology_Levy

Physiology_Levy. In the short run, eating is controlled by a number of mechanisms. First, the stomach wall has stretch receptors that signal distention as food fills the stomach. These signals are conveyed by the afferents of the vagus nerve to the solitary nucleus in the medulla. From there the information is relayed to several brain areas, including the hypothalamus, either directly or via a relay in the parabrachial nucleus, to organize autonomic responses to the ingested material, and the thalamus and cortex, for conscious awareness of the fullness of the stomach. In the hypothalamus, the paraventricular, dorsomedial, and arcuate nuclei and the lateral hypothalamus are the major targets of these signals.


Physiology_Levy

Physiology_Levy. Sensory afferents also sense the concentrations of glucose and lipids in the intestines and the hepatic portal circulation and send this information to the solitary nucleus and, from there, to the hypothalamus, in a manner similar to that described for the stretch receptors. In addition, the stomach and gut release a number of hormones in response to feeding, including cholecystokinin, peptide YY, glucagonlike peptide-1 (GLP-1), and ghrelin. Hypothalamic cells have receptors for many of these hormones and can be influenced directly by them. In addition, cells in other brain areas have receptors for these hormones and thus may provide an indirect pathway to the hypothalamus. One such region is the area postrema, which is just dorsal to the solitary nucleus and projects to it. The area postrema is not protected by the blood-brain barrier (it is one of the circumventricular organs), and its neurons respond to cholecystokinin and GLP-1, which leads to decreased food intake.


Physiology_Levy

Physiology_Levy. Control of body weight over the long run is influenced by many factors and involves the interaction of the nervous and endocrine systems. In this section, the focus is on the role of hypothalamus and its control of the autonomic nervous system, which provides another example of how the hypothalamus is part of a servomechanism. In this case, adiposity is the controlled parameter. For further details on the endocrine system’s role, see


Physiology_Levy

Physiology_Levy. Early studies in which researchers used lesions and electrical stimulation provided evidence that the ventromedial and ventrolateral hypothalamus are involved in energy homeostasis. A lesion in the ventromedial region causes an increase in food intake (hyperphagia) that results in obesity, whereas electrical stimulation of the same region decreases feeding behavior. These lesions were also shown to alter autonomic activity, increasing parasympathetic and decreasing sympathetic tone, both of which lead to high blood insulin levels, which in turn promote energy conservation and storage (see ). These observations led to the idea that the ventromedial hypothalamus contains a satiety center. However, an alternative interpretation is that the primary controlled variable may not be simply eating behavior per se but rather body weight and, even more specifically, body fat levels (i.e., adiposity). Thus modulation of feeding behavior may be just one of several actions used to defend a body


Physiology_Levy

Physiology_Levy. behavior per se but rather body weight and, even more specifically, body fat levels (i.e., adiposity). Thus modulation of feeding behavior may be just one of several actions used to defend a body weight set point. Evidence for this is that although lesions cause an initial period of dynamic weight gain in which hyperphagia is present, this is followed by a static period in which the higher weight is maintained without hyperphagia. Moreover, animals with a lesion in the ventromedial hypothalamus that are fed a fixed (normal) amount of food to prevent hyperphagia nonetheless become obese, which implies changes in the regulation of other metabolic processes. Last, lesions of the ventromedial hypothalamus have been shown to alter levels of energy expenditure.


Physiology_Levy

Physiology_Levy. In contrast to lesions of the ventromedial hypothalamus, those of the lateral hypothalamus suppress food intake (hypophagia) and lead to a decrease in body weight; indeed, animals can starve to death after such lesions. Conversely, electrical stimulation of the medial forebrain bundle in the lateral hypothalamus evokes exploratory behavior and eating, if food is present. This stimulation also provides a dopamine-dependent reward that mediates the incentive effects of natural rewards (food, sex) as well as the rewarding effects of most drugs of abuse. These observations led to the view that the lateral hypothalamus contains a feeding center. This interpretation, however, is complicated by the fact that the dopaminergic axons of substantia nigra neurons pass just lateral to the lateral hypothalamus on their way to the striatum, and so loss or stimulation of these fibers could account for the effects produced in these experiments. However, lateral hypothalamic neurons have been found to


Physiology_Levy

Physiology_Levy. on their way to the striatum, and so loss or stimulation of these fibers could account for the effects produced in these experiments. However, lateral hypothalamic neurons have been found to synthesize peptides, such as orexin, that affect feeding behavior, and so the lateral hypothalamus probably does play a role in energy homeostasis.


Physiology_Levy

Physiology_Levy. In newer studies, investigators have identified a number of hormones and neuropeptides involved in feeding and control of body weight, and many of the interactions between the endocrine and nervous systems that underlie energy homeostasis have been clarified. In normal individuals, blood insulin levels are correlated with adiposity (in addition to varying acutely with blood levels of glucose and other substances). Similarly, the level of the protein leptin, a hormone released by adipocytes (primarily those forming white adipose tissue), is correlated with adiposity. High levels of leptin inhibit food intake and stimulate catabolic processes, including loss of fat tissue, whereas low leptin levels trigger the reverse actions. Similarly, high insulin levels promote energy storage processes.


Physiology_Levy

Physiology_Levy. The ability of leptin and insulin to regulate body weight has been linked to their actions on the hypothalamus, particularly the arcuate nucleus, whose neurons express receptors for both hormones (see also ). Two major classes of arcuate nucleus neurons that respond to leptin and insulin have been identified. Neurons that express proopiomelanocortin (POMC) and cocaine-and amphetamine-related transcript (CART) are stimulated by leptin and insulin, and their activity leads to increased catabolism. In contrast, the activity of a second group of neurons, those that express neuropeptide Y (NPY) and agouti-related peptide (AgRP), triggers anabolic processes but is inhibited by leptin and insulin. Thus increased body fat levels lead to high leptin and insulin levels, which in turn both (1) increase the activity of POMCand CART-expressing neurons, leading to increased catabolism, and (2) decrease the activity of NPYand AgRP-expressing neurons, leading to decreased anabolism; both of which act


Physiology_Levy

Physiology_Levy. the activity of POMCand CART-expressing neurons, leading to increased catabolism, and (2) decrease the activity of NPYand AgRP-expressing neurons, leading to decreased anabolism; both of which act to return body fat levels to their set point. Lowering body fat levels would result in a sequence of events opposite to that just described to increase body fat levels to their original level or set point.


Physiology_Levy

Physiology_Levy. The efferent limb that mediates the actions of these sets of arcuate neurons is not fully worked out. However, the arcuate nucleus projection to the paraventricular hypothalamic nucleus appears to be an important step in the pathway. Paraventricular neurons contain oxytocin. Many of them project to the posterior pituitary gland and are involved in lactation and uterine contractions during labor (see ). However, the paraventricular neurons involved in body weight regulation are a distinct subset of neurons that project down to the brainstem and spinal cord, where they probably synapse with autonomic and preautonomic nuclei that control parasympathetic vagal fibers to the pancreas, which act to stimulate insulin release, and sympathetic fibers, which act to inhibit its release. Regulation of Water Intake Water intake also depends on a servomechanism. Fluid intake is influenced by blood osmolality and volume ( Fig. 11.5


Physiology_Levy

Physiology_Levy. Regulation of Water Intake Water intake also depends on a servomechanism. Fluid intake is influenced by blood osmolality and volume ( Fig. 11.5 With water deprivation, the extracellular fluid becomes hyperosmotic, which in turn causes the intracellular fluid to become hyperosmotic. The brain contains neurons that serve as osmoreceptors for detection of increases in the osmotic pressure of extracellular fluid (see also ). The osmoreceptors appear to be located in the organum


Physiology_Levy

Physiology_Levy. Angiotensin II receptors Angiotensin II receptors Osmotic receptors Blood vessels Drinking circuit, including vasopressin-releasing neurons in the posterior pituitary B •Fig. 11.5 A, Structuresthoughttoplayaroleintheregulationofwaterintakeinrats.LHA,lateralhypothalamicarea.B, Neuralcircuitsthatsignalchangesinbloodosmolalityandvolume.(A, RedrawnfromShepherdGM.Neurobiology. NewYork:OxfordUniversityPress;1983.) vasculosum of the lamina terminalis, which is a circumventricular organ. Circumventricular organs surround the cerebral ventricles and lack a blood-brain barrier. The subfornical organ and the organum vasculosum are involved in thirst.


Physiology_Levy

Physiology_Levy. Water deprivation also causes a decrease in blood volume, which is sensed by receptors in the low-pressure side of the vasculature, including the right atrium of the heart (see also ). In addition, decreased blood volume triggers the release of renin by the kidneys. Renin breaks down angiotensinogen into angiotensin I, which is then hydrolyzed to angiotensin II (see ). This peptide stimulates drinking by an action on angiotensin II receptors in another of the circumventricular organs, the subfornical organ. Angiotensin II also causes vasoconstriction and release of aldosterone and antidiuretic hormone (ADH).


Physiology_Levy

Physiology_Levy. Insufficient water intake is usually a greater problem than excessive water intake. However, when more water is taken in than required, it is easily eliminated by inhibition of the release of ADH from neurons in the supraoptic nucleus at their terminals in the posterior pituitary gland (see ). As mentioned previously, signals that inhibit release of ADH include increased blood volume and decreased osmolality of extracellular fluid. Other areas of the hypothalamus, particularly the preoptic region and lateral hypothalamus, help regulate water intake, as do several structures outside the hypothalamus.


Physiology_Levy

Physiology_Levy. Several regions of the forebrain other than the hypothalamus also play a role in autonomic control. These regions include the central nucleus of the amygdala and the bed nucleus of the stria terminalis, as well as a number of areas of the cerebral cortex. Information reaches these higher autonomic centers from viscera through an ascending system that involves the nucleus of the solitary tract, the parabrachial nucleus, the periaqueductal gray matter, and the hypothalamus. Descending pathways that help control autonomic activity originate in such structures as the paraventricular nucleus of the hypothalamus, noradrenergic cell group A5, the rostral ventrolateral medulla, and the raphe nuclei and adjacent structures of the ventromedial medulla. Neural Influences on the Immune System


Physiology_Levy

Physiology_Levy. Neural Influences on the Immune System Environmentalstresscancauseimmunosuppression,inwhich the number of helper T cells and the activity of natural killer cells are reduced. Immunosuppression can even be the result of classical conditioning. One mechanism for such an effect involves the release of corticotropin-releasing factor from the hypothalamus. Corticotropin-releasing factor causes the release of adrenocorticotropic hormone (ACTH) from the pituitary gland; release of ACTH stimulates the secretion of adrenal corticosteroids, which cause immunosuppression (see ). Other mechanisms include direct neural actions on lymphoid tissue. The immune system may also influence neural activity. 1.


Physiology_Levy

Physiology_Levy. 1. The autonomic nervous system controls smooth muscle, cardiac muscle, and glands. It helps maintain homeostasis and coordinates responses to external stimuli. It has sensory and motor components, and the motor component consists of sympathetic and parasympathetic divisions. The enteric nervous system is often considered as part of the autonomic nervous system but is concerned specifically with control of the gastrointestinal tract. 2.


Physiology_Levy

Physiology_Levy. 2. Autonomic motor pathways have preganglionic and postganglionic neurons. Preganglionic neurons reside in the CNS, whereas postganglionic neurons lie in peripheral ganglia. Sympathetic preganglionic neurons are located in the thoracolumbar region of the spinal cord, and sympathetic postganglionic neurons are located in paravertebral and prevertebral ganglia. Parasympathetic preganglionic neurons are located in cranial nerve nuclei or in the sacral portion of the spinal cord. Parasympathetic postganglionic neurons reside in ganglia located in or near the target organs. 3. Autonomic afferent fibers innervate sensory receptors in the viscera. Most function to activate reflexes; for some, activation also leads to sensations that are experienced consciously. 4.


Physiology_Levy

Physiology_Levy. 3. Autonomic afferent fibers innervate sensory receptors in the viscera. Most function to activate reflexes; for some, activation also leads to sensations that are experienced consciously. 4. The enteric nervous system includes the myenteric and submucosal plexuses in the wall of the gastrointestinal tract. The myenteric plexus regulates motility, and the submucosal plexus regulates ion and water transport and secretion. 5. Neurotransmitters at the synapses of preganglionic neurons in autonomic ganglia include acetylcholine (acting at both nicotinic and muscarinic receptors) and a number of neuropeptides. Interneurons in Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol. 2011;301: R1207-R1228.


Physiology_Levy

Physiology_Levy. Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol. 2011;301: R1207-R1228. the ganglia release catecholamines. Norepinephrine (acting on adrenergic receptors) is the neurotransmitter generally released by sympathetic postganglionic neurons; neuropeptides are also released. Sympathetic postganglionic neurons that supply sweat glands release acetylcholine. Parasympathetic postganglionic neurons release acetylcholine (acting on muscarinic receptors). 6. The pupil is controlled reciprocally by the sympathetic and parasympathetic nervous systems. Sympathetic activity causes pupillary dilation (mydriasis); parasympathetic activity causes pupillary constriction (meiosis). 7.


Physiology_Levy

Physiology_Levy. 7. Emptying of the urinary bladder depends on parasympathetic outflow during the micturition reflex. Sympathetic constriction of the internal sphincter of the urethra prevents voiding. The micturition reflex is triggered by stretch receptors, and it is controlled in normal adults by a micturition center in the pons. 8. The hypothalamus contains many nuclei that have a variety of functions related to regulation of basic bodily functions, including body temperature, body weight, and fluid intake. 9. The goal of hypothalamic function is to maintain homeostasis of critical physiological parameters by acting as a servomechanism. The hypothalamus receives information about specific physiological parameters and uses this information to maintain each of these parameters at a specific set point. It does so via multiple mechanisms. This chapter illustrates how it maintains homeostasis via its control of the autonomic system.


Physiology_Levy

Physiology_Levy. Saper CB, Chou TC, Elmquist JK. The need to feed: homeostatic and hedonic control of eating. Neuron. 2002;36:199-211. Squire L, Berg D. Fundamental Neuroscience. 4th ed. New York: Academic Press; 2012. SECTION 3Muscle JAMES M. WATRAS Upon completion of this chapter, the student should be able to answer the following questions: 1. Describe the organization of skeletal muscle, including the structural features/proteins within the skeletal muscle fiber that link the contractile elements to the extracellular matrix and bone to effect movement. While describing the various linkages, identify congenital conditions that commonly affect particular structures and how they might contribute to a myopathy. 2. Describe the molecular mechanisms by which an action potential in the α motor neuron in the ventral horn of the spinal column can lead to contraction of a skeletal muscle. 3. Describe the mechanisms by which the force of skeletal muscle contraction increases. 4.


Physiology_Levy

Physiology_Levy. 3. Describe the mechanisms by which the force of skeletal muscle contraction increases. 4. Compare skeletal muscle fiber types in terms of recruitment pattern, metabolic characteristics, contractile characteristics, and thus their suitability for various types of activity. 5. Discuss the signaling pathways that contribute to the expression of the slow-twitch muscle phenotype versus the fast-twitch muscle phenotype. 6. Describe general signaling pathways that contribute to hypertrophy or atrophy. 7. Discuss mechanisms underlying the development of muscular fatigue. 8. Describe mechanisms underlying the monosynaptic reflex. 9. Discuss the length-tension curves and force-velocity curves for skeletal muscle, including the molecular bases of both curves.


Physiology_Levy

Physiology_Levy. 8. Describe mechanisms underlying the monosynaptic reflex. 9. Discuss the length-tension curves and force-velocity curves for skeletal muscle, including the molecular bases of both curves. Muscle cells are highly specialized for the conversion of chemical energy to mechanical energy. Specifically, muscle cells use the energy in adenosine triphosphate (ATP) to generate force or do work. Because work can take many forms (such as locomotion, pumping blood, or peristalsis), several types of muscle have evolved. The three basic types of muscle are skeletal muscle, cardiac muscle, and smooth muscle.


Physiology_Levy

Physiology_Levy. Skeletal muscle acts on the skeleton. In limbs, for example, skeletal muscle spans a joint, thereby allowing a lever action. Skeletal muscle is under voluntary control (i.e., controlled by the central nervous system) and plays a key role in numerous activities such as maintenance of posture, locomotion, speech, and respiration. When viewed under the microscope, skeletal muscle exhibits transverse striations (at intervals of 2 to 3 µm) that result from the highly organized arrangement of actin and myosin molecules within the skeletal muscle cells. Thus skeletal muscle is classified as a striated muscle. The heart is composed of cardiac muscle, and although it is also a striated muscle, it is an involuntary muscle (i.e., controlled by an intrinsic pacemaker and modulated by the autonomic nervous system). Smooth muscle (which lacks the striations evident in skeletal and cardiac muscle) is an involuntary muscle typically found lining hollow organs such as the intestine and blood vessels.


Physiology_Levy

Physiology_Levy. system). Smooth muscle (which lacks the striations evident in skeletal and cardiac muscle) is an involuntary muscle typically found lining hollow organs such as the intestine and blood vessels. In all three muscle types, force is generated by the interaction of actin and myosin molecules, a process that requires transient elevation of intracellular [Ca++].


Physiology_Levy

Physiology_Levy. In this chapter, attention is directed at the molecular mechanisms underlying contraction of skeletal muscle. Mechanisms for regulating the force of contraction are also addressed. To put this information into perspective, it is important to first examine the basic organization of skeletal muscle. Organization of Skeletal Muscle


Physiology_Levy

Physiology_Levy. Organization of Skeletal Muscle Fig. 12.1 illustrates skeletal muscles spanning the elbow joint. The muscles are attached to bone on either side of the joint. The point of attachment closest to the spine (proximal) is called the origin, whereas the point of attachment on the far side of the joint (distal) is called the insertion. These points of attachment occur through tendons (connective tissue) at the end of the muscle. Note that the point of insertion is close to the elbow joint, which enables a broad range of motion. Also note that the joint is spanned by a flexor muscle on one side and an extensor muscle on the opposite side of the joint. Thus contraction of the flexor muscle (see the biceps muscle in Fig. 12.1 ) results in a decrease in the angle of the elbow joint (bringing the forearm closer to the shoulder), whereas contraction of the extensor muscle (see the triceps muscle in Fig. 12.1 ) results in the reverse motion (extending the arm).


Physiology_Levy

Physiology_Levy. Fig. 12.1 ) results in the reverse motion (extending the arm). The basic structure of skeletal muscle is shown in Fig. 12.2 . Each muscle is composed of numerous cells called • Fig. 12.1. Skeletal Muscle Attaches to the Skeleton by Way of Tendons and Typically Spans a Joint. The proximal and distal points of attachment of the tendon are termed origin and insertion, respectively. Note that the insertion is close to the joint, which allows a broad range of motion. Also note that skeletal muscles span both sides of the joint, which allows both flexion and extension of the forearm.


Physiology_Levy

Physiology_Levy. • Fig. 12.2. Skeletal muscle is composed of bundles of muscle fibers; each such bundle is called a fasciculus. A muscle fiber represents an individual muscle cell and contains bundles of myofibrils. The striations are due to the arrangement of thick and thin filaments. See text for details. (Redrawn from Bloom W, Fawcett DW. A Textbook of Histology. 10th ed. Philadelphia: Saunders; 1975.) muscle fibers. A connective tissue layer called the endomysium surrounds each of these fibers. Individual muscle fibers are then grouped together into fascicles, which are surrounded by another connective tissue layer called the perimysium. Within the perimysium are the blood vessels and nerves that supply the individual muscle fibers. The fascicles are joined together to form the muscle. The connective tissue sheath that surrounds the muscle is called the epimysium. At the ends of the muscle, the connective tissue layers come together to form a tendon, which attaches the muscle to the skeleton. The


Physiology_Levy

Physiology_Levy. tissue sheath that surrounds the muscle is called the epimysium. At the ends of the muscle, the connective tissue layers come together to form a tendon, which attaches the muscle to the skeleton. The myotendinous junction is a specialized region of the tendon where the ends of the muscle fibers interdigitate with the tendon for the transmission of the force of contraction of the muscle to the tendon to effect movement of the skeleton (discussed later in this section). The tendon and the connective tissue layers are composed mainly of elastin and collagen fibers, and thus they also contribute to passive tension of muscle and prevent damage to the muscle fibers as a result of overstretching or contraction.


Physiology_Levy

Physiology_Levy. Individual skeletal muscle cells are narrow (≈10 to 80 µm in diameter), but they can be extremely long (up to 25 cm in length). Each skeletal muscle fiber contains bundles of filaments, called myofibrils, running along the axis of the cell. The gross striation pattern of the cell results from a repeating pattern in the myofibrils. Specifically, it is the regular arrangement of the thick and thin filaments within these myofibrils, coupled with the highly organized alignment of adjacent myofibrils, that gives rise to the striated appearance of skeletal muscle. Striations can be observed in intact muscle fibers and in the underlying myofibrils.


Physiology_Levy

Physiology_Levy. Fig. 12.3 ). The sarcomere is demarcated by two dark lines called Z lines and represents a repeating contractile unit in skeletal muscle. The average length of a sarcomere is 2 µm. On either side of the Z line is a light band (I band) that contains thin filaments composed primarily of the protein actin. The area between two I bands within a sarcomere is the A band, which contains thick filaments composed primarily of the protein myosin. The thin actin filaments extend from the Z line toward the center of the sarcomere and overlap a portion of the thick filaments. The dark area at the end of the A band represents this region of overlap between thick and thin filaments. A light area in the center of the sarcomere is called the H band. This area represents the portion of the A band that contains myosin thick filaments but no thin actin filaments. Thus thin actin filaments extend from the Z line to the edge of the H band and overlap a portion of the thick filament in the A band. A dark


Physiology_Levy

Physiology_Levy. myosin thick filaments but no thin actin filaments. Thus thin actin filaments extend from the Z line to the edge of the H band and overlap a portion of the thick filament in the A band. A dark line called the M line is evident in the center of the sarcomere and includes proteins that appear to be critical for organization and alignment of the thick filaments in the sarcomere.


Physiology_Levy

Physiology_Levy. Fig. 12.3, each myofibril in a muscle fiber is surrounded by sarcoplasmic reticulum (SR). The SR is an intracellular membrane network that plays a critical •Fig. 12.3. A, Myofibrilsarearrangedinparallelwithinamusclefiber.B, Eachfibrilissurroundedbysarcoplasmicreticulum(SR).TerminalcisternaeoftheSRarecloselyassociatedwithTtubulesandformatriadatthejunctionoftheIandAbands.TheZlinesdefinetheboundaryofthesarcomere.Thestriationsareformedbyoverlapofthecontractileproteins.Threebandscanbeobserved:theAband,Iband,andHband.AnMlineisvisibleinthemiddleoftheHband.C, Organizationoftheproteinswithinasinglesarcomere.Thecross-sectionalarrangementoftheproteinsisalsoillustrated.


Physiology_Levy

Physiology_Levy. role in the regulation of intracellular [Ca++]. Invaginations of the sarcolemma, called T tubules, pass into the muscle fiber near the ends of the A band (i.e., close to the SR). The SR and the T tubules, however, are distinct membrane systems: The SR is an intracellular network, whereas the T tubules are in contact with the extracellular space. A gap (≈15 nm in width) separates the T tubules from the SR. The portion of the SR nearest the T tubules is called the terminal cisternae, and it is the site of Ca++ release, which is critical for contraction of skeletal muscle (see the section “ ”). The longitudinal portions of the SR are continuous with the terminal cisternae and extend along the length of the sarcomere. This portion of the SR contains a high density of Ca++ pump protein (i.e., SERCA: Sarcoplasmic Endoplasmic Reticulum Ca++-ATPase), which is critical for reaccumulation of Ca++ in the SR and hence for relaxation of the muscle.


Physiology_Levy

Physiology_Levy. The thick and thin filaments are highly organized in the sarcomere of myofibrils (see Fig. 12.3 ). As mentioned, thin actin filaments extend from the Z line toward the center of the sarcomere, whereas thick myosin filaments are centrally located and overlap a portion of the opposing thin actin filaments. The thick and thin filaments are oriented in such a way that in the region of overlap within the sarcomere, each thick myosin filament is surrounded by a hexagonal array of thin actin filaments. The Ca++-dependent interaction of the thick myosin filaments and the thin actin filaments generate the force of contraction after stimulation of the muscle (see the section “Actin-Myosin Interaction:


Physiology_Levy

Physiology_Levy. The thin filament is formed by aggregation of actin molecules (termed globular actin or G-actin) into a two-stranded helical filament called filamentous actin or F-actin. The elongated cytoskeletal protein nebulin extends along the length of the thin filament and may participate in regulation of the length of the thin filament. Dimers of the protein tropomyosin extend over the entire actin filament and cover myosin binding sites on the actin molecules. Each tropomyosin dimer extends across seven actin molecules, with sequential tropomyosin dimers arranged in a head-to-tail configuration. A troponin complex consisting of three subunits (troponin T, troponin I, and troponin C) is present on each tropomyosin dimer and influences the position of the tropomyosin molecule on the actin filament and hence the ability of tropomyosin to inhibit binding of myosin to the actin filament at low cytosolic Ca concentrations (see the section “Actin-Myosin Interaction: Cross-Bridge Formation”).


Physiology_Levy

Physiology_Levy. Cross-Bridge Formation”). Binding of cytosolic Ca++ to troponin C promotes the movement of tropomyosin on the actin filament that exposes myosin binding sites on actin, thereby facilitating actin-myosin interaction, and hence contraction (see the section “Actin-Myosin Interaction: ”). Additional proteins associated with the thin filament include tropomodulin, α-actinin, and CapZ protein. Tropomodulin is located at the end of the thin filament, toward the center of the sarcomere, and may participate in setting the length of the thin filament.


Physiology_Levy

• Fig.

Physiology_Levy. • Fig.


Physiology_Levy

Physiology_Levy. 12.4. The force of contraction of the muscle fiber is transmitted both longitudinally to the tendon (at the myotendinous junction) and laterally to adjacent extracellular connective tissue (at costameres). The force of contraction is transmitted from the end of the muscle fiber (M) to the tendon by connections with numerous collagen fibers (A, tip of arrow). Folds in the sarcolemma at the end of the muscle fiber (B) result in an interdigitation of the muscle fiber with the tendon, and represents the myotendinous junction. Costameres are located on the sides of the muscle fibers, and represent the bridges between the Z lines in the subsarcolemmal myofibrils and the extracellular connective tissue (C). Costameres facilitate the lateral transmission of force of contraction, which helps stabilize the sarcolemma. DGC, dystrophinassociated glycoprotein complex. (A and B, From Tidball JG. Myotendinous junction: morphological changes and mechanical failure associated with muscle cell atrophy.


Physiology_Levy

Physiology_Levy. lize the sarcolemma. DGC, dystrophinassociated glycoprotein complex. (A and B, From Tidball JG. Myotendinous junction: morphological changes and mechanical failure associated with muscle cell atrophy. Exp


Physiology_Levy

Physiology_Levy. Molec Pathol. 1984;40:1-12. C, From Hughes D, Wallace M, Baar K. Effects of aging, exercise, and disease on force transfer in skeletal muscle. Am J Physiol Endocrin Metab. 2015;309:E1-E10.)


Physiology_Levy

Physiology_Levy. CapZ protein and α-actinin serve to anchor the thin fila-of sarcomeres across muscles and the lateral transmission of ment to the Z line. force (described later in this section). The thick myosin filaments are tethered to the Z lines by The force of contraction is transmitted both longitua cytoskeletal protein called titin. Titin is a very large, elastic dinally to the tendon (via myotendinous junctions) and protein (molecular weight, >3000 kDa) that extends from laterally to connective tissue adjacent to the muscle fibers the Z line to the center of the sarcomere and appears to be (via costameres). The myotendinous junction represents a important for organization and alignment of the thick fila-specialized region where the muscle fiber connects to the ments in the sarcomere. Some forms of muscular dystrophy tendon ( Fig. 12.4A and B).


Physiology_Levy

Physiology_Levy. Fig. 12.4A and B). Folding of the sarcolemma have been attributed to defects in titin (i.e., titinopathies). at the myotendinous junction results in an interdigitation


Physiology_Levy

Physiology_Levy. The cytoskeleton (including the intermediate filament of the tendon with the end of the muscle fiber, which protein desmin) participates in the highly organized align-increases the contact area between the muscle fiber and ment of sarcomeres. Desmin extends from the Z lines of the connective tissue and hence reduces the force per adjacent sarcomeres to the integrin protein complexes on unit area at the end of the muscle fiber. Some forms of the sarcolemma and thus participates in both the alignment muscular dystrophy are associated with decreased folding at the myotendinous junction. Proteins involved in longitudinal transmission of force at the myotendinous junction include the talin-vinculin-integrin protein complexes and the dystrophin-glycoprotein complexes. The myotendinous junction also contains Z disk proteins that have been implicated in signaling.


Physiology_Levy

Physiology_Levy. Lateral transmission of the force of contraction involves costameres, which link the Z lines of subsarcolemmal sarcomeres to extracellular matrix through a series of proteins (see Fig. 12.4C ). This is particularly important for muscle fibers that do not extend the entire length of the muscle. The lateral transmission of force is also thought to stabilize the sarcolemma and to protect it from damage during contraction. The myotendinous junction and the costameres also contain signaling molecules.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Althoughdefectsinthedystrophin-glycoproteincomplexareinvolvedinmanyformsofmusculardystrophy,someformsofmusculardystrophythatinvolveothermechanismshavebeenidentified.Specifically,adefectinsarcolemmarepair(attributedtoloss/mutationoftheproteindysferlin)appearstounderlieatleastoneformofmusculardystrophy(limb-girdle muscular dystrophy 2B, associatedwithmusclewastinginthepelvicregion).Defectsintheproteintitin(titinopathies)havebeenimplicatedinotherformsofmusculardystrophy(e.g.,limb-girdle muscular dystrophy 2J andtibial muscular dystrophy).Mutationsintheproteasecalpain 3 (resultinginlossofproteaseactivity)havealsobeenimplicatedinsometypesofmusculardystrophy(e.g.,limb-girdlemusculardystrophy2A),apparentlysecondarytoapoptosis. Organization of the thick filament is shown in


Physiology_Levy

Physiology_Levy. Fig. 12.6 . Myosin is a large protein (≈480 kDa) that consists of six different polypeptides with one pair of large heavy chains (≈200 kDa) and two pairs of light chains (≈20 kDa). The heavy chains are wound together in an α-helical configuration to form a long rod-like segment, and the N-terminal portions of each heavy chain form a large globular head. The head region extends away from the thick filament toward the actin thin filament and is the portion of the molecule that can bind to actin. Myosin is also able to hydrolyze ATP, and ATPase activity is located in the globular head as well. Two pairs of light chains are associated with the globular head. One of these pairs of light chains, termed essential light chains, is crucial for the ATPase activity of myosin. The other pair of light chains, called regulatory light chains, can be phosphorylated by Ca++/calmodulin-dependent myosin light chain protein kinase, which can influence the interaction of myosin with actin (see the section


Physiology_Levy

Physiology_Levy. chains, called regulatory light chains, can be phosphorylated by Ca++/calmodulin-dependent myosin light chain protein kinase, which can influence the interaction of myosin with actin (see the section “


Physiology_Levy

Physiology_Levy. Skeletal Muscle Types”). Thus myosin ATPase activity occurs in the globular head of myosin and requires the presence of light chains (namely, the “essential” light chains).


Physiology_Levy

Physiology_Levy. Myosin filaments form by a tail-to-tail association of myosin molecules, which results in a bipolar arrangement of the thick filament. The thick filament then extends on either side of the central bare zone by a head-to-tail association of myosin molecules, thus maintaining the filament’s bipolar organization centered on the M line. Such a bipolar arrangement is critical for drawing the Z lines together (i.e., shortening the length of the sarcomere) during contraction. The mechanisms controlling this highly organized structure of the myosin thick filament are not clear, although the cytoskeletal protein titin is thought to participate in the formation of a scaffold for organization and alignment of the thick filament in the sarcomere. Additional proteins found in the thick filaments (e.g., myomesin and C protein) may also participate in the bipolar organization or packing of the thick filament (or both). Control of Skeletal Muscle Activity


Physiology_Levy

Physiology_Levy. Control of Skeletal Muscle Activity Skeletal muscle is controlled by the central nervous system. Specifically, each skeletal muscle is innervated by an α motor neuron. The cell bodies of α motor neurons are located in the ventral horn of the spinal cord ( Fig. 12.7 ). The motor axons exit via the ventral roots and reach the muscle through mixed peripheral nerves. The motor nerves branch in the muscle, and each branch innervates a single muscle fiber. The specialized cholinergic synapse that forms the neuromuscular junction and the neuromuscular transmission process that generates an action potential in the muscle fiber are described in A motor unit consists of the motor nerve and all the muscle fibers innervated by the nerve. The motor unit is the functional contractile unit because all the muscle cells within a motor unit contract synchronously when the motor nerve fires. The size of motor units within a muscle varies, depending on the function of the muscle.


Physiology_Levy

Physiology_Levy. 12.5. A, Organization of the dystrophin-glycoprotein complex in skeletal muscle. The dystrophinglycoprotein complex provides a structural link between the cytoskeleton of the muscle cell and the extracellular matrix, which appears to stabilize the sarcolemma and hence prevents contraction-induced injury (rupture). Duchenne’s muscular dystrophy is associated with loss of dystrophin. Numbers in dystrophin indicate hinge regions (e.g., H1, H2) and spectrin-like repeat domains (e.g., 4, 8, 12). ABD, actin-binding domain; C, carboxy terminus; CC, coiled-coil domain; DBD, dystroglycan-binding domain; N, amino terminus; nNOSµ, neuronal nitric oxide synthase µ; SBS, syntrophin-binding site; SSPN, sarcospan; Syn, syntrophin. Electron micrographs of a longitudinal view (B) and a cross-sectional view (C) show the distribution of dystrophin in skeletal muscle of a normal patient (CTRL). Another cross-sectional view (D) shows the loss of dystrophin from skeletal muscle in a patient with Duchenne’s


Physiology_Levy

Physiology_Levy. w (C) show the distribution of dystrophin in skeletal muscle of a normal patient (CTRL). Another cross-sectional view (D) shows the loss of dystrophin from skeletal muscle in a patient with Duchenne’s muscular dystrophy (DMD). (A, From Allen D, Whitehead N, Froehner S. Absence of dystrophin disrupts skeletal muscle signaling: roles of Ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy. Physiol


Physiology_Levy

Physiology_Levy. Rev. 2016;96:253-305. B, From Anastasi G, et al. Costameric proteins in human skeletal muscle during muscular inactivity. J Anat. 2008;213:284-295. C and D, From Beekman C, et al. A sensitive, reproducible and objective immunofluorescence analysis method of dystrophin in individual fibers in samples from patients with Duchenne muscular dystrophy. PLoS One. 2014;9[9]:e107494.)


Physiology_Levy

Physiology_Levy. Activation of motor units with a small number of fibers cardiac muscle, in contrast, is approximately 200 msec. facilitates fine motor control. Activation of varying numbers The short duration of the skeletal muscle action potential of motor units within a muscle is one way in which the allows very rapid contractions of the fiber and provides tension developed by a muscle can be controlled (see yet another mechanism by which the force of contrac“Recruitment” in the section “Modulation of the Force of tion can be increased. Increasing tension by repetitive ”). stimulation of the muscle is called tetany (see the section The neuromuscular junction formed by the α motor “


Physiology_Levy

Physiology_Levy. The neuromuscular junction formed by the α motor “ Modulation of the Force of Contraction ”). neuron is called an end plate (see for details). Acetylcholine released from the α motor neuron at the neuromuscular junction initiates an action potential in the muscle fiber that rapidly spreads along its length. When an action potential is transmitted along the sarco-The duration of the action potential in skeletal muscle is lemma of the muscle fiber and then down the T tubules, less than 5 msec. The duration of the action potential in Ca++ is released from the terminal cisternae SR into the


Physiology_Levy

Physiology_Levy. Globular heads (S-1) with light chains Proteolytic cleavage • Fig. 12.6. Organization of a Thick Filament. A thick filament is formed by the polymerization of myosin molecules in a tail-to-tail configuration extending from the center of the sarcomere (A). An individual myosin molecule has a tail region and a cross-bridge region. The cross-bridge region is composed of an arm and globular heads (B). The globular heads contain light chains that are important for the function of myosin ATPase activity. LMM, light meromyosin; S-1 and S-2, myosin subfragments 1 and 2. myoplasm. This release causes intracellular [Ca++] to rise, which in turn promotes actin-myosin interaction and contraction. The time course for the increase in intracellular [Ca++] in relation to the action potential and development of force is shown in


Physiology_Levy

Physiology_Levy. Fig. 12.8 . The action potential is extremely short-lived (≈5 msec). The elevation in intracellular [Ca++] begins slightly after the action potential and peaks at approximately 20 msec. This increase in intracellular [Ca++] initiates a contraction called a twitch. The mechanism underlying the elevation in intracellular [Ca++] involves an interaction between protein in the T tubule and the adjacent terminal cisternae of the SR. As previously described (see Fig. 12.3 ), the T tubule represents an invagination of the sarcolemma that extends into the muscle fiber and forms a close association with two terminal cisternae of the SR. The association of a T tubule with two opposing terminal cisternae is called a triad. Although there is a gap (≈15 nm in width) between the T tubule and the terminal cisternae, proteins bridge this gap. On the basis of their appearance on electron micrographs, these bridging proteins are called feet (


Physiology_Levy

Physiology_Levy. Fig. 12.9 ). These feet are the Ca++ release channels in the membrane of the terminal cisternae that are responsible for the elevation in intracellular [Ca++] in response to the action potential. Because this channel binds the drug ryanodine, it is commonly called the ryanodine receptor (RYR). RYR is a large protein (≈500 kDa) that exists as a homotetramer. Only a small portion of the RYR molecule is actually embedded in the SR membrane. Most of the RYR molecule appears to be in the myoplasm and spans the gap between the terminal cisternae and the T tubule ( Fig. 12.10


Physiology_Levy

Physiology_Levy. Fig. 12.10 At the T tubule membrane, the RYR is thought to interact with a protein called the dihydropyridine receptor (DHPR). DHPR is an L-type voltage-gated Ca++ channel with five subunits. One of these subunits binds the dihydropyridine class of channel-blocking drugs and appears to be crucial for the ability of the action potential in the T tubule to induce release of Ca++ from the SR. However, influx of Ca++ into the cell through the DHPR is not needed for the initiation of Ca++ release from the SR. In fact, skeletal muscle is able to contract in the absence of extracellular Ca++ or with a mutated DHPR that does not conduct Ca++ . Instead, release of Ca++ from the terminal cisternae of the SR is thought to result from a conformational change in the DHPR as the action potential passes down the T tubule, and this conformational change in the DHPR, by means of a protein-protein interaction, opens the RYR and releases Ca++ into the myoplasm.


Physiology_Levy

Physiology_Levy. Structural analysis, including the use of freeze-fracture techniques, provides evidence for a close physical association of DHPR and RYR (see Fig. 12.9 ). DHPR in the T tubule membrane appears to reside directly opposite the four corners of the underlying homotetrameric RYR channel in the SR membrane. Studies have shown that the SH3-cysteine rich domain 3 protein Stac3 is also critical for coupling of the DHPR to the RYR during excitation-contraction coupling in skeletal muscle SR. Stac3 is not present in cardiac muscle, which relies on Ca++ influx through the sarcolemma to initiate Ca++ release from the RYR instead of the direct coupling of the DHPR and the RYR in skeletal muscle. Other proteins that reside near the RYR include calsequestrin, triadin, and junctin (see


Physiology_Levy

Physiology_Levy. Fig. 12.10 ). Calsequestrin is a low-affinity Ca++-binding protein that is present in the lumen of the terminal cisternae. It allows Ca++ to be “stored” at high concentration and thereby establishes a favorable concentration gradient that facilitates the efflux of Ca++ from the SR into the myoplasm when the RYR opens. Triadin and junctin are in the terminal cisternae membrane and bind both RYR and calsequestrin; they could anchor calsequestrin near the RYR and thereby increase Ca++ buffering capacity at the site of Ca++ release. Histidine-rich calcium-binding protein is another low-affinity Ca++-binding protein in the SR lumen, although it is less abundant than calsequestrin. It appears to bind triadin in a Ca++-dependent manner, which raises the possibility that it has a role more important than serving simply as a Ca++ buffer. There is also evidence for the presence of store-operated Ca entry (SOCE) in skeletal muscle (e.g., via the Orai/Stim1 complex) during tetany. Inhibition of


Physiology_Levy

Physiology_Levy. than serving simply as a Ca++ buffer. There is also evidence for the presence of store-operated Ca entry (SOCE) in skeletal muscle (e.g., via the Orai/Stim1 complex) during tetany. Inhibition of Ca influx did not affect excitation-contraction coupling but did reduce maximal tetanic tension at high rates of electrical stimulation, which suggests that there may be some extrusion of intracellular Ca during tetany, which is compensated by Ca influx to maintain maximal tetanic tension.


Physiology_Levy

Physiology_Levy. •Fig. 12.7. Skeletal Muscle Is Voluntary Muscle Controlled by the Central Nervous System, With Efferent Signals (i.e., action potentials) Passing Through an α Motor Neuron to Muscle Fibers. Eachmotorneuronmayinnervatemanymusclefiberswithinamuscle,althougheachmusclefiberisinnervatedbyonlyonemotorneuron(A). Ascanningelectronmicrograph(B) showsinnervationofseveralmusclefibersbyasinglemotorneuron.(B, FromBloomW,FawcettDW:A Textbook of Physiology. 12thed.NewYork:Chapman&Hall;1994.) AvarietyofmutationalstudieshavebeenconductedtoascertaintheregionoftheDHPRthatiscriticalforopeningoftheRYR.Onepossiblesiteofinteraction(depictedin


Physiology_Levy


Physiology_Levy

Physiology_Levy. a. Action potential potential Sarcolemma b. Myoplasmic [Ca++] c. Twitch force Calsequestrin Terminal cisternae of SRRYR Actin-myosin interaction DHPR T tubule Ca++ Ca++ SERCA ATP ADP + Pi 0 8040 120 160 200 •Fig. 12.8. A, StimulationofaskeletalmusclefiberinitiatesanactionpotentialinthemusclethattravelsdowntheTtubuleandinducesreleaseofCa++ fromtheterminalcisternaeofthesarcoplasmicreticulum(SR).Theriseinintracellular[Ca++]causesacontraction.AsCa++ ispumpedbackintotheSRbysarcoplasmicendoplasmicreticulumCa++-ATPase(SERCA),relaxationoccurs.DHPR,dihydropyridinereceptor;Pi,inorganicphosphate;RYR,ryanodinereceptor.B, Timecoursesoftheactionpotential,myoplasmicCa++ transient,andforceofthetwitchcontraction.


Physiology_Levy

Physiology_Levy. Terminal T tubule RYR DHPR cisternae of SR •Fig. 12.9. A, Electronmicrographofatriadillustratingthe“feet”(arrows) betweentheTtubuleandthesarcoplasmicreticulum(SR),whicharethoughttobetheryanodinereceptors(RYRs)intheSR.B, EachRYRintheSRisassociatedwithfourdihydropyridinereceptors(DHPRs)intheTtubule.(FromProtasiF,etal.RYR1andRYR3havedifferentrolesintheassemblyofcalciumreleaseunitsofskeletalmuscle.Biophys J. 2000;79:2494.)


Physiology_Levy

Physiology_Levy. Relaxation of skeletal muscle occurs as intracellular Ca++ is resequestered by the SR. Uptake of Ca++ into the SR is due to the action of a Ca++ pump (i.e., Ca++-ATPase). This pump is not unique to skeletal muscle; it is found in all cells in association with the endoplasmic reticulum. Accordingly, it is named SERCA, which stands for sarcoplasmic endoplasmic reticulum calcium ATPase. SERCA is the most abundant protein in the SR of skeletal muscle, and it is distributed throughout the longitudinal tubules and the terminal cisternae as well. It transports two molecules of Ca++ into its lumen for each molecule of ATP hydrolyzed. Thus the Ca++ transient seen during a twitch contraction (see


Physiology_Levy

Physiology_Levy. Thus the Ca++ transient seen during a twitch contraction (see Fig. 12.8 ) reflects release of Ca++ from the terminal cisternae via the RYR and reuptake primarily into the longitudinal portion of the SR by SERCA. The low-affinity Ca++-binding protein sarcalumenin is present throughout the longitudinal tubules of the SR and nonjunctional regions of the terminal cisternae and is thought to be involved in the transfer of Ca++ from sites of Ca++ uptake in the longitudinal tubules to sites of Ca++ release in the terminal cisternae. Results of studies suggest that sarcalumenin increases Ca++ uptake by SERCA, at least in part by buffering luminal Ca++ near the pump. The endogenous micropeptides phospholamban, sarcolipin, and myoregulin have been shown to regulate the activity of SERCA by decreasing the Ca sensitivity of Ca uptake (


Physiology_Levy

Physiology_Levy. Ca++ near the pump. The endogenous micropeptides phospholamban, sarcolipin, and myoregulin have been shown to regulate the activity of SERCA by decreasing the Ca sensitivity of Ca uptake ( Fig. 12.11 ). Protein kinase A–dependent phosphorylation of phospholamban in slow-twitch skeletal muscle has been reported to increase Ca transport in the SR, similar to the effect of phospholamban phosphorylation in the heart. Phospholamban and sarcolipin are present in slow-twitch muscle, whereas myoregulin is present in both fastand slow-twitch muscle. *During the transport of Ca++ , SERCA exchanges two Ca++ ions for two H+ ions (i.e., H+ is pumped out of the SR).


Physiology_Levy

Physiology_Levy. *During the transport of Ca++ , SERCA exchanges two Ca++ ions for two H+ ions (i.e., H+ is pumped out of the SR). •Fig. 12.10. Molecular Structure and Relationships Between the Dihydropyridine Receptor (DHPR) in the T Tubule Membrane and the Ryanodine Receptor (RYR) in the Sarcoplasmic Reticulum (SR) Membrane. TriadinisanassociatedSRproteinthatmayparticipateintheinteractionofRYRandDHPR.Calsequestrinisalow-affinityCa++-bindingproteinthathelpsaccumulateCa++ intheterminalcisternae.Seetextfordetails.COOH,carboxylicacid.(FromRossiAE,DirksenRT.Sarcoplasmicreticulum:thedynamiccalciumgovernorofmuscle.Muscle Nerve. 2006;33:715.) movement of the associated tropomyosin molecule toward


Physiology_Levy

Physiology_Levy. Actin-Myosin Interaction: the cleft of the actin filament. This movement of tropo myosin exposes myosin binding sites on the actin filament As noted, contraction of skeletal muscle requires an increase and allows a cross-bridge to form and thereby generate in intracellular [Ca++]. Moreover, the process of contraction tension (see section “ Cross-Bridge Cycling: Sarcomere is regulated by the thin filament. As shown in


Physiology_Levy

Physiology_Levy. Fig. 12.12 ”). Troponin C has four Ca++ binding sites. Two contractile force (i.e., tension) increases in a sigmoidal of these sites have high affinity for Ca++ but also bind manner as intracellular [Ca++] is elevated above 0.1 µM, Mg++ at rest. These sites seem to be involved in control-with half-maximal force occurring at less than 1 µM Ca++ . ling and enhancing the interaction between the troponin The mechanism by which Ca++ promotes this increase in I and troponin T subunits. The other two binding sites tension is as follows: Ca++ released from the SR binds to have lower affinity and bind Ca++ as its concentration rises troponin C. Once bound with Ca++ , troponin C facilitates after release from the SR. Binding of myosin to the actin • Fig.


Physiology_Levy

Physiology_Levy. the SR binds to have lower affinity and bind Ca++ as its concentration rises troponin C. Once bound with Ca++ , troponin C facilitates after release from the SR. Binding of myosin to the actin • Fig. 12.11. Identification of three endogenous micropeptides that inhibit sarcoplasmic endoplasmic reticulum Ca++-ATPase (SERCA; A), and their predicted organization in the SR membrane (B). MLN, myoregulin; PLN, phospholamban; SCL, sarcolamban; SLN, sarcolipin. (Modified from Anderson DM, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160:595-606.) 0 0.01 0.1 1 10 100 • Fig. 12.12. The contractile force of skeletal muscle increases in a Ca++-dependent manner as a result of binding of Ca++ to troponin C and the subsequent movement of tropomyosin away from myosin binding sites on the underlying actin molecules. See text for details. (Redrawn from Hartshorne DJ. In Lapedes DN. ed. Yearbook of Science and


Physiology_Levy

Physiology_Levy. of Science and Technology. New York: McGraw-Hill; 1976.) filaments appears to cause a further shift in tropomyosin. Although a given tropomyosin molecule extends over seven actin molecules, it is hypothesized that the strong binding of myosin to actin results in movement of an adjacent tropomyosin molecule, perhaps exposing myosin binding sites on as many as 14 actin molecules. This ability of one tropomyosin molecule to influence the movement of another may be a consequence of the close proximity of adjacent tropomyosin molecules.


Physiology_Levy

Physiology_Levy. Cross-Bridge Cycling: Sarcomere Shortening Once myosin and actin are bound, ATP-dependent conformational changes in the myosin molecule result in movement of the actin filaments toward the center of the sarcomere. Such movement shortens the length of the sarcomere and thereby contracts the muscle fiber. The mechanism by which myosin produces force and shortens the sarcomere is thought to involve four basic steps that are collectively termed the cross-bridge cycle (labeled a to d in Fig. 12.13 ). In the resting state, myosin is thought to have partially hydrolyzed ATP (state a). When Ca++ is released from the terminal cisternae of the SR, it binds to troponin C, which in turn promotes movement of tropomyosin on the actin filament in such a way that myosin-binding sites on actin are exposed. This then allows the “energized”


Physiology_Levy

Physiology_Levy. Brody’sdiseaseischaracterizedbypainlessmusclecrampingandimpairedmusclerelaxationduringexercise.Whileanaffectedpersonrunsupstairs,forexample,musclesmaystiffenandtemporarilycannotbeused.Thisrelaxation myosin head to bind to the underlying actin (state b). Myosin next undergoes a conformational change termed “ratchet action” that pulls the actin filament toward the center of the sarcomere (state c). Myosin releases adenosine diphosphate (ADP) and inorganic phosphate during the transition to state c. Binding of ATP to myosin decreases the affinity of myosin for actin, thereby resulting in the release of myosin from the actin filament (state d). Myosin then partially hydrolyzes the ATP, and part of the energy in the ATP is used to recock the head and return to the resting state.


Physiology_Levy

Physiology_Levy. If intracellular [Ca++] is still elevated, myosin undergoes another cross-bridge cycle and produces further contraction of the muscle. The ratchet action of the cross-bridge is capable of moving the thin filament approximately 10 nm. The cycle continues until the SERCA pumps Ca++ back into the SR. As [Ca++] falls, Ca++ dissociates from troponin C, and the troponin-tropomyosin complex moves and blocks the myosin binding sites on the actin filament. If the supply of ATP is exhausted, as occurs with death, the cycle stops abnormalityisseeninmusclesofthelegs,arms,andeyelid,andtheresponseisworsenedincoldweather.Brody’sdiseasecanbeeitherautosomalrecessiveorautosomaldominantandmayinvolvemutationsinuptothreegenes;however,itisrare(affecting1per10,000,000births).ItappearstoresultfromdecreasedactivityoftheSERCA1Ca++ pumpfoundinfast-twitchskeletalmuscle(seethesection


Physiology_Levy

Physiology_Levy. in state c with the formation of permanent actin-myosin complexes (i.e., the rigor state). In this state, the muscle is rigid, and the condition is termed rigor mortis. As already noted, formation of the thick filaments involves the association of myosin molecules in a tail-totail configuration to produce a bipolar orientation (see Fig. 12.6 ). Such a bipolar orientation allows myosin to pull the actin filaments toward the center of the sarcomere during the cross-bridge cycle. The myosin molecules are also oriented in a helical array in the thick filament in such a way that cross-bridges extend toward each of the six thin filaments surrounding the thick filament (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 12.3 ). These myosin projections/cross-bridges can be seen on electron micrographs of skeletal muscle and appear to extend perpendicular from the thick filaments at rest. In the contracted state, the myosin cross-bridges slant toward the center of the sarcomere, which is consistent with the ratchet action of the myosin head. The cross-bridge cycling mechanism just described is called the sliding filament theory because the myosin Cycle stops here in relaxed living muscle (because of actions of regulatory mechanisms)


Physiology_Levy

Physiology_Levy. The cross-bridge cycling mechanism just described is called the sliding filament theory because the myosin Cycle stops here in relaxed living muscle (because of actions of regulatory mechanisms) Tension Time0 G. 40 S. 90 msec L.R. 7.5 0 0.5 1.0 •Fig. 12.13. Cross-Bridge Cycle. Intherelaxedstate(statea),ATPispartiallyhydrolyzed(M•ADP•Pi).InthepresenceofelevatedmyoplasmicCa++ (stateb),myosin(M)bindstoactin(A).HydrolysisofATPiscompleted(statec)andcausesaconformationalchangeinthemyosinmoleculethatpullstheactinfilamenttowardthecenterofthesarcomere.AnewATPmoleculebindstomyosinandcausesreleaseofthecross-bridge(stated).PartialhydrolysisofthenewlyboundATPrecocksthemyosinhead,whichisnowreadytobindagainandagain.Ifmyoplasmic[Ca++]isstillelevated,thecyclerepeats.Ifmyoplasmic[Ca++]islow,relaxationresults.


Physiology_Levy

Physiology_Levy. cross-bridge is pulling the actin thin filament toward the center of the sarcomere, which results in an apparent “sliding” of the thin filament past the thick filament. There is, however, uncertainty about how many myosin molecules contribute to the generation of force and whether both myosin heads in a given myosin molecule are involved. It has been calculated that there may be 600 myosin heads per thick filament, with a stoichiometry of 1 myosin head per 1.8 actin molecules. As a result of steric considerations, it is unlikely that all myosin heads can interact with actin, and calculations suggest that even during maximal force generation, only 20% to 40% of the myosin heads bind to actin.


Physiology_Levy

Physiology_Levy. The conversion of chemical energy (i.e., ATP) to mechanical energy by muscle is highly efficient. In isolated muscle preparations, maximum mechanical efficiency (≈65% efficiency) is obtained at a submaximal force of 30% maximal tension. In humans performing steady-state ergometer exercise, mechanical efficiencies range from 40% to 57%.


Physiology_Levy

Physiology_Levy. Skeletal muscle fibers can be classified into two main groups according to the speed of contraction: fast-twitch •Fig. 12.14. A, Musclesvaryintermsofthespeedofcontraction.G,gastrocnemiusmuscleoftheleg;LR,lateralrectusmuscleoftheeye;S,soleusmuscleoftheleg.B, ThespeedofshorteningiscorrelatedwithmyosinATPaseactivity.N-SOL,normalsoleusmuscle(slowtwitch);N-EDL,normalextensordigitorumlongusmuscle(fasttwitch);S-EDL,self-innervatedextensordigitorumlongusmuscle(EDLmotornervetransectedandresutured);S-SOL,self-innervatedsoleusmuscle(soleusmotornervetransectedandresutured);X-EDL,cross-innervatedextensordigitorumlongusmuscle(EDLinnervatedbysoleusmotornerve);X-SOL,cross-innervatedSOLmuscle(soleusinnervatedbyEDLmotornerve).(A, FromMontcastleV[ed].Medical Physiology. 12thed.St.Louis:Mosby;1974.B, FromBárányM,CloseRI.J Physiol. 1971;213:455.) and slow-twitch muscle fibers. As shown in