Lecture 1 Skin Functions - humsc.net

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PHYSIOLOGY LECTURES-MSS MODULE -FALL 2021…………………………..…………………………….DR.SHAIMAA NASR AMIN

Lecture 1

Skin Functions 1-PROTECTIVE FUNCTION

First and foremost, the skin forms a protective covering over the entire body,

safeguarding underlying parts from physical trauma and pathogen invasion.

a-The innate immune system:

The innate immune system comprises mechanisms of immediate host defense,

including (1)physical barriers (epithelia) and (2) soluble factors such as

antimicrobial peptides, chemokines, cytokines, and the complement system, which

can be produced by a variety of resident cells (eg, keratinocytes, fibroblasts) and

infiltrating leukocytes such as polymorphonuclear leukocytes (PMNs),

monocytes/macrophages, dendritic cells (DCs), and natural killer (NK) cells.

Antimicrobial peptides (AMPs) are molecules that bind membranes of microbes and

form pores in the membrane, resulting in microbial killing. The most important

keratinocyte-derived AMPs in human skin are the human β-defensins. Human sweat

glands produce the AMP dermcidin which has broad antimicrobial activity.

b-Adaptive immune responses of the skin:

An effective immune response in human skin is usually initiated by dendritic antigen

presenting cells (APC) in the epidermis Langerhans Cells (LCs) and dermal DCs

(DDCs), in the dermis and is finally executed by T lymphocytes or B-cell–derived

antibodies, or both. Induction of a sufficient adaptive immune response requires the

recognition of a given antigen by lymphocytes.

c-The melanocytes in skin protect it from UV radiation and help prevent bacterial

invasion.

The major types of melanin are:

Pheomelanin – an orange to red pigment, expressed in the hair and skin. Low

protective properties against DNA damage induced by UV radiation.

Eumelanin – a brown to black pigment, expressed in the hair and skin. Higher

protective properties against DNA damage induced by UV radiation.

Neuromelanin – expressed in several regions in the brain. Its loss is associated with

several neurological disorders.

Melanin formation and the functional interaction between melanocytes and

Keratinocytes:

The cellular site of melanin synthesis, storage, and transportation is a membrane-

bound subcellular organelle known as melanosome produced by melanocytes. While

in the perinuclear region of melanocytes, melanosomes are immature and non-

pigmented. As they migrate to dendrites, they undergo a series of conformational

changes and become mature, pigmented and electron opaque.

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In the epidermis, melanocytes are inserted into the keratinocytes due to their long

and fine prolongations. A melanocyte is surrounded by approximately 36

keratinocytes with which it forms the epidermal unit, whose activity is paracrine

regulated. On the one hand, the synthesized quantity of melanic pigments at the

melanocyte level is influenced (stimulated or inhibited) by a series of factors

secreted by the keratinocytes, and on the other hand, melanocytes secrete a series of

substances which act upon keratinocytes. Through extensions, the melanosomes of

melanocytes are transferred to the surrounding keratinocytes, where they distribute

uniformly to achieve a homogeneous pigmentation and create a screen which covers

the nucleus of keratinocytes. Keratinocytes take over melanosomes through a

phagocytosis process, dependent on the ultraviolet radiation and regulated by the α-

melanocyte stimulating hormone (α-MSH).

During melanogenesis, mixtures of eumelanin as well as pheomelanin have been

produced at different ratio. The ratio is decided by tyrosinase activity.

Cells communicate by a variety of mechanisms. One mechanism is by gap junctions.

Keratinocytes and melanocytes have gap junctions in addition to cytokines release

that act on the surrounding cells by paracrine mode of action. Endothelin-1 (ET-1)

and basic fibroblast growth factor (bFGF) are secreted by keratinocytes, which

stimulates proliferation, chemotaxis, and pigment production in melanocytic cells.

Ultraviolet irradiation (UVR) induces an increase in ET-1 and bFGF secretion by

keratinocytes.

d-The sebaceous glands secret acidic oily secretions which retards the growth of

bacteria.

2-SKIN HELPS REGULATE WATER LOSS:

In the epidermis of the skin, a water gradient exists, with the moisture content of the

stratum corneum being lower than that of the deeper dermal layers. Due to this

gradient, passive diffusion of water occurs from the inner layers, towards the stratum

corneum. Most of the water evaporates from the skin surface, while a fraction of the

water is retained within the stratum corneum. This insensible loss of water from the

skin, due to evaporation (in the absence of sweat), is referred to as Transepidermal

water loss (TEWL). TEWL is a noninvasive in vivo measurement of water loss

across the stratum corneum. In healthy skin. The stratum corneum acts as a

protective barrier against water loss, due to the presence of layers of keratin and

glycolipids in the stratum corneum. Since outer skin cells are dead and keratinized,

the skin is waterproof, thereby preventing water loss.

Hydration refers to the water content of the skin, whereas moisturization is the skin’s

ability to retain those water molecules. Therefore, your skin needs both elements to

maintain desirable levels of TEWL.

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Aquaporins (AQPs) are components of the epidermis that impact both hydration as

well as barrier. This family of transmembrane proteins form water channels across

cell membranes. Thirteen different AQP have been recognized in mammals, where

some are selective water channels and others transport both water and glycerol.

AQP-3 (aquaglyceroporin) is detected and found to be significant in SC hydration.

Nevertheless, other aquaporins have also been found in skin epidermis : in human

skin, AQP10 has been detected in undifferentiated keratinocytes, whereas AQP9 was

found in differentiated keratinocytes.

3-EXCRETION

This function of the skin assists the urinary system, as do the sweat glands, which

excrete some urea when sweating occurs.

Apocrine and eccrine are the two types of sweat glands present. Apocrine is

concentrated in the axilla, pubis and areola of the breast. The gland cells are

innervated by the sympathetic adrenergic fibers. Its secretion starts at the time of

puberty and the adrenal androgens stimulate the secretion. The apocrine secretion

initially is colorless and odorless. But the bacterial flora present on the skin surface,

acts on it and gives the characteristic odor. The gland cells are stimulated by

emotional excitement and mediated through the sympathetic adrenergic innervation.

The eccrine glands have a coiled duct system, which opens into the skin surface.

They are distributed more in the palm, hand, chest and forehead. The cells of eccrine

glands are supplied by sympathetic cholinergic fibers. The eccrine gland is

stimulated in response to the increase in the body temperature.

The nerve impulses to the eccrine sweat glands are transmitted in the autonomic

pathways to the spinal cord and then through sympathetic outflow to the skin. the

sweat glands are innervated by cholinergic nerve fibers (fibers that secrete

acetylcholine but that run in the sympathetic nerves along with the adrenergic

fibers). These glands can also be stimulated to some extent by epinephrine or

norepinephrine circulating in the blood, even though the glands themselves do not

have adrenergic innervation. This mechanism is important during exercise, when

these hormones are secreted by the adrenal medullae and the body needs to lose

excessive amounts of heat produced by the active muscles.

Mechanism of Sweat Secretion: the sweat gland is shown to be a tubular structure

consisting of two parts: (1) a deep subdermal coiled portion that secretes the sweat,

and (2) a duct portion that passes outward through the dermis and epidermis of the

skin. As is true of so many other glands, the secretory portion of the sweat gland

secretes a fluid called the primary secretion or precursor secretion; the

concentrations of constituents in the fluid are then modified as the fluid flows

through the duct.

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The precursor secretion is an active secretory product of the epithelial cells lining

the coiled portion of the sweat gland. The composition of the precursor secretion is

similar to that of plasma, except that it does not contain plasma proteins. As this

precursor solution flows through the duct portion of the gland, it is modified by

reabsorption of most of the sodium and chloride ions. The degree of this reabsorption

depends on the rate of sweating.

4-NEUROENDOCRINE FUNCTION:

Sensory Function:

The sensory receptors in the dermis specialized for touch, pressure, pain, hot, and

cold are associated with the nervous system. These receptors supply the central

nervous system with information about the external environment.

Skin touch and oxytocin:

The sensory receptors also account for the use of the skin as a means of

communication between people, promotes social bonding, increases oxytocin

relieve, decreases stress. For example, the touch receptors play a major role in sexual

arousal, which assists the reproductive system.

Skin-to-skin contact is an intervention, whereby the baby is placed on the mother’s

chest immediately after birth and which is associated with positive clinical outcomes

for both mothers and newborns. Kangaroo care, which involves repeated episodes

of skin-to skin contact between parents and a premature baby is also linked to such

positive effects. Repeated sessions of skin-to-skin contact in full term infants is also

associated with long-term beneficial effects. During these practices behavioral and

physiological effects are induced in both mother/father and infant. Social interaction

and bonding/attachment between parents and baby are stimulated. In addition, the

levels of anxiety, stress and pain are decreased in both of them, whereas milk

production is promoted in the mother and growth/weight gain and development in

the newborn. The sense of wellbeing may also be increased.

The oxytocinergic system, which comprises of oxytocin released into the circulation

and into the brain from oxytocinergic nerves in the hypothalamus, is an important

mediator/integrator of the positive effects caused by skin-to-skin treatment and

kangaroo care in both mother/father and baby. In support of this a rise of oxytocin

levels has been observed in response to skin-to-skin contact in both mothers, fathers

and newborns. Oxytocin released into the circulation as well as within the brain

participates in these effects and the oxytocinergic nerves in the brain mediate the

effects on social interaction/bonding, the anxiolytic, pain and stress relieving as well

as the restorative, growth promoting effects.

Skin cells produce hormones, neurotransmitters and neuropeptides and

corresponding functional receptors. Hormones and neurotransmitters are either

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produced locally in epidermal, adnexal and dermal cells or released in situ from

cutaneous nerve endings.

Cutaneous (local) Hypothalamo-pituitary adrenal (HPA) Axis

The main adaptive responses to systemic stress are mediated by the HPA axis.

Activation of the HPA system starts with hypothalamic production of corticotropin-

releasing hormone (CRH), which induces production and release of the

proopiomelanocortin (POMC)-derived peptides adrenocorticotropin (ACTH), α-

melanocyte-stimulating hormone and α-endorphin. ACTH stimulates production

and secretion of cortisol by the adrenal cortex.

It has been proposed that the homolog of the HPA axis has developed in the skin as

an efficient way to deal with environmental stressors. This concept is strengthened

by the evidence that skin expresses CRH and related peptides, POMC, which its

further processed to β-endorphin (β-END), ACTH, and melanocyte-stimulating

hormone (MSH). In addition, skin cells express the corresponding functional CRH-

R1, melanocortin (MC), and opiate receptors.

Accordingly, exposure to UV light (physical stress) or biological or chemical stress

would trigger multiple pathways involving structuralized or simultaneous local

production of CRH and CRH-related peptides and POMC-derived messages. Hence,

signals generated by the integrated actions of these peptides would counteract the

local effects of the stress and attenuate the attendant cutaneous responses.

Vitamin D synthesis:

The cells contain a precursor molecule that is converted to vitamin D in the body

after UV exposure; only a small amount of UV radiation is needed. Vitamin D leaves

the skin and enters the liver and kidneys, where it is converted to a hormone called

calcitriol. Calcitriol circulates throughout the body, regulating calcium uptake by the

digestive system and both calcium and phosphorus metabolism in cells.

Skin as a target for vitamin D:

1-Inhibition of proliferation and induction of differentiation in keratinocytes.

2-Stimulate melanocyte differentiation and melanin formation.

2-Immunomodulatory and antimicrobial effects in the skin.

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Lecture 2

Skin Functions (contin.)//Biological clocks and the skin

5-SKIN HELPS REGULATE BODY TEMPERATURE

Body Core Temperature and Skin Temperature: the “core” of the bod usually

remains very constant, within ±1°F(±0.6°C), except when a person has a febrile

illness. The skin temperature, in contrast, rises and falls with the temperature of the

surroundings. The skin temperature is important when we refer to the skin’s ability

to lose heat to the surroundings. The average normal core temperature is generally

considered to be between 36°C and 37.5°C when measured orally.

The signals generated by the temperature receptors of the hypothalamus are

extremely powerful in controlling body temperature, receptors in other parts of the

body play additional roles in temperature regulation. This is especially true of

temperature receptors in the skin and in a few specific deep tissues of the body. the

skin is endowed with both cold and warmth receptors with 10 times cold receptors

as warmth receptors. Deep body temperature receptors are found mainly in the spinal

cord, in the abdominal viscera, and in or around the great veins in the upper abdomen

and thorax. These deep receptors function differently from the skin receptors

because they are exposed to the body core temperature rather than the body surface

temperature. Body Temperature Is Controlled by Balancing Heat Production and

Heat Loss

Blood Flow to the Skin from the Body Core Provides Heat Transfer

(Countercurrent heat exchange):

Blood vessels are distributed profusely beneath the skin. Especially important is a

continuous venous plexus that is supplied by inflow of blood from the skin

capillaries. In the most exposed areas of the body—the hands, feet, and ears—blood

is also supplied to the plexus directly from the small arteries through highly muscular

arteriovenous anastomoses. A high rate of skin flow causes heat to be conducted

from the body core to the skin with great efficiency, whereas reduction in the rate of

skin flow can decrease heat conduction from the core to very little. Therefore, the

skin is an effective controlled “heat radiator” system, and the flow of blood to the

skin is a most effective mechanism for heat transfer from the body core to the skin.

Control of Heat Conduction to the Skin by the Sympathetic Nervous System. Heat

conduction to the skin by the blood is controlled by the degree of vasoconstriction

of the arterioles and the arteriovenous anastomoses that supply blood to the venous

plexus of the skin. This vasoconstriction is controlled almost entirely by the

sympathetic nervous system in response to changes in body core temperature and

changes in environmental temperature.

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Basic Physics of Heat Loss from the Skin Surface

1- heat radiation: as infrared electromagnetic rays, not in contact, the surroundings

should be less than body temperature, normally 60% of heat loss is by radiation.

Heat rays are also being radiated from the walls of rooms and other objects toward

the body.

2-conduction: the objects must be in contact, 3% of heat loss to objects. heat is

“conducted” from molecule to molecule. The body surface loses or gains heat by

conduction through direct contact with cooler or warmer substances, including the

air or water. Not all substances, however, conduct heat equally. Water is a better

conductor of heat than is air; therefore, more heat is lost from the body in water than

in air of similar temperature.

3- convection: Convection is the process whereby conductive heat loss or gain is

aided by movement of the air or water next to the body. Convection is always

occurring because warm air is less dense and therefore rises, but it can be greatly

facilitated by external forces such as wind or fans. Consequently, convection aids

conductive heat exchange by continuously maintaining a supply of cool air.

4-evaporation: When water evaporates from the body surface, 0.58 Calorie

(kilocalorie) of heat is lost for each gram of water that evaporates. Even when a

person is not sweating, water still evaporates insensibly from the skin and lungs at a

rate of about 600 to 700 ml/day. This insensible evaporation causes continual heat

loss at a rate of 16 to 19 Calories per hour. Insensible evaporation through the skin

and lungs cannot be controlled for purposes of temperature regulation because it

results from continual diffusion of water molecules through the skin and respiratory

surfaces. However, loss of heat by evaporation of sweat can be controlled by

regulating the rate of sweating. The most important factor determining evaporation

rate is the water vapor concentration of the air—that is, the relative humidity. The

discomfort suffered on humid days is due to the failure of evaporation; the sweat

glands continue to secrete, but the sweat simply remains on the skin or drips off.

Acclimatization of the Sweating Mechanism to Heat—The Role of Aldosterone.

Although a normal, unacclimatized person seldom produces more than about 1 liter

of sweat per hour, when this person is exposed to hot weather for 1 to 6 weeks, he

or she begins to sweat more profusely, often increasing maximum sweat production

to as much as 2 to 3 L/hr. This increased effectiveness of the sweating mechanism

is caused by a change in the internal sweat gland cells to increase their sweating

capability. Also associated with acclimatization is a further decrease in the

concentration of sodium chloride in the sweat, which allows progressively better

conservation of body salt. Most of this effect is caused by increased secretion of

aldosterone by the adrenocortical glands, which results from a slight decrease in

sodium chloride concentration in the extracellular fluid and plasma.

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Temperature-Decreasing Mechanisms by the skin when the body is too hot:

1. Vasodilation of skin blood vessels. In almost all areas of the body, the skin blood

vessels become intensely dilated. This dilation is caused by inhibition of the

sympathetic centers in the posterior hypothalamus that cause vasoconstriction. Full

vasodilation can increase the rate of heat transfer to the skin as much as eightfold.

2. Sweating. The effect of increased body temperature to cause sweating.

Temperature-Increasing Mechanisms by the skin When the Body Is Too Cold:

1. Skin vasoconstriction throughout the body. This vasoconstriction is caused by

stimulation of the posterior hypothalamic sympathetic centers.

2. Piloerection. Piloerection means hairs “standing on end.” Sympathetic stimulation

causes the arrector pili muscles attached to the hair follicles to contract, which brings

the hairs to an upright stance and produces “goose bumps” on the skin at the base of

the hairs. This mechanism is not important in human beings, but in many animals,

upright projection of the hairs allows them to entrap a thick layer of “insulator air”

next to the skin, so transfer of heat to the surroundings is greatly depressed.

Biological Clocks and The Skin To “tell time,” Most living organisms use timekeeping mechanisms known as

“biological clocks.” These “clocks” coordinate our physiological and behavioral

functions, thereby optimizing the adaptations to and interactions with our

environment.

Entrainment is the synchronization of the internal biological clock rhythm, to

external time cues, such as the natural dark-light cycle. Circadian entrainment

represents an adaptation of organisms to their environment.

Visible light is considered the most powerful evolutionarily conserved organismal

“master” clock entrainment cue in humans, acting through the retina (not directly on

peripheral tissues). light acts to reset the central pacemaker located in the

suprachiasmatic nucleus (SCN), which then initiates hormonal and neuronal signals

that coordinate oscillations in physiological processes throughout the body.

Peripheral organs and cells are functionally synchronized using additional cues such

as nutritional components, through autonomous clocks driving oscillating

expression of gene products and metabolites. At a cellular level, the circadian clock

mechanism is composed of interdependent feedback loops of transcription and

translation of specific gene products. That skin cells, from keratinocytes, fibroblasts,

melanocytes to mast cells and hair follicles, contain robust autonomous clocks.

The master clock in the SCN communicates timing information to the skin via a

combination sympathetic innervation and secreted hormones

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The skin as an organ is directly exposed to external conditions, including

temperature, light, humidity, UV radiation and pathogens. Under normal, healthy

conditions, it has been reported that many attributes of human skin follow a

periodicity: hydration and transepidermal water loss (TEWL), capillary blood flow,

sebum production, temperature, surface pH, keratinocyte proliferation rates.

Skin blood flow has a pattern characterized by low morning rates, with the highest

rates in the afternoon and a second peak in the late evening just before sleep. Skin

temperature typically reflects cutaneous blood flow. Facial sebum secretion varies

with a circadian rhythmicity, lowest during the night and peaking in the early

afternoon. Skin pH was highest in the morning,

In human epidermis, cellular proliferation in keratinocytes has been measured to be

30-fold higher at night than at noon and epidermal stem cells show a similar pattern

and have a higher rate of proliferation at night versus day.

Skin cell division, as well as DNA replication and repair, have long been observed

to occur with high correlation to a diurnal type of cycle and the clinical implications

of this are significant. These rhythms impact both acute (erythema, DNA damage

and immune suppression) and long-term (skin cancers and photo aging)

consequences of UVR exposure. Skin adapting to boost its protective functions

during the day to ward off environmental threats during evening and night processes

are then directed at regeneration.

Chronotherapy: The goal of chronotherapy is to coordinate drug administration

with circadian rhythms such that the therapeutic effect is maximized while side

effects are minimized. In line with this idea, various metabolism genes, including

drug-metabolizing enzymes, show prominent circadian variation in the skin. While

highly speculative at this stage, drugs could be administered when their targets are

expressed at the highest level and/or when pathways that metabolize them are at their

nadir. Another promising direction for skin chronotherapy relates to improving the

transdermal delivery of topical drugs.

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Lecture 3

Physiology of Skeletal Muscles The striated pattern in skeletal muscle results from the arrangement of cytosolic

proteins organized into two types of filaments. The larger are thick filaments and the

smaller are thin filaments.

The thick filaments are composed mainly of the protein myosin. The myosin

molecule is composed of two large polypeptide heavy chains and four smaller light

chains. These polypeptides combine to form a molecule that consists of two globular

heads (containing heavy and light chains) and a long tail formed by the two

intertwined heavy chains. The tail of each myosin molecule lies along the axis of the

thick filament, and the two globular heads extend out to the sides, forming cross-

bridges, which make contact with the thin filament and exert force during muscle

contraction. Each globular head contains two binding sites, one for attaching to the

thin filament and one for ATP. The ATP binding site also functions as an enzyme

(called myosin-ATPase) that hydrolyzes the bound ATP, harnessing its energy for

contraction.

The thin filaments (which are about half the diameter of the thick filaments) are

principally composed of the protein actin, troponin and tropomyosin—that have

important functions in regulating contraction. An actin molecule is a globular protein

composed of a single polypeptide (a monomer) that polymerizes with other actin

monomers to form a polymer made up of two intertwined, helical chains. These

chains make up the core of a thin filament. Each actin molecule contains a binding

site for myosin.

Sarcomere Structure: The thick and thin filaments are arranged in an orderly,

parallel manner that is apparent in a microscopic view of skeletal muscle. One unit

of this repeating pattern of thick and thin filaments is known as a sarcomere (from

the Greek sarco,“muscle,” and mer, “part”). The thick filaments are located in the

middle of each sarcomere, where they create a wide, dark band known as the A band.

Each sarcomere contains two sets of thin filaments, one at each end. One end of each

thin filament is anchored to a network of interconnecting proteins known as the Z

line, whereas the other end overlaps a portion of the thick filaments. Two successive

Z lines define the limits of one sarcomere.

The sarcotubular system: In addition to force-generating mechanisms, skeletal

muscle fibers have an elaborate system of membranes that participate in the

activation of contraction. The sarcoplasmic reticulum in a muscle fiber is

homologous to the endoplasmic reticulum found in most cells. This structure forms

a series of sleeve like segments around each myofibril. At the end of each segment

are two enlarged regions, known as terminal cisternae.

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A separate tubular structure, the transverse tubule (T-tubule), lies directly between—

and is intimately associated with—the terminal cisternae of adjacent segments of the

sarcoplasmic reticulum. T-tubules are continuous with the plasma membrane (which

in muscle cells is also referred to as the sarcolemma), and action potentials

propagating along the surface membrane also travel throughout the interior of the

muscle fiber by way of the T-tubules. The lumen of the T-tubule is continuous with

the extracellular fluid surrounding the muscle fiber.

Molecular Mechanisms of Skeletal Muscle Contraction

The term contraction, as used in muscle physiology refers to activation of the force-

generating sites within muscle fibers—the cross-bridges.

For example, holding a dumbbell steady with your elbow bent requires muscle

contraction but not muscle shortening. We begin our explanation of how skeletal

muscles contract by first describing the mechanism by which they are activated by

neurons.

Membrane Excitation: The Neuromuscular Junction

Stimulation of the neurons to a skeletal muscle is the only mechanism by which

action potentials are initiated in this type of muscle. The neurons whose axons

innervate skeletal muscle fibers are known as alpha motor neurons (or simply as

motor neurons), and their cell bodies are located in the brainstem and the spinal cord.

The axons of motor neurons are myelinated and are the largest-diameter axons in the

body. They are therefore able to propagate action potentials at high velocities,

allowing signals from the central nervous system to travel to skeletal muscle fibers

with minimal delay.

Upon reaching a muscle, the axon of a motor neuron divides into many branches,

each branch forming a single synapse with a muscle fiber. A single motor neuron

innervates many muscle fibers, but each muscle fiber is controlled by a branch from

only one motor neuron. Together, a motor neuron and the muscle fibers it

innervates are called a motor unit. The muscle fibers in a single motor unit are

located in one muscle, but they are distributed throughout the muscle and are not

necessarily adjacent to each other. When an action potential occurs in a motor

neuron, all the muscle fibers in its motor unit are stimulated to contract.

The myelin sheath surrounding the axon of each motor neuron ends near the surface

of a muscle fiber, and the axon divides into a number of short processes that lie

embedded in grooves on the muscle fiber surface. The axon terminals of a motor

neuron contain vesicles that contain the neurotransmitter acetylcholine (ACh). The

region of the muscle fiber plasma membrane that lies directly under the terminal

portion of the axon is known as the motor end plate.

The junction of an axon terminal with the motor end plate is known as a

neuromuscular junction. When an action potential in a motor neuron arrives at the

axon terminal, it depolarizes the plasma membrane, opening voltage sensitive Ca2+

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channels and allowing calcium ions to diffuse into the axon terminal from the

extracellular fluid. This Ca2+ binds to proteins that enable the membranes of Ach

exocytosis into the extracellular cleft separating the axon terminal and the motor end

plate. ACh diffuses from the axon terminal to the motor end plate where it binds to

ionotropic receptors of the nicotinic type. The binding of ACh opens an ion channel

in each receptor protein; both sodium and potassium ions can pass through these

channels. Because of the differences in electrochemical gradients across the plasma

membrane , more Na+ moves in than K+ out (also the permeability of acetylcholine

receptors for sodium is higher than potassium), producing a local depolarization of

the motor end plate known as an end-plate potential (EPP).

As neurotransmitter is released over a larger surface area, binding to many more

receptors and opening many more ion channels. For this reason, one EPP is normally

more than sufficient to depolarize the muscle plasma membrane adjacent to the end-

plate membrane to its threshold potential, initiating an action potential. This action

potential is then propagated over the surface of the muscle fiber and into the T-

tubules. Most neuromuscular junctions are located near the middle of a muscle fiber,

and newly generated muscle action potentials propagate from this region in both

directions toward the ends of the fiber.

Excitation–Contraction Coupling

Excitation–contraction coupling refers to the sequence of events by which an action

potential in the plasma membrane activates the force-generating mechanisms. An

action potential in a skeletal muscle fiber lasts 1 to 2 msec and is completed before

any signs of mechanical activity begin. Once begun, the mechanical activity

following an action potential. The electrical activity in the plasma membrane does

not directly act upon the contractile proteins but instead produces a state of increased

cytosolic Ca2+ concentration, which continues to activate the contractile apparatus

long after the electrical activity in the membrane has ceased.

Function of Ca2+ in Cross-Bridge Formation: Chains of tropomyosin molecules

cover the myosin-binding site on actin, thereby preventing the cross-bridges from

making contact with actin. Each tropomyosin molecule is held in this blocking

position by the smaller globular protein, troponin. Troponin, which interacts with

both actin and tropomyosin, is composed of three subunits designated by the letters

I (inhibitory), T (tropomyosin-binding), and C (Ca2+-binding). One molecule of

troponin binds to each molecule of tropomyosin and regulates the access to myosin-

binding sites on actin in contact with that tropomyosin. This is the status of a resting

muscle fiber; troponin and tropomyosin cooperatively block the interaction of cross-

bridges with the thin filament.

To allow cross-bridges from the thick filament to bind to the thin filament,

tropomyosin molecules must move away from their blocking positions on actin. This

happens when Ca2+ binds to specific binding sites on the Ca2+-binding subunit of

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troponin. The binding of Ca2+ produces a change in the shape of troponin, which

relaxes its inhibitory grip and allows tropomyosin to move away from the myosin-

binding site on each actin molecule. Conversely, the removal of Ca2+ from troponin

reverses the process, turning off contractile activity. Thus, the cytosolic Ca2+

concentration determines the number of troponin sites occupied by Ca2+, which in

turn determines the number of actin sites available for cross-bridge binding.

In a resting muscle fiber, the concentration of free, ionized Ca2+ in the cytosol

surrounding the thick and thin filaments is very low and very few of the Ca2+-

binding sites on troponin are occupied and, thus, cross-bridge activity is largely

blocked by tropomyosin. Following an action potential, there is a rapid increase in

cytosolic Ca2+ concentration and Ca2+ binds to troponin removing the blocking

effect of tropomyosin and allowing myosin cross-bridges to bind actin. The source

of the increased cytosolic Ca2+ is the sarcoplasmic reticulum within the muscle

fiber.

A specialized mechanism couples T-tubule action potentials with Ca2+ release from

the sarcoplasmic reticulum. The T-tubules are in intimate contact with the terminal

cisternae of the sarcoplasmic reticulum forming foot process. This junction involves

two integral membrane proteins, one in the T-tubule membrane and the other in the

membrane of the sarcoplasmic reticulum. The T-tubule protein is known as the

dihydropyridine (DHP) receptor. The main function of the DHP receptor is to act as

a voltage sensor. The protein embedded in the sarcoplasmic reticulum membrane is

known as the ryanodine receptor, it is a large molecule not only includes the foot

process that connects to the DHP receptor but also forms a Ca2+ channel. During a

T-tubule action potential, the DHP receptor protein induce a conformational change,

which acts via the foot process to open the ryanodine receptor channel. Ca2+ is then

released from the terminal cisternae of the sarcoplasmic reticulum into the cytosol,

where it can bind to troponin.

The increase in cytosolic Ca2+ in response to a single action potential is normally

enough to briefly saturate all troponin-binding sites on the thin filaments.

Sliding-Filament Mechanism

When force generation produces shortening of a skeletal muscle fiber, the

overlapping thick and thin filaments in each sarcomere move past each other,

propelled by movements of the cross bridges. This is known as the sliding-filament

mechanism of muscle contraction.

One stroke of a cross-bridge produces only a very small movement of a thin filament

relative to a thick filament. As binding sites on actin remain exposed, however, each

cross-bridge repeats its motion many times, resulting in large displacements of the

filaments.

The sequence of events that occurs between the time a crossbridge binds to a thin

filament, moves, and then is set to repeat the process is known as a cross-bridge

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cycle. Each cycle consists of four steps: (1) attachment of the cross-bridge to a thin

filament; (2) movement of the cross-bridge, producing tension in the thin filament;

(3) detachment of the cross-bridge from the thin filament; and (4) energizing the

cross-bridge so it can again attach to a thin filament and repeat the cycle.

The interaction between actin and myosin requires:

a-exposure of myosin binding sites on actin (depends on cytosolic calcium level)

b-high affinity of myosin to actin (only when it is energized or coked=ADP+Pi bind

to the head).

The cross-bridges in a resting muscle fiber are in an energized state (cocked)

resulting from the splitting of ATP, and the hydrolysis products ADP and inorganic

phosphate (Pi) are still bound to myosin.

Cross-bridge cycling is initiated when the excitation–contraction coupling

mechanism increases cytosolic Ca2+ and the binding sites on actin are exposed. The

cycle begins with the binding of an energized myosin cross-bridge (M) to a thin

filament actin molecule (A):

Step 1 Actin binding

The binding of energized myosin to actin triggers the release of the strained

conformation of the energized cross-bridge, which produces the movement of the

bound cross-bridge (sometimes called the power stroke) and the release of Pi and

ADP:

Step 2 cross-bridge movement

During the cross-bridge movement, myosin is bound very firmly to actin, but this

linkage must be broken to allow the crossbridge to be reenergized and repeat the

cycle. The binding of a new molecule of ATP to myosin decreases myosin’s affinity

for actin bound at another site.

Following the dissociation of actin and myosin, the ATP bound to myosin is

hydrolyzed by myosin-ATPase, thereby reforming the energized state of myosin and

returning the crossbridge to its pre-power-stroke position.

Note that the hydrolysis of ATP and the movement of the cross-bridge are not

simultaneous events. If binding sites on actin are still exposed after a cross-bridge

finishes its cycle, the cross-bridge can reattach to a new actin monomer in the thin

filament and the cross-bridge cycle repeats.

Muscle relaxation:

-Acetyl choline is hydrolyzed by acetylcholine esterase at the neuromuscular

junction.

-A contraction is terminated by removal of Ca2+ from troponin, which is achieved

by lowering the Ca2+ concentration in the cytosol back to its prerelease level. The

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membranes of the sarcoplasmic reticulum contain primary active-transport

proteins— Ca2+-ATPases—that pump calcium ions from the cytosol back into the

lumen of the reticulum. As contraction results from the release of Ca2+ stored in the

sarcoplasmic reticulum, so contraction ends, and relaxation begins as Ca2+ is

pumped back into the reticulum. ATP is required to provide the energy for the Ca2+

pump.

-The presence of the Ca2+-binding protein calsequestrin in the terminal cisternae

allows the storage of a large quantity of Ca2+ without having to transport it against

a large concentration gradient.

-Note: ATP is essential for both contraction and relaxation of skeletal muscles:

a-ATP performs two distinct functions in the cross-bridge cycle: (1) The energy

released from ATP hydrolysis ultimately provides the energy for cross-bridge

movement; and (2) ATP binding (not hydrolysis) to myosin breaks the link formed

between actin and myosin (detachment) during the cycle, allowing the next cycle to

begin.

b-It regulates cytosolic Ca2+ through activity of Calcium pump on the sarcoplasmic

reticulum.

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Lecture 4

Changes Following Skeletal Muscle Stimulation

Stimulation of the skeletal muscle through its nerve supply is followed by many

changes:

a- Electrical changes.

b- Excitability changes

c- Mechanical changes.

d- Metabolic changes.

(A) Electrical Changes Following Skeletal Muscle Stimulation:

The electrical events in skeletal muscle and the ionic fluxes underlying them are

similar to those in nerve, although there are quantitative differences in timing and

magnitude. The resting membrane potential of skeletal muscle is about - 90m V. The

action potential lasts 2-4 ms and is conducted along the muscle fibre at about 5

m/sec. The action potential precedes the contraction by about 2 msec.

(B) Excitability Changes Following Skeletal Muscle Stimulation:

Skeletal muscle fibre, like nerve fibre, is refractory to re- stimulation during the

action potential. It will be noted that as the muscle begins to contract, it regains its

excitability. The latent period of the mechanical response coincides with the

ascending limb and part of the descending limb of spike potential, which

corresponds to the absolute refractory period.

(C) Mechanical Changes Following Skeletal Muscle Stimulation:

The contractile Response Molecular Mechanism of Muscle Contraction

1- "Excitation-Contraction (EC) Coupling": It is the process by which an action

potential initiates the contractile process.

2- Generation of tension: Tension [the force developed when a muscle contracts] is

generated by the cycling of the cross-bridges which occurs after they bind to the thin

filament.

3- Relaxation.

The All or None Law:

A single skeletal muscle fibre obeys all or none law. The skeletal muscle fibre

contracts maximally or does not contract at all. A threshold stimulus produces

maximal contraction provided that the experimental conditions remain the same.

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The Muscle Twitch:

A brief contraction followed by relaxation caused by a single action potential. This

response is called a muscle twitch.

Summation of contractions: The force of contraction can be increased by

increasing the frequency of muscle stimulation because more Ca2+ is released from

the SR each time the muscle is stimulated. With rapidly repeated stimulation,

activation of the contractile mechanism occurs repeatedly before any relaxation has

occurred, and the individual responses fuse into one continuous contraction called a

tetanus. It is complete tetanus when there is no relaxation between stimuli and an

incomplete tetanus (or clonus) when there are periods of incomplete relaxation

between the gathered stimuli. This phenomenon is known as summation of

contractions. During a complete tetanus, the tension developed is about 4 times that

developed by the individual twitch contractions. This phenomenon may be described

as follows: By repeatedly stimulating the muscle, the level of free calcium ions in

the myofibrils remains continuously above the level required for full activation of

the contractile process i.e. continuous cycling of the cross-bridges.

Treppe "The Staircase Phenomenon”:

It refers to the progressive increase in the magnitude of separate twitch contraction

of skeletal muscle to a plateau value during repetitive stimulation after a period of

rest. this phenomenon is explained by the persistent elevated levels of free Ca2+ in

the cytoplasm and warming up of the muscle.

Definitions:

- Load: the force exerted on the muscle by an object.

- Tension: The force exerted on an object by a contracting muscle

-Preload: is the load that a muscle experiences before the onset of contraction

(represented the passive precontraction or resting length at which resting muscle is

stretched).

-After load is a load that is encountered by the muscle only after it starts to contract.

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Types of Contraction of Skeletal Muscle:

At the level of the muscle fibre (motor unit) level, two primary types of contraction

that depend on whether the muscle fibre changes length or tension during

contraction:

1- Isotonic contraction:

This occurs when the muscle length change, but the muscle tension remains constant.

2- Isometric contraction:

Refers to a contraction in which the external length of the muscle does not change

through the tension is highly increased.

Tension is produced internally within the sarcomeres, considered the contractile

component of the muscle, as a result of cross-bridge activity and the resulting sliding

of filaments. However, the sarcomeres are not attached directly to the bones. Instead,

the tension generated by these contractile elements must be transmitted to the bone

via the connective tissue sheaths and tendons before the bone can be moved.

Connective tissue sheaths and tendon, as well as other components of the muscle

have a certain degree of passive elasticity. These noncontractile tissues are called

the series-elastic component (SEC) of the muscle; they behave like a stretchy spring

placed between the internal tension-generating contractile elements (CE) and the

bone that is to be moved against an external load.

During muscle contraction a load (weight) is moved:

a. In isotonic contraction, the “CE" shortens and the “SEC" is not markedly stretched

“because the load is moved ". So, the whole muscle is shortened & its tension

remains constant.

b. In isometric Contraction, the " CE" shortens & the " SEC" is greatly stretched "

because the load is not moved " So, the whole muscle is not shortened & its tension

is markedly increased.

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Lecture 5

Muscle Physiology

The work done by the muscle is:

Weight in Kg X the distance the weight is moved

There basic differences between isometric and isotonic contractions:

1- Tension changes. Mentioned above

2- Length changes. Mentioned above

3- In isotonic contraction a load is moved a distance, which involves the

phenomenon of inertia [that is the weight being moved must first be accelerated].

4- Isotonic contraction does external work since the load is moved a distance. The

mechanical efficiency (the percentage of energy input that is converted into work

instead of heat) is about 20-25%. In isometric contraction since load X distance is

zero, no external work is done by the muscle and the mechanical efficiency is

zero.

Isotonic muscle contractions can be either concentric or eccentric:

Concentric: the muscle shortens, e.g. contraction of the biceps to produce elbow

flexion.

Eccentric: muscle lengthen or is stretched while contracting, e.g. lowering a load on

the ground.

N.B.: Muscles can contract both isometrically and isotonically in the body, but most

contractions are actually a mixture of the two:

-When standing, person tenses the quadriceps muscles to tighten the knee joints and

to keep the leg stiff (isometric contraction).

-During running, contractions of leg muscles are a mixture of isometric [when the

legs hit the ground] and isotonic contractions [to move the limbs].

-When a person lifts a heavy weight using the biceps, the contraction starts

isometrically and completed isotonically. With heavier loads: The duration of

isometric contraction phase is longer and the rate and extent of muscle shortening

during isotonic contraction is less.

Length-tension relationship:

Measures tension developed during isometric contractions when the muscle is set to

fixed lengths (preload).

a. Passive tension: is the tension developed by stretching the muscle to different

lengths.

b. Total tension: is the tension developed when the muscle is stimulated to contract

at different lengths.

c. Active tension: is the difference between total tension and passive tension.

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There is a relationship between the initial muscle fibre length and the active tension

developed during its isometric contraction.

a- Maximal force is obtained when the muscle fibre length is set at a sarcomere

length of 2.2 u. This is the resting length of the muscle inside the body. At this length,

the overlap between thick and thin filaments is optimal, since every cross-bridges

from the thick filament is opposite an actin molecule.

b- Increasing the length of the muscle fibre causes a decrease in the force

development. At sarcomere length greater than 2.2 u, the overlap between thick and

thin filaments is decreased. Thus, some cross-bridges do not have actin filaments to

combine with.

c- Decreasing the sarcomere length below 2.2 u causes a decrease in force

development. At this condition, the ends of the two actin filaments overlap each

other, in addition to overlapping the myosin filaments, making it more difficult for

the muscle to develop force.

Load-Velocity Relationship:

In isotonic contraction, for the muscle to shorten, it must lift a weight, called

afterload, which is applied after the muscle begins to contract. Increasing the

afterload has the following effects:

The velocity and the amount of shortening decreases as the afterload increases. The

maximal velocity of shortening (V max) occurs when there is no external load (zero

load).

N.B. -Vmax is theoretical, because load cannot be zero.

Metabolic Changes Following Skeletal Muscle Stimulation:

Energy Sources and Muscle Metabolism:

I-During Rest: The skeletal muscles consume energy for: Maintenance of the

resting membrane potential, synthesis of chemical substances e.g. glycogen. And

Production of Muscle tone (reflex that causes a state of continuous subtetanic

contraction of the muscle,,,,,details in CNS).

II- During Contraction: Energy consumption is markedly increased. ATP is the

only immediate energy source for the contraction of muscle. ATP is hydrolyzed

anaerobically into ADP and the muscle protein myosin acts as the enzyme adenosine

triphosphatase. ATP inside the muscle is not enough except for maximal contraction

for only 5 or 6 seconds. Therefore, ATP is reformed continuously by means of three

different metabolic mechanisms:

(1) Phosphoereatine ; (phosphogen system)

- Most muscle cells have five times as much phosphocretine as A.T.P

- Energy transfer from phosphocreatine to A.T.P. within a small fraction of second.

- The cell phosphocreatine plus its A.T.P. are called the phosphogen energy system

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These together can provide maximal muscle power for a period of 5-8 seconds.

(2) The Glycogen lactic Acid system:

-Under optimal conditions the glycogen - lactic acid system can provide 30 to 60

second of excess muscle activity.

Lactic acid causes extreme fatigue which serves as a self-limitation to further use of

this system for energy. Removal of the lactic acid from all the body fluids requires

an hour or more. Removal of the lactic acid from the blood and other body fluid

achievement in three ways:

a- Some of the lactic acid converts to pyruvic acid then metabolized directly by all

the body tissues.

b- Much of the lactic acid ———> glucose by the liver and the glucose in turn is

used mainly to replenish the glycogen stores of the muscles.

c- It is used as a fuel in the heart.

(3) The Aerobic System:

The aerobic system means the oxidation of foodstuffs in the mitochondria to provide

energy, (glucose, fatty acids and amino acids from food). Aerobic system has

Unlimited time “as long as nutrients and O2 are available

Ill- During recovery (oxygen Debt):

During muscular exercise, the muscle blood vessels dilate, and blood flow is

increased so that the available O2 supply is increased. Up to a point, the increase in

O2 consumption is proportionate to the energy expended, and all the energy needs

are met by aerobic processes. When muscular exertion is very great, some ATP

synthesis is accomplished by using the anaerobic pathway, when ATP, creatine

phosphate stores and oxygen supply from myoglobin are depleted.

After a period of exertion is over, the rate of ventilation remains high for some time,

extra O2 is consumed to remove the excess lactate, replenish the ATP, and creatine

phosphate stores, and replace the small amounts of O2 that have come from

myoglobin. This extra post-exercise O2 consumption is called [oxygen debt].

Safety Factor at NMJ: Fatigue Each impulse that arrives at the NMJ causes about three times as much end plate

potential as that required to stimulate the muscle fiber. Therefore, the normal

neuromuscular junction is said to have a high safety factor. However, stimulation of

the nerve fiber at rates greater than 100 times per second for several minutes often

diminishes the number of acetylcholine vesicles so much that impulses fail to pass

into the muscle fiber. This is called fatigue of the neuromuscular junction, and it is

the same effect that causes fatigue of synapses in the central nervous system when

the synapses are overexcited.

Under normal functioning conditions, measurable fatigue of the neuromuscular

junction occurs rarely, and even then, only at the most exhausting levels of muscle

activity.

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Muscle Fatigue: Prolonged and strong contraction of a muscle leads to a state of

muscle fatigue, which decreases the strength of contraction, prolongs its duration,

and relaxation becomes incomplete. Muscle Fatigue is due to:

a- Accumulation of lactic acid which decreases myoplasmic pH altering Ca++

binding to troponin C and that decreases the maximum number of actin-myosin

interactions.

b- Depletion of muscle ATP, glycogen and creatine phosphate. elevation in [Pi] can

reduce tension by inhibition of Ca++ release from the SR.

c- Interruption of blood flow through a contracting muscle and loss of nutrient

supply, especially loss of oxygen.

d- Diminished transmission at neuromuscular junction.

Types of skeletal Muscle fibers:

According to the abundance of the different types of enzymatic machinery available

for synthesizing ATP. Some fibers contain numerous mitochondria and thus have a

high capacity for oxidative phosphorylation. These fibers are classified as oxidative

fibers. Most of the ATP that such fibers produce is dependent upon blood flow to

deliver oxygen and fuel molecules to the muscle. Not surprisingly, therefore, these

fibers are surrounded by many small blood vessels.

They also contain large amounts of an oxygen-binding protein known as myoglobin,

which increases the rate of oxygen diffusion into the fiber and provides a small store

of oxygen. The large amounts of myoglobin present in oxidative fibers give the

fibers a dark red color; thus, oxidative fibers are often referred to as red muscle

fibers. In contrast, glycolytic fibers have few mitochondria but possess a high

concentration of glycolytic enzymes and a large store of glycogen. Corresponding

to their limited use of oxygen, these fibers are surrounded by relatively few blood

vessels and contain little myoglobin. The lack of myoglobin is responsible for the

pale color of glycolytic fibers and their designation as white muscle fibers.

Myosin ATPase activity is positively correlated with muscle contraction velocity.

According to MyosinATPase activity and the metabolic profile of the muscle

fibers, we can classify muscle fibers into the following types:

1. Slow-oxidative fibers (type I) combine low myosinATPase activity with high

oxidative capacity.

2. Fast-oxidative-glycolytic fibers (type IIA) combine high myosin-ATPase activity

with high oxidative capacity and intermediate glycolytic capacity.

3. Fast-glycolytic fibers (type IIB) combine high myosinATPase activity with high

glycolytic capacity. These three types of fibers also differ in their capacity to resist

fatigue. Fast-glycolytic fibers fatigue rapidly, whereas slow oxidative fibers are very

resistant to fatigue, which allows them to maintain contractile activity for long

periods with little loss of tension. Fast-oxidative-glycolytic fibers have an

intermediate capacity to resist fatigue.

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Skeletal muscle/fiber classification

Page 25 of 28


Lecture 6

Muscle Physiology Increasing the force (tension) of the contracting Muscle (Grading of Muscle

activity):

a-With minimal voluntary activity, a few motor units discharge, and with increasing

voluntary effort more units contract. Motor unit size varies considerably from one

muscle to another. The muscles in the hand and eye, which produce very delicate

movements, contain small motor units. For example, one motor neuron innervates

only about 13 fibers in an eye muscle. In contrast, in the more coarsely controlled

muscles of the legs, each motor unit is large, containing hundreds and in some cases

several thousand fibers.

When a muscle is composed of small motor units, the total tension the muscle

produces can be increased in small steps by activating additional motor units. If the

motor units are large, large increases in tension will occur as each additional motor

unit is activated. Thus, finer control of muscle tension is possible in muscles with

small motor units. The force a single fiber produces, as we have seen earlier, depends

in part on the fiber diameter—the greater the diameter, the greater the force.

The process of increasing the number of motor units that are active in a muscle at

any given time is called Recruitment of Motor Units. It is achieved by activating

excitatory synaptic inputs to more motor neurons. The greater the number of active

motor neurons, the more motor units recruited and the greater the muscle tension.

Size Principle of Motor Units Recruitment:

Motor neuron size is important in the recruitment of motor units. The smallest

neurons will be recruited first—that is, they will begin to generate action potentials

first and the larger neurons will be recruited later. Because the smallest motor

neurons innervate the slow-oxidative motor units, these motor units are recruited

first, followed by fast-oxidative glycolytic motor units, and finally, during very

strong contractions, by fast-glycolytic motor units.

b- The force of a voluntary movement is also increased by increasing the frequency

of discharge of impulses to the motor unit leading to tetanic contractions.

Factors Affecting Skeletal Muscle Contraction:

1- Type of muscle fibers

2-Stimulus Factors:

a- Strength of the stimulus:

Increasing the strength of stimulus will increase the number of activated fibers

[recruitment] with gradual increase in whole muscle response. Maximal stimulus

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activates all muscle fibers. Supra maximal stimulus would not give further response

as each fiber responds maximally according to all or none law.

b- The frequency of muscle stimulation: The force of contraction can be increased

by increasing the frequency of muscle stimulation and allowing summation to occur

with the possibility for genesis of tetanus.

3- Initial length of the muscle (Length-tension relationship.

4- The afterload (Load-Velocity Relationship).

5- Muscle Fatigue.

Remodeling Of Muscle To Match Function

Muscular hypertrophy:

It is the increase in size of muscle as a result of forceful muscular activity. The

number of the muscle fibers in the muscle does not change. The muscle fibers

increase in thickness. They gain in total number of myofibrils as well as in their

content of ATP, creatine phosphate and glycogen.

Muscle Atrophy:

When a muscle remains unused for many weeks, the rate of degradation of the

contractile proteins is more rapid than the rate of replacement. Therefore, muscle

atrophy occurs. The pathway that appears to account for much of the protein

degradation in a muscle undergoing atrophy is the ATP-dependent ubiquitin-

proteasome pathway. Proteasomes are large protein complexes that degrade

damaged or unneeded proteins by proteolysis, a chemical reaction that breaks

peptide bonds. Ubiquitin is a regulatory protein that basically labels which cells will

be targeted for proteosomal degradation.

Reaction of muscle to denervation:

If the nerve supply to the muscle is injured, the muscle is paralyzed. This is known

as lower motor neuron lesion (details in CNS).

Abnormalities in muscle contraction & sites of blocking of neromuscular

transmission:

1-Rigor Mortis:Several hours after death all the muscles of the body go into a state

of contracture. The muscle contracts and becomes rigid even without action

potentials.

Mechanism:

Absence of ATP→ No reuptake of Ca2+ into the SR as Ca2+ uptake also requires

ATP-dependant Ca2+ pump → Ca2+ level of sarcoplasm ↑ →continued binding of

Ca2+ to Troponin C →Abnormal, rigid and uninterrupted contraction.

No ATP →No relaxation a new molecule of ATP must attach to the myosin head for

detachment of actin- myosin interaction →thus, when NO ATP is present, then

myosin heads cannot detach themselves from actin.

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Time Taken:

In humans, it commences after about three to four hours after death, reaches

maximum stiffness after 12 hours, and gradually dissipates until approximately 48

to 60 hours (three days) after death.

When does Rigor Mortis end:

when contractile proteins of the muscle like other body tissues undergo autolysis

caused by enzymes released by lysosomes.

2-Botulinum toxin prevents the release of Ach by blocking the fusion of Ach

containing vesicles with the postsynaptic membrane & thus prevents the exocytosis

of these vesicles. It has some therapeutic use to relieve pain of pathological

contraction. Low doses of one type of botulinum toxin (Botox) are injected

therapeutically to treat a number of conditions, including facial wrinkles, severe

sweating, uncontrollable blinking.

3- Myasthenia Gravis:

Myasthenia gravis is a serious and sometimes fatal disease in which skeletal muscles

are weak and tire easily. It is an autoimmune disease in which patients have

developed antibodies against their own acetylcholine-activated receptors. If the

disease is intense enough, the patient dies of paralysis, particularly of respiratory

muscles. A number of approaches are used to treat the disease. One is to administer

acetylcholinesterase inhibitors (e.g.,Neostigmine, pyridostigmine). This can

partially compensate for the reduction in available ACh receptors by prolonging the

time that acetylcholine is available at the synapse. Other therapies aim at blunting

the immune response. Treatment with glucocorticoids is one way that immune

function is suppressed. Removal of the thymus (thymectomy) reduces the production

of antibodies and reverses symptoms in about 50% of patients. Plasmapheresis is a

treatment that involves replacing the liquid fraction of blood (plasma) that contains

the offending antibodies. A combination of these treatments has greatly reduced the

mortality rate for myasthenia gravis

4-Hypocalceamic tetany:

Hypocalcemic tetany is the involuntary tetanic contraction of skeletal muscles that

occurs when the extracellular Ca2+ concentration decreases to about 40% of its

normal value. This may seem surprising, because we have seen that Ca2+ is required

for excitation–contraction coupling. However, recall that this Ca2+ is sarcoplasmic

reticulum Ca2+, not extracellular Ca2+. The effect of changes in extracellular Ca2+

is exerted not on the sarcoplasmic reticulum Ca2+ but directly on the plasma

membrane. Low extracellular Ca2+ (hypocalcemia) increases the opening of Na+

channels in excitable membranes, leading to membrane depolarization and the

spontaneous firing of action potentials.

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MYOKINES : are proteins that are secreted from myocytes and communicate with

cells locally within the muscles (autocrine/paracrine) or to other distant tissues

(endocrine).

Muscle–Muscle Crosstalk: Some myokines involved in the regulation of muscle

mass or muscle metabolism:

Myostatin : negatively regulates myogenesis in an autocrine manner.

Decorin : acts as an antagonist to myostatin. Circulating levels of decorin are

increased in response to exercise in humans, whereas exercise training reduces the

levels of myostatin within muscles and blood.

Musclin has been identified as an exercise-induced factor promoting skeletal muscle

mitochondrial biogenesis and abolishes muscle atrophy.

IL-6 increases both basal glucose uptake.

Muscle–Brain Crosstalk: Physical exercise has a positive impact on stress, anxiety,

and depression, memory, learning, reaction time and academic achievement.

Physical activity has also beneficial effects on sleep, and mood.

Brain derived Neurotropic factor (BDNF) released during exercise, is a growth

factor for the hippocampus and involved in cell survival and learning

Muscle-Adipocytes crosstalk: physical inactivity and muscle disuse lead to

accumulation of visceral fat and consequently to the activation of a network of

inflammatory pathways, which promote development of insulin resistance and type

2 diabetes. IL-6 can enhance lipolysis and fat oxidation.

Brown fat play a role in glucose homeostasis, insulin sensitivity, and lipid

metabolism—all factors related to pathogenesis of type 2 diabetes. The fact that

white adipose tissue can shift into a brown-like phenotype, the discovery of brown

fat in humans, and the potentially beneficial effects of lifestyle, such as exercise, can

contribute to induce browning of white fat. Irisin was reported as a myokine with

the ability to brown white adipose tissue.

Muscle–Liver Crosstalk: In order to maintain glucose homeostasis during exercise,

glucose uptake in muscle is accompanied by increased glucose production from the

liver. the existence of direct muscle–liver crosstalk. Muscle-derived IL-6 plays a role

in triggering glucose output from the liver during exercise in humans.

Muscle–Gut Crosstalk: Acute elevations in IL-6 stimulates Glucagon Like Peptide-

1 (GLP-1) secretion from both intestinal L‐cells and pancreatic β‐cells, leading to

improved secretion of insulin.

Muscle–Vascular Bed Crosstalk: Follistatin-like 1 (FSTL1) was shown to be

produced by both skeletal and cardiac muscle cells. FSTL1 has cardioprotective

effects, promoting endothelial cell function and revascularization.

Muscle–Skin Crosstalk: Exercise retards skin aging via a mechanism that involves

muscle-derived IL-15.

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