amudu: What is Muscle physiology

Monday, February 6, 2017

What is Muscle physiology

· Voluntary muscles (supplied by somatic nerves)

o Skeletal muscle: for locomotion, positional change & convection of respiratory gases.

· Involuntary muscles: (supplied by autonomic nerves)

o Cardiac muscle: for pumping the blood

o Smooth muscle: motor of internal organs & blood vessels.

Feature	Smooth	Cardiac	Skeletal
Myofibrils	Absent	Present	Present
T tubules	Absent	Short & broad	Long & thin
Depolarization	Spontaneous	Spontaneous	Upon stimulation
Summation	Possible	Not possible	Possible
RMP	Unstable	Stable	Stable
Source of Ca	Extracellular	SR	SR
Neuromuscular junction	Not well defined	Not well defined	Well defined

SKELETAL MUSCLE

· The muscle mass is separated from neighbouring tissues by à fascia

· Beneath the fascia, the muscle is covered by à epimysium

· Muscle fiber bundle or fascicule is covered by à perimysium

· Each muscle fiber is covered by à endomysium

· Muscle cell or fibers are à multinucleated with peripheral nuclei located just beneath the sarcolemma.

· Each striated muscle fiber is invested by a cell membrane à the sarcolemma, which surrounds the sarcoplasm, several mitochondria (sarcosomes) & myofibrils.

Structure of a myofibril

Each myofibril consists of a number of two alternating bands:

Light band: I band - Isotropic in nature (contain only actin filaments)

Dark band: A band - Anisotropic in nature (actin & myosin filaments overlap in this region)

(Isotropic: when polarized light is passed thru the muscle fiber, the light rays are refracted at the same angle)

Z lines or Z plates (plate-like proteins) subdivide each myofibril into striated compartments called sarcomeres (2μm long).

Sarcomere:

The portion of myofibril in btwn two Z lines.

It is the structural & functional unit of skeletal muscle.

H zone: lies in the middle of A band. Contains only myosin filaments.

M line: situated in the middle of H zone. It is formed by myosin binding proteins.

Sarcomere consists of myofilaments à action & myosin filaments

Actin Filaments: Thin filaments, Extend to z line, I band & upto H zone of A band.

Myosin Filaments: Thick filaments, Situated in A band, including the H zone.

During contraction: H zone & I band are shortened and the Z lines come closer.

Types of Skeletal Muscle proteins

Contractile proteins: Actin, Myosin

Regulatory proteins:

· Skeletal & cardiac muscle – tropomyosin, troponin

· Smooth muscle - Calmodulin

Nebulin: responsible for positioning of action.

Titin (connectin)

Contractile protein connected with Z disc: Actin

Contractile protein connected with M disc: Myosin

Titin is connected with z disc & M disc

MYOSIN

Myosin I – present in sperms

Myosin II - present in sarcomere (skeletal muscles)

· Each myosin filament consists of a bundle of myosin-II molecules.

· Each myosin molecule is made up of 6 polypeptide chains: 2 heavy chains & 4 light chains

· At one end, the 2 heavy chains twist around each other to form a double helix – the tail.

· At the other end, both the chains turn away in opposite directions & form – globular head.

· Each myosin head is attached with 2 light chains (one regulatory & one essential).

· Each myosin head has 2 sites: an actin binding site & a motor domain with a nucleotide binding pocket (for ATP or ADP + Pi)

· Conformational changes in the head–neck segment allow the myosin head to “tilt” when interacting with actin (sliding filaments).

· In the central part of myosin filament (H zone) à Myosin head is absent.

ACTIN

· Each actin molecule is called F actin & it is a polymer of a small protein called G actin.

· Actin molecules in actin filament are also arranged in the form of a double helix, which is positioned by the equally long protein nebulin.

· Each F actin molecule has an active site for the attachment of myosin head.

During rest, Actin is detached from myosin by relaxing (inhibitory) proteins:

· Tropomyosin: covers the myosin binding sites on F-actin molecules.

· Troponin which is formed of 3 subunits:

o Troponin T: binds to tropomyosin

o Troponin I: binds with actin & prevents the filaments from sliding when at rest

o Troponin C: has two regulatory bindings sites for Ca2+ at the amino end

Other proteins of the muscle:

· Actinin: Attaches actin filament to Z line.

· Desmin: binds Z line with sarcolemma.

· Nebulin: runs parallel to actin filaments.

· Titin (connectin): Connected to M line (at its carboxyl end) & Z line (at its amino end). Provides elasticity to the muscle.

Longest known polypeptide chain & comprises 10% of the total muscle mass.

[when the muscle is stretched, titin unfolds itself.

If the stretching is more, it offers resistance & protects the sarcomere from overstretching.]

· Dystrophin: connects actin filament to to the membrane of muscle cell. It is connected to sarcoglycans of the sarcolemma.

· Merosin binds the sarcoglycans to the collagen fibrils of the extracellular matrix.

Mutation of these proteins leads to muscular dystrophy (Duchenne muscular dystrophy, limb-girdle dystrophy, congenital muscular dystrophy) implying the degeneration of muscle fibers with increasing muscular weakness.

Sarcotubular System

Formed by: T tubules & L tubules (sarcoplasmic reticulum)

T tubules: Formed by transverse invaginations of the sarcolemma.

Function:

They act as the inward pathway for action potential.

It contains DHPR which are volt sensitive receptors.

Sarcoplasmic Retiuculum (L tubules)

The ER is modified as longitudinal tubules with terminal expansion called – cisternae which store Ca ions & contain RYR1.

Triad of skeletal muscle: T tubule along with terminal cisternae on either side.

They are situated at the junction btwn A band & I band.

When AP reaches DHPR on T tubules, it opens RYR1 on the cisternae à Ca efflux from the cisternae into sarcoplasm.

The released Ca binds with troponin C & uncovers the active sites for myosin on actin.

Skeletal muscle formed of:

· Central contractile part – contains sk. Muscle fibers

· Peripheral non-contractile ends – elastic non-contractile stretchable tissues

Contraction of sk muscle à shortening of central contractile part (In the form of shortening of sarcomeres.

Types of sk muscle contraction:

Isometric contraction	Isotonic contraction
Shortening of central contractile part = lengthening of peripheral non-contractile parts	Shortening of central contractile part as well as shortening & stretching of peripheral ends.
Total length is constant	Total tension is constant.
Eg: During upright position in lower sk muscles to maintain the body posture.	Could be associated with shortening or lengthening (Lifting or placing down of object with a constant tension (eg: picking of precious objects very slowly).
No external work done.	External work done
In cardiac muscle, this represents isovolumetric contraction, bcoz the muscle length determines the atrial or ventricular volume.)	In cardiac muscle, this represents isobaric contraction, bcoz the muscle force determines the atrial or ventricular pressure.

Auxotonic contractions: muscle length & force both vary simultaneously.

Afterloaded contraction: An isotonic or auxotonic contraction that builds on an isometric one.

Types of skeletal muscle fibers depending on myosin ATPase activity:

Type I or slow twitch fibers – have small diameter

Type II or fast twitch fibers – have large diameter. Have two subtypes, FR (2 A) & FF (2 B).

Each motor unit contains only one type of fiber, this classification also applies to the motor unit.

Based on contraction time, skeletal muscles are classified into two types:

Feature	Red (slow) muscles	Pale (fast muscles)
Fiber type	Type I fibers are more	Type II fibers are more
Myoglobin content	High, so it is red ( for short-term O2 storage)	Less (FF<< FR)
Blood supply	Rich	Relatively Less
Mitochondria	Rich	Relatively Less
Sarcoplasmic retiuculum	Less extensive	More extensive
Latent period	Long	Short
Power of Contraction	Less powerful	More powerful
Duration of contraction	Sustained contraction (longer contraction time)	Brief and rapid contractions.
Fatigue	Occurs slowly	Occurs quickly (FF > FR)
Energy source	Depends on cellular respiration (aerobic) Have conc. of fat droplets (high-energy substrate reserves) Rich in oxidative enzymes	Depends on glycolysis (anaerobic) Rich in glycogen (FF > FR)
Examples	Back muscles & gastrocnemius	Soleus (for upright position), Hand muscles & ocular muscles

Each fiber type can also be converted to the other type.

If, prolonged activation of fast-twitch fibers leads to a chronic in cytosolic Ca2+ conc. fast-twitch fibers will be converted to slow-twitch fibers & vice versa.

Motor End-plate (MEP)

It is a type of chemical synapse where transmission of stimuli from a motor axon to a skeletal muscle fiber occurs.

Neurotransmitter à ACh

Receptors at the subsynaptic muscle membrane: N_M(nicotinergic)-ionotropic cholinoceptors

The N-cholinoceptor of the MEP (TypeN_M) has 5 subunits: (2α, 1β,1γ, 1δ), each containing 4 membrane spanning α-helices.

Unlike voltage-gated Na+-channels, the open probability po of the N_M-cholinoceptor is not increased by depolarization, but is determined by the ACh conc. in the synaptic cleft.

Endplate potential:

It is the change in the RMP (-90mV) when an impulse reaches the NMJ. It is a graded potential.

At RMP, binding of ACh molecule to the two α-subunits à brief opening of channel (specific to cations such as Na+, K+, Ca2+) à influx of Na+ ions mainly (& a much lower outflow of K+) à Depolarization of the subsynaptic membrane à endplate potential (EPP)

Miniature end plate current:

Release of a small quantity of Ach from the axon terminal à Single-channel currents à that are summated à yielding miniature end-plate current when spontaneous exocytosis occurs & a vesicle releases a quantum of ACh activating thousands of N_M-cholinoceptors.

Miniature end plate current: May occur spontaneously due to rupture & release of few Ach into synaptic cleft due to muscular contraction.

Can be described as fibrillation – can’t be seen with naked eye.

If they can be seen with naked eye – they are called twitches.

But generation of a postsynaptic action potential requires a motor neuron that triggers exocytosis of a 100 vesicles à opening of 200,000 channels at the same time à neurally induced end-plate current (IEP)

End-plate current (IEP) is dependent on:

· No. of open channels = total number of channels (n) x the open-probability (po)

[po is determined by the conc. of ACh in the synaptic cleft (up to 1 mmol/L)]

· Single-channel conductance γ

· Membrane potential, Em, since the electrical driving “force” (= Em–ENa,K) becomes smaller when Em is less -ve.

[ENa,K = common equilibrium potential for Na+ & K+ (@ 0mV).

It is also called the reversal potential bcoz the direction of IEP (= INa + IK), which enters the cell when Em is -ve (Na+ influx > K+ outflow), reverses when Em is positive (K+ outflow > Na+ influx).

IEP = n . po . γ . (Em – ENa, K)

Because neurally induced EPPs in skeletal muscle are much larger (depolarization by 70 mV) than neuronal EPSPs (only a few mV), single motor axon action potentials are above threshold.

The EPP is transmitted electrotonically to the adjacent sarcolemma, where muscle AP’s are generated by means of voltage-gated Na+ channels à muscle contraction.

Termination of synaptic transmission in MEPs occurs by

(1) Rapid degradation of ACh in the synaptic cleft by acetylcholinesterase localized at the subsynaptic basal membrane, and

(2) Diffusion of ACh out of the synaptic cleft

Neuromuscular blockers

A motor end-plate can be blocked by certain poisons & drugsà muscular weakness & paralysis.

Botulinum neurotoxin: inhibits the discharge of NT’s from the vesicles.

α-bungarotoxin in snake venom: blocks the opening of ion channels.

Receptor blocker:

· Competitive inhibitors to ACh: Curare-like substances such as (+)-tubocurarine à used as muscle relaxants in surgical operations. Displace ACh from its binding site but do not have a depolarizing effect of their own.

· ACh-like substances: suxamethonium, succinylcholine or carbamylcholine act like Ach & keep the muscle in a depolarized state.

· Since they are not destroyed by acetylcholinesterase, the muscle remains in a depolarized state for a long time à paralysis bcoz permanent depolarization also permanently inactivates Na+ channels near the motor end-plate on the sarcolemma.

Drugs stimulating Neuromuscular Junction:

· Decurarinization: The inhibitory effect of curare can be reversed by cholinesterase inhibitors such as neostigmine.

· These agents Ach conc. in the synaptic cleft, thereby displacing curare.

· Entry of anticholinesterase agents into intact synapses à Ach conc. à paralysis due to permanent depolarization.

Motility and Muscle Types

Active motility is due to either:

· Interaction of energy-consuming motor proteins (fueled by ATPase) such as myosin, kinesin & dynein with other proteins such as actin or

· Polymerization & depolymerization of actin & tubulin.

Motor Unit of Skeletal Muscle

Smooth muscle (single unit type) & cardiac muscle fibers pass electric stimuli to each other thru gap junctions or nexus, while

Skeletal muscle fibers are not stimulated by adjacent muscle fibers, but by motor neurons.

[In fact, muscle paralysis occurs if the nerve is severed].

Motor unit (MU): One motor neuron together with all muscle fibers innervated by it.

To supply its muscle fibers, a motor neuron splits into collaterals with terminal branches.

A given motor neuron may supply only 25 muscle fibers (mimetic muscle) or well over 1000 (temporal muscle).

Motor pool: all ant. horn cells & the innervated muscle fibers for one sk. Muscle.

Not all the ant. horn cells are active at the same time i.e not all sk. Muscle fibers contracting at the same moment. There is alternative activity to avoid fatigue.

Recruitment of motor units: gradation of sk. Muscle contraction.

stimulus strength à activation of more motor units à force of contraction.

Frequency of action potential generated by motor cortex.

Graded muscle activity:

· It is possible because a variable number of motor units can be recruited as needed.

· The more motor units a muscle has, the more finely graded its contractions.

· Contractions are much finer in the external eye muscles (2000 motor units), than in the lumbrical muscles (100 motor units).

· Larger the number of motor units recruited, the stronger the contraction.

· The no. & type of motor units recruited depends on the type of movement involved (fine or coarse, intermittent or persistent contraction etc.).

· Strength of each motor unit can be increased by à the frequency of neuronal impulses, as in the tetanization of skeletal muscle.

Stimulation of muscle fibers

Release of Ach at the MEP of sk. muscle à end-plate current that spreads electrotonically à activation of fast voltage-gated Na+ channels in the sarcolemma à firing of an AP that travels rapidly along the sarcolemma of the entire muscle fiber & penetrates deep into it thru T tubules

[C:N - Genetic defects of these Na+ channels slow down their deactivation à hyperexcitability à extended contraction & delayed muscle relaxation (myotonia).]

The extended muscular activity à K+ efflux to ECF à hyperkalemia à ¯ muscular resting potential à inactivation of Na+ à temporary muscle paralysis (familial hyperkalemic periodic paralysis)

Electromechanical coupling

The conversion of excitation of a muscle into a contraction.

In the skeletal muscle:

· This process begins with the AP that excites the voltage- sensitive dihydropyridine receptors (DHPR) of the sarcolemma in the region of the triads.

· The DHPR are arranged in rows & directly opposite them in the adjacent membrane of the SR are rows of Ca2+ channels called ryanodine receptors (RYR1 in sk. muscle).

· Every other RYR1 is associated with a DHPR.

· RYR1 open when they directly “sense” by mechanical means an AP-related conformational change in the DHPR.

· In skeletal muscle, DHPR stimulation at a single site is enough to trigger the coordinated opening of an entire group of RYR1 à reliability of impulse transmission.

In the myocardium:

· Each DHPR is part of a voltage-gated Ca2+ channel (L-type) of the sarcolemma that opens in response to an action potential.

· Small quantities of EC Ca2+ enter the cell thru this channel à opening of myocardial RYR2 (trigger effect of Ca2+ or Ca2+ spark).

Ca2+ ions stored in the SR now flow thru the opened RYR1 or RYR2 channels into the cytosol à [Ca2+]i à saturation of the Ca2+ binding sites on troponin-C à canceling of the troponin-mediated inhibitory effect of tropomyosin on filament sliding à strong (high affinity) actin-myosin-II binding.

[C:N - In patients with genetic defects of RYR1, general anesthesia à massive release of Ca2+ à intense muscle contractions à rapid & life threatening increase of body temperature: malignant hyperthermia.]

Sliding filament mechanism of muscle contraction

ATP: essential for filament sliding & hence, for muscle contraction.

Myosin heads act as the motors (motor proteins) of this process à due to their ATPase activity.

· Myosin heads connect with actin filaments at a particular angle forming à cross-bridges.

· Conformational change in the region of nucleotide binding site of myosin, (the spatial extent of which is increased by concerted movement of the neck region) à tilting down of myosin head à power stroke (drawing the thin filament a length of 4–12nm).

· The head then detaches & “tenses” in preparation for the next “oarstroke” when it binds to actin anew.

· Kinesin independently advances on the microtubule by incremental movement of its 2 heads, as in tug-of-war. In this case, 50% of the cycle time is “work time” (duty ratio = 0.5).

· Btwn two consecutive interactions with actin in skeletal muscle, myosin-II “jumps” 36nm (or multiples of 36) to reach the next suitably located actin binding site (C3, jump from a to b).

· Meanwhile, the other myosin heads working on this particular actin filament must make at least another 10 to 100 oarstrokes of around 4–12nm each.

· The duty ratio of a myosin head is therefore à 0.1 to 0.01.

· This division of labor by the myosin heads ensures that a certain percentage of the heads will always be ready to generate rapid contractions.

When filament sliding occurs:

· Z plates approach each other à shortening of I band

· Overlap region of thick & thin filaments becomes larger à shortening of H zone

· Length of the filaments remains unchanged.

Max. muscle shortening occurs à When the ends of thick filaments bump against the Z plate à overlapping of the ends of thin filaments.

Shortening of the sarcomere therefore occurs at both ends of the myosin bundle, but in opposite directions.

Contraction cycle

Binding of ATP to each of the 2 myosin heads (with the aid of Mg2+) à M-ATP complex lying at 45° angle to the rest of the myosin filament à weak affinity of myosin for actin binding.

Influence of cytosolic Ca2+ conc. on the troponin–tropomyosin complex à activation of myosin’s ATPase by actin à hydrolysis of ATP (ATP à ADP + Pi) à formation of A-M-ADP-Pi complex à lifting of myosin heads (conformational change) à actin-myosin association constant by 10⁴.

1^st step of power stroke: Detachment of Pi from the complex à 40° tilt of the myosin heads à sliding of actin & myosin filaments past each other.

2^nd step of power stroke: Release of ADP initiates à final positioning of the myosin heads

The remaining A-M complex (rigor complex) is stable & can again be transformed into a much weaker bond when the myosin heads bind ATP anew (“softening effect” of ATP,D4).

flexibility of muscle at rest is important for: processes such as cardiac filling or the relaxing of the extensor muscles during rapid bending movement.

If the cytosolic Ca2+ conc. remains high, the D1 to D4 cycle will begin anew. This depends mainly on whether subsequent AP’s arrive. Only a portion of the myosin heads that pull actin filaments are “on duty” (low duty ratio) to ensure the smoothness of contractions.

The Ca2+ ions released from the sarcoplasmic reticulum (SR): continuously pumped back to the SR actively by Ca2+-ATPase (SERCA).

If the RYR-mediated release of Ca2+ from the SR is interrupted, the cytosolic Ca2+ conc. rapidly drops & filament sliding ceases (resting position).

Parvalbumin:

· It is a protein occuring in the cytosol of fast-twitch muscle fibers (type F).

· Accelerates muscle relaxation after short contractions by binding cytosolic Ca2+ in exchange for Mg2+.

· Its binding affinity for Ca2+ is higher than that of troponin, but lower than that of SR’s Ca2+-ATPase.

· It therefore functions as a “slow” Ca2+ buffer.

During isotonic contractions (where muscle shortening occurs): The course of the filament sliding cycle as described above takes place.

During strictly isometric contractions (tension increases but length remains unchanged): tilting of the myosin heads & the filament sliding cannot take place.

Instead, the isometric force is created thru the deformation of myosin heads.

Skeletal muscle cramp: no ATP

For the myosin head to return back to its resting state, it needs to be energized.

Lack of ATP à sk. muscle cramps

May occur due to ischemia as decreased blood supply à decreased ATP supply.

If it occurs during death à rigor morse.

Muscle fibers of a dead body do not produce any ATP. So, after death:

· Ca2+ is no longer pumped back into SR

· ATP reserves needed to break down stable A-M complexes are depleted.

This results in stiffening of the dead body or rigor (firmness) mortis, which passes only after the actin & myosin molecules in the muscle fibers decompose.

Sk. Muscle relaxation is active due to two factors:

· Energization of myosin head: binding of ATP to myosin head to bring it back to resting state.

· Active Ca reuptake by longitudinal tubules (by Ca2+ ATPase).

Mechanical Features of Skeletal Muscle

AP’s generated in muscle fibers à [Ca2+]i à triggering of contraction

In skeletal muscles, gradation of contraction force is achieved by:

· Variable recruitment of motor units

· Changing the AP frequency

Single stimulus always à max. Ca2+ release à max. single twitch of sk. muscle fiber if above threshold (all-or-none response).

But a single stimulus does not induce max. shortening of muscle fiber: bcoz it is too brief to keep the sliding filaments in motion long enough for the end position to be reached.

Muscle shortening continues only if à a 2^nd stimulus arrives before the muscle has completely relaxed after the first stimulus.

Effects of two successive stimuli:

3 different effects are noticed depending upon the interval btwn the two stimuli:

Beneficial effect: when the 2^nd stimulus falls after the relaxation period of 1^st twitch, 2 separate curves are obtained but the force of 2^nd twitch is greater due to temp. à ¯viscosity of muscle after 1^st twitch.

Superposition: if the 2^nd stimulus falls during relaxation period of 1^st twitch, 1^st curve is superimposed by the 2^nd curve.

Summation: If 2^nd stimulus is applied during contraction period, 2 contractions are summed up & single curve is obtained with an amplitude gr8r than the simple muscle curve.

Treppe or Staircase Phenomenon

Gradual increasein force of contraction of muscle when it is stimulated repeatedly with a maximal strength at a low frequency. It is different from summation & tetanus.

Tetanus: summation of contraction without relaxation due to marked in the frequency of excitation.

Tetany: neuromuscular excitability due to hypocalcemia caused by hypoparathyroidism etc

Tetanus

· It is the sustained maximum contraction of the motor units.

· It occurs if the frequency of stimulation becomes so high that the muscle can no longer relax at all btwn stimuli.

[It occurs at 20 Hz in slow-twitch muscles & at 60–100 Hz in fast-twitch muscles].

· Muscle force during tetanus is as much as 4 times larger than that of single twitches.

· The Ca2+ conc., which decreases to some extent btwn superpositioned stimuli, remains high in tetanus.

Contracture: Not caused by AP’s, but by persistent local depolarization due to:

· [K+]o (K+ contracture) or

· Drug-induced intracellular Ca2+ release, e.g., in response to caffeine.

The contraction of tonus fibers (specific fibers in external eye muscles & in muscle spindles) is also a form of contracture.

· Tonus fibers do not respond to stimuli acc. to the all-or-none law, but contract in proportion with the magnitude of depolarization.

· Magnitude of contraction of tonus fibers regulated by à variation of the cytosolic Ca2+ conc. (not by action potentials!)

· The individual contractions cannot be detected bcoz the motor units are alternately (asynchronously) stimulated.

[When apparently at rest, muscles such as the postural muscles are in this involuntary state of tension]

Resting muscle tone:

Continuous & partial contraction of muscles with certain degree of tension. It is maintained by different mechanisms:

· In skeletal muscle: Regulated by reflexes (reflex tone). It is neurogenic i.e due to the arrival of normal AP’s at the individual motor units. It increases as the state of attentiveness increases.

· In Smooth & cardiac muscle: It is myogenic i.e muscle themselves control the tone. It depends upon Ca2+ level & no. of cross bridges.

Muscle extensibility

A resting muscle containing ATP can be stretched like a rubber band.

The force required to start the stretching action (extension force at rest) is very small, but increases exponentially when the muscle is under high elastic strain.

Musscle’s resistance to stretch à keeps the sliding filaments in the sarcomeres from separating.

It is due to 2 factors:

· Fascia (fibrous tissue) – to a small extent

· Titin (connectin): giant filamentous elastic molecule incorporated in the sarcomere (6 titin molecules per myosin filament).

In the A band: Titin lies adjacent to a myosin filament & helps to keep it in the center of the sarcomere.

In the I band: Titin molecules are flexible & function as “elastic bands” that counteract passive stretching of a muscle & influence its shortening velocity.

Extensibility of titin molecules:

· Titin molecules can stretch up to 10 times their normal length in sk. muscle & somewhat less in cardiac muscle.

· It is mainly due to frequent repetition of the PEVK motif (proline-glutamate-valine-lysine).

· In very strong muscle extension, which represents the steepest part of the resting extensibility curve (_D), globular chain elements called Ig C2 domains also unfold.

· The quicker the muscle stretches, the more sudden & crude this type of “shock absorber” action will be.

Types of tension in sk. Muscle:

During rest: passive tension – minimal binding btwn actin & myosin, minimal baseline contraction. Sk. Muscle length is shorter than the distance btwn origin & insertion. This leads to their minimal stretching.

During voluntary movement: active tension + passive tension = total tension

[Active force is determined by the magnitude of all potential actin myosin interactions. Hence it varies in accordance with the initial sarcomere length]

Vmax: Maximal velocity of shortening of sarcomere after loading.

Lmax = 2 to 2.2 μm

Maximal length of sarcomere at which maximal tension will be developed.

It is the max. active (isometric) force (F₀) that a skeletal muscle can develop from its resting length.

When (L< Lmax):

Sarcomeres shorten & part of thin filaments overlap à so only forces smaller than F₀ develop.

When L = 70% of Lmax (sarcomere length: 1.65 μm): Thick filaments make contact with the Z disks & F becomes even smaller.

When L > Lmax:

The muscle is greatly pre-extended & can develop only restricted force bcoz à no. of potentially available actin–myosin bridges is reduced.

When extended to 130% or more of Lmax, the extension force at rest becomes a major part of the total muscle force.

Functional differences btwn cardiac muscle & skeletal muscle:

Skeletal muscle	Cardiac muscle
More extensible	Less extensible, so the passive extension force at rest is greater.
Functions in the plateau region of its length–force curve.	Operates in the ascending limb (below Lmax) of its length–force curve without a plateau. So, the ventricle responds to diastolic filling loads by its force development (Frank–Starling mechanism).
	Extension also affects troponin’s sensitivity to Ca2+ à steeper curve
AP’s are of shorter duration. Uses IC Ca2+, so no plateau phase.	AP’s are of much longer duration bcoz gK¯ & gCa temporarily after rapid inactivation of Na+ channels à slow influx of EC Ca2+ à plateau phase of AP. As a result, the refractory period does not end until a contraction has almost subsided. So, tetanus cannot be evoked in cardiac muscle.
Contains motor units.	Has no motor units. The stimulus spreads across all myocardial fibers of the atria & ventricles à all-or-none contraction of both atria & thereafter, both ventricles.
No change	Duration of AP can change the force of contraction (which is controlled by the variable influx of Ca2+ into the cell).

If shortening does not occur à Maximal force & small amount of heat develops.

Greater the force (load) à lower the velocity of an (isotonic) contraction.

Without a stress load à Max. velocity & a lot of heat develops. So, light loads can be picked up more quickly than heavy loads.

The total amount of energy consumed for work & heat is greater in isotonic contractions than in isometric ones.

Muscle power: product of force & shortening velocity.

N· m · s–1 = W

Frank Starling Law

Force of contraction is directly proportional to the initial length of muscle fibers within physiological limits.

Energy Supply for Muscle Contraction

Direct source of chemical energy for muscle contraction à ATP

A muscle cell contains only a limited amount of ATP– only enough to take a sprinter.

So, spent ATP is continuously regenerated to keep the [ATP]i constant, even when large quantities of it are needed.

The three routes of ATP regeneration are:

1. Dephosphorylation of creatine phosphate (for short term peak performance)

2. Anaerobic glycolysis (for medium term high performance, occurs in cytoplasm, faster, produces few molecules of ATP)

3. Aerobic oxdn of glucose & fatty acids (for long term performance, occurs in mitochondria, needs O2, slower, produces large no. of ATP)

Creatine phosphate (CrP):

· Provides chemical energy needed for rapid ATP regeneration (as routes 2 & 3 are relatively slow)

· CrP reserve of the muscle is sufficient for short-term high-performance bursts of 10–20 s (e.g., for a 100-m sprint).

mitochondrial creatine kinase

ADP -------------------------------------- > ATP & Cr

Anaerobic glycolysis

Occurs later than CrP dephosphorylation (after a max. of 30 s).

glucose-6-phosphate

Muscle glycogen -----------------------> Lactic acid (lactate + H+)

Yields 3 ATP molecules for each glucose residue

Aerobic oxidation of glucose & fatty acids

· Takes place @ 1 min after less productive anaerobic form of ATP regeneration.

· Glucose must be imported from the liver where it is formed by glycogenolysis & gluconeogenesis.

· Imported glucose yields only 2 ATP for each molecule of glucose, bcoz one ATP is required for 6-phosphorylation of glucose.

During light exercise: lactate is broken down in the heart & liver whereby H+ ions are used up.

During strenuous exercise: Anaerobic glycolysis must be continued along with aerobic oxdn if it does not supply sufficient quantities of ATP.

For sustained exercise: Aerobic regeneration of ATP from glucose (about 32 ATP per glucose residue) or fatty acids is required.

Cardiac output = HR x stroke volume

· Total ventilation must be to meet the metabolic requirements of the muscle; the HR then becomes constant.

· The several minutes that pass before this steady state is achieved are bridged by:

o Anaerobic energy production

o O2 extraction from the blood

o Depletion of short-term O2 reserves in the muscle (myoglobin).

· The interim (short term) btwn the 2 phases is perceived as the “low point” of physical performance.

O2 affinity of myoglobin > Hb, but lower than that of respiratory chain enzymes.

Thus, myoglobin is normally saturated with O2 & can pass on its O2 to the mitochondria during brief arterial O2 supply deficits.

Endurance limit:

In top athletes = 370W (@0.5 HP)

Mainly dependent on the speed at which O2 is supplied & speed of aerobic oxdn.

When the endurance limit is exceeded à steady state cannot occur à continuous in HR

The muscles can temporarily compensate for the energy deficit but the H+-consuming lactate metabolism cannot keep pace with the persistently high level of anaerobic ATP regeneration.

An excess of lactate & H+ ions à lacticacidosis

When endurance limit exceeds by 60%: it is equivalent to max. O2 consumption à sharp in plasma lactate conc. à anaerobic threshold at 4 mmol/L

No significant increase in performance can be expected after that point (as lactic acid inhibits myosin ATPase as it is very sensitive to acidic pH à Limits sk. Muscle endurance)

Plasma lactate

Aerobic threshold: 2mmol (can be tolerated for prolonged periods of exercise)

Anaerobic threshold: 4mmol (indicate that the performance limit will soon be reached)

Exercise must eventually be interrupted, not bcoz of lactate conc., but bcoz of acidosis.

Systemic drop in pH à inhibition of chemical rxns needed for muscle contraction à ATP deficit à rapid muscle fatigue à stoppage of muscle work

CrP metabolism & anaerobic glycolysis enable the body to achieve 3 times the performance possible with aerobic ATP regeneration, although for only about 40 s.

These processes à O2 deficit that must be compensated for in the post-exercise recovery phase (O2 debt)

The body “pays off” the O2 debt by:

· Regenerating its energy reserves

· Breaking down the excess lactate in the liver & heart.

The O2 debt after strenuous exercise is much larger (up to 20 L) than the O2 deficit for several reasons.

PhysicalWork

There are three types of muscle work:

+ve dynamic work: requires muscles involved to alternately contract & relax (e.g., going uphill).

-ve dynamic work: requires muscles involved to alternately extend while braking (braking work) & contract without a load (e.g., going downhill).

Static postural work: requires continuous contraction (e.g., standing upright).

Many activities involve a combination of 2 or 3 types of muscle work.

Outwardly directed mechanical work is produced in dynamic muscle activity, but not in purely postural work.

Purely postural work

Force x distance = 0

Chemical energy is still consumed & completely transformed into a form of heat called maintenance heat (= muscle force x duration of postural work).

in blood flow is prevented as the continuously contracted muscle squeezes its own vessels. The muscle then fatigues faster than in rhythmic dynamic work.

Light to moderate exercise: HR soon levels out at a new constant level, and no fatigue occurs.

Strenuous exercise:

· Muscles require up to 500 times more O2 than when at rest.

· At the same time, the muscle must rid itself of metabolic products such as H+, CO2 & lactate. Muscle work therefore requires drastic cardiovascular & respiratory changes.

· In untrained subjects (UT): CO rises to a maximum of 15–20 L/min during exercise

· Work-related activation of the sympathetic nervous system:

the HR up to 2.5 fold

the SV up to 1.2 fold

Very strenuous exercise:

· Must soon be interrupted bcoz the heart cannot achieve the required long-term performance.

· CO: provides more blood for the muscles & the skin (heat loss).

· Blood flow in the kidney & intestine: reduced by the sympathetic tone below the resting value. Ps rises while Pd remains constant à moderate increase in the mean pressure.

Smaller the muscle mass involved in the work à higher the increase in B.P

Hence, the B.P increase in arm activity (cutting hedges) is higher than that in leg activity (cycling).

[C:N- In patients with coronary artery disease or cerebrovascular sclerosis, arm activity is therefore more dangerous than leg activity due to the risk of myocardial infarction or brain hemorrhage.]

Muscular blood flow

At the maximum work level, blood flow in 1 kg of active muscle rises to: 2.5 L/min @10% of the max. CO

Hence, no more than 10 kg of muscle (<1/3 the total muscle mass) can be fully active at any one time.

Vasodilatation (for blood flow) achieved thru: local chemical influences (PCO2, PO2, pH¯) or NO release.

During physical exercise:

Feature	Resting value	During exercise (max. value)
Ventilation (V.E)	7.5 L/min	90 to 120 L/min
Respiratory rate		40–60 min^–1max
Tidal volume		2 L
O2 consumption (V.O2)	0.3 L/min	3 L/min (due toO2 consumption in tissues)
Respiratory equivalent (V.E/V.O2)	25 (i.e 25 L of air has to be ventilated to take up 1 L of O2 at rest)	40–50
Pulmonary transit time (Minimal time sufficient for gas exchange)	0.75s	0.25s (Time less than 0.25s, no proper gas exchange)

¯pH & temp. shift the O2 binding curve towards the right.

O2 consumption: calculated as the arteriovenous difference in O2 conc. =

avDO2 (L/L blood) x Blood flow (L/min)

Maximum O2 consumption (V.O2 max) is defined as:

V. O2 max = HRmax· SVmax · avDO2max

Ideal measure of physical exercise capacity: V.O2 max per body weight

Physical Fitness and Training

Physical exercise capacity can be measured by using à ergometry.

Ergometry: assesses the effects of exercise on physiological parameters such as V.O2, respiration rate, HR & plasma lactate conc.

Measured physical power (performance) is expressed in: watts(W) or W/kg body weight (BW).

In bicycle ergometry: a brake is used to adjust the watt level.

In “uphill” ergometry: a treadmill is set at an angle α.

Margaria step test: the test subject is required to run up a staircase as fast as possible after a certain starting distance.

Short-term performance tests (10–30 s): measure performance achieved thru rapidly available energy reserves (CrP, glycogen).

Medium-term performance tests: measure performance fueled by anaerobic glycolysis.

Longer term aerobic exercise performance: measure performance fueled thru oxdn of glucose & FFA by measuring V.O2 max.

In strenuous exercise (2/3 the max. physical capacity or more), aerobic mechanisms do not produce enough energy, so anaerobic metabolism must continue as a parallel energy source à lactacidosis.

Physical training

Raises & maintains the physical exercise capacity.

There are 3 types of physical training strategies:

Motor learning	Endurance training	Strength training
rate & accuracy of motor skills	Improves submaximal long-term performance	Improves max. short-term performance level
e.g., typewriting	e.g., running a marathon	e.g., in weight lifting
These activities primarily involve the CNS	To the oxidative capacity of slow-twitch motor units*	To muscle mass by the size of the muscle fibers (hypertrophy) & to the glycolytic capacity of type F motor units.

*e.g., by the mitochondrial density, CO à V. O2 max à heart weight à SV & tidal volumes à very low resting HR & respiratory rates.

Trained athletes: can therefore achieve larger increases in CO & ventilation.

In individuals practicing endurance training, exercise-related rise in the lactate conc. is also lower & occurs later than in UT.

V.O2 max of a healthy individual is limited by à the cardiovascular capacity & NOT the respiratory capacity.

Excessive physical exercise causes à muscle soreness & stiffness (not due to lactic acid accumulation), but sarcomere microtrauma à muscle swelling & pain.

During exercise: contraction of muscle squeezes the blood vessels.

Veins are squeezed à impaired venous drainage à so the metabolites & lactic acid cannot escape.

[Exercise increases venous drainage for the veins in between the sk. Muscles.]

Since the arterial blood pressure is high, it can overcome the sk. Muscle pressure & flow thru them.

Accumulation of metabolites (due to protein breakdown & lactate production) in the sarcomere à osmotic pressure à extraction of water from ECF à swelling à ¯ blood flow à reflex tension à pain

Muscle ache à sign of microinflammation.

Fatigue: decreased sk. Muscle contraction

Neuromuscular fatigue: repeated stimulation of sk. Muscle by motor nerve. It is due to ¯ time for Ach production.

Depression: ¯ descending motor signals from the brain (motor efferent impulses), despite no sk. muscle work being done.

Muscle fatigue: may be peripheral or central.

Peripheral fatigue: caused by the exhaustion of energy reserves & accumulation of metabolic products in the active muscle. This is particularly quick to occur during postural work.

Central fatigue: characterized by work-related pain in the involved muscles & joints that prevents the continuation of physical exercise or decrease the individual’s motivation to continue the exercise.

Myasthemia Gravis

My – muscle, Athemia – weakness, Grave – generalized

Autoimmune disease leading to formation of antibodies against Ach receptors.

Anticholinesterase is given to increase Ach conc. so that Ach can find the receptors.

· Digitalis à blocks Na/K pump in the heart

· Single action potential is called à Spike potential

· All or none rule: nerve & cardiac muscle.

· The Na channels have 2 gates: activation gate (outside) & inactivation gate (inside).

· The cell membrane contains more K+ leaky channels than Na. So the inside of the membrane become –ve.

· Ionic basis for depolarization: Decreased membrane potential due to Na+ influx.

· Peak of ascending limb of depolarization at à 35mv

· We are using ATP not immediately during the action potential.