Summary of events during Summary of events during skeletal muscle contractionskeletal muscle contraction

RestRest

actin and myosin uncoupledactin and myosin uncoupled

calcium stored in SRcalcium stored in SR

ExcitationExcitationnerve impulse generatednerve impulse generated

ACH released from the vesiclesACH released from the vesicles

sarcolemma depolarizedsarcolemma depolarized

muscle impulse transmitted through the fibermuscle impulse transmitted through the fiber

calcium released from the cisternaecalcium released from the cisternae

calcium binds to troponincalcium binds to troponin

actin binding sites activatedactin binding sites activated

myosin ATPase activatedmyosin ATPase activated

ContractionContraction

Myosin cross-bridges swivelMyosin cross-bridges swivel

Release ADP + Pi Release ADP + Pi

Actin slides over myosinActin slides over myosin

RegenerationRegeneration

ATP attaches to myosinATP attaches to myosin

actin and myosin dissociateactin and myosin dissociate

ATP ATP → ADP + Pi→ ADP + Pi

contraction process repeatscontraction process repeats

RelaxationRelaxation

ACH decomposed by cholinesteraseACH decomposed by cholinesterase

nerve impulse stopsnerve impulse stops

calcium removed by calcium pumpcalcium removed by calcium pump

actin binding sites inhibited actin binding sites inhibited (Tn/tropomyosin complex returns to (Tn/tropomyosin complex returns to original position)original position)

muscle returns to resting statemuscle returns to resting state

Excitation Contraction CouplingExcitation Contraction Coupling

process by which myofibrils translate process by which myofibrils translate nerve impulses into muscle contractionnerve impulses into muscle contraction

depolarization of t-tubule membrane (a depolarization of t-tubule membrane (a change in the membrane potential) results change in the membrane potential) results in the calcium release from the terminal in the calcium release from the terminal cisternae of the SRcisternae of the SR

this results in muscle contractionthis results in muscle contraction

also know calcium is resequestered in the also know calcium is resequestered in the SR via active calcium-ATPase pumpsSR via active calcium-ATPase pumps

not clear is how the change in membrane not clear is how the change in membrane potential of the t-tubule system is potential of the t-tubule system is communicated into the SR to cause communicated into the SR to cause calcium releasecalcium release

Structure and Function of the Structure and Function of the TriadTriad

t-tubules and SR communicate at the triad t-tubules and SR communicate at the triad junctionjunction

a ryanodine receptor is a large protein a ryanodine receptor is a large protein complex which is the release channel of complex which is the release channel of the sarcoplasmic calcium, located at the t-the sarcoplasmic calcium, located at the t-tubule SR junctiontubule SR junction

the receptor has two parts: channel region the receptor has two parts: channel region and a large cytoplasmic regionand a large cytoplasmic region

within t-tubule is another protein within t-tubule is another protein complex, believed to be the voltage complex, believed to be the voltage sensor which controls the opening and sensor which controls the opening and closing of the ryanodine receptor, this is closing of the ryanodine receptor, this is the DHP or dihydropyridine receptor the DHP or dihydropyridine receptor complexcomplex

hypothesized: ryanodine receptor and hypothesized: ryanodine receptor and the DHP receptor interact with each the DHP receptor interact with each other to cause the action potential to other to cause the action potential to induce calcium release from the SRinduce calcium release from the SR

Theories of CommunicationTheories of Communication

Calcium-induced tubule membranesCalcium-induced tubule membranes

Voltage-induced changes in the t-tubuleVoltage-induced changes in the t-tubule

Changes in the voltage gradientChanges in the voltage gradient

Calcium induced tubule Calcium induced tubule membranesmembranes

Cause an opening of the calcium channel Cause an opening of the calcium channel calcium released: calcium released:

stimulation of t-tubule induces a release of stimulation of t-tubule induces a release of calcium ions from the gates within the SRcalcium ions from the gates within the SR

Con: block calcium release channels of the Con: block calcium release channels of the cell membrane does not inhibit calcium cell membrane does not inhibit calcium release from the SRrelease from the SR

Nor reduce tension developmentNor reduce tension development

Also, amount of calcium needed to induce Also, amount of calcium needed to induce release is not clear (may not be release is not clear (may not be physiologic)physiologic)

Voltage-induced changes in the Voltage-induced changes in the t-tubulet-tubule

induce the formation of D-myosinositol induce the formation of D-myosinositol 1,4,5-triphosphate (IP3)1,4,5-triphosphate (IP3)

IP3 then increases the permeability of the IP3 then increases the permeability of the SR membranes to cause calcium releaseSR membranes to cause calcium release

Pros: elevated IP3 production has been Pros: elevated IP3 production has been demonstrated in skeletal muscle demonstrated in skeletal muscle following electrical stimulationfollowing electrical stimulation

Release of calcium in skinned fibers Release of calcium in skinned fibers induced by IP3induced by IP3

An augmented muscle response following An augmented muscle response following inhibition of IP3 breakdowninhibition of IP3 breakdown

A reduction of IP3 release from RBCsA reduction of IP3 release from RBCsCons: is the concentration of IP3 Cons: is the concentration of IP3

necessary for activation and is its rate necessary for activation and is its rate of activation physiologic?of activation physiologic?

Changes in the voltage gradientChanges in the voltage gradient

Activation of calcium is due to perturbation Activation of calcium is due to perturbation of the normal H+ gradient across the SR of the normal H+ gradient across the SR membranesmembranes

Cons: the pH changes during muscle Cons: the pH changes during muscle contraction may be too small to induce the contraction may be too small to induce the necessary gradients in order to stimulate necessary gradients in order to stimulate calcium releasecalcium release

Hypothesized Mechanisms for Hypothesized Mechanisms for ECCECC

Calcium-induced calcium releaseCalcium-induced calcium release

Chemical intermediateChemical intermediate

Allosteric InteractionAllosteric Interaction

Calcium induced calcium releaseCalcium induced calcium release

stimulation of t-tubules causes a small stimulation of t-tubules causes a small amount of calcium to cross the t-tubule amount of calcium to cross the t-tubule membranemembrane

an amount insufficient to cause muscle an amount insufficient to cause muscle contractioncontraction

This induces the release of additional This induces the release of additional calcium in greater amounts, from the SR calcium in greater amounts, from the SR (calcium channels are open)(calcium channels are open)

Cons: blocking the DHP channels of the t-Cons: blocking the DHP channels of the t-tubule membrane does not inhibit calcium tubule membrane does not inhibit calcium release from the SRrelease from the SR

Or decrease force developmentOr decrease force development

Are the amounts of calcium required Are the amounts of calcium required physiologic?physiologic?

Chemical IntermediateChemical Intermediate

voltage-induced changes in the t-tubules voltage-induced changes in the t-tubules induce the formation of inositol 1,4,5 induce the formation of inositol 1,4,5 triphosphate (InsP3)triphosphate (InsP3)

IP3 then increases the permeability of the IP3 then increases the permeability of the SR membranes to cause calcium releaseSR membranes to cause calcium release

Pros: after electrical stimulation, there is an Pros: after electrical stimulation, there is an elevated production IP3elevated production IP3

The release of calcium in skinned fibers The release of calcium in skinned fibers induced by IP3induced by IP3

If IP3 release from the RBCs is inhibited, If IP3 release from the RBCs is inhibited, there is a reduction of calcium transients in there is a reduction of calcium transients in skeletal muscleskeletal muscle

If IP3 breakdown is inhibited, there is an If IP3 breakdown is inhibited, there is an augmented skeletal muscle responseaugmented skeletal muscle response

Cons: is the concentration of IP3 necessary Cons: is the concentration of IP3 necessary for activation?for activation?

Is its rate of activation physiologic?Is its rate of activation physiologic?

Allosteric Interaction Hypothesis Allosteric Interaction Hypothesis (aka, Plunger Hypothesis)(aka, Plunger Hypothesis)

there is a mechanical or allosteric link there is a mechanical or allosteric link between DHP channels of the t-tubules between DHP channels of the t-tubules and the ryanodine channels of the SR and the ryanodine channels of the SR (junctional foot proteins)(junctional foot proteins)There is a foot structure composed There is a foot structure composed primarily of SR calcium channel proteins primarily of SR calcium channel proteins clustered next to the t-tubule membrane clustered next to the t-tubule membrane called channel protein or electron dense called channel protein or electron dense feetfeet

This suggests a role for protein-protein This suggests a role for protein-protein interactions to transmit the depolarization interactions to transmit the depolarization signal across the junction. signal across the junction. Most popular Most popular mechanism of signal transmission is a variant of mechanism of signal transmission is a variant of the plunger hypothesis:the plunger hypothesis:

Imagine a mobile positive charge in the t-Imagine a mobile positive charge in the t-tubule membrane (it may be associated tubule membrane (it may be associated with the DHP voltage sensor) with the DHP voltage sensor)

The charge is connected by a rod to a plug The charge is connected by a rod to a plug in the calcium release channel of the SR in the calcium release channel of the SR

Depolarization of the t-tubule membrane Depolarization of the t-tubule membrane causes charge movement in the t-tubule causes charge movement in the t-tubule membranemembrane

Results in the unplugging of the SR Results in the unplugging of the SR calcium release channelcalcium release channel

Suspect that the mobile charge is Suspect that the mobile charge is contained within specific amino acids contained within specific amino acids contained within a segment of the DHP contained within a segment of the DHP receptor complexreceptor complex

Ryanodine receptor complex has a large Ryanodine receptor complex has a large cytoplasmic portion spanning the gap cytoplasmic portion spanning the gap between membranes, and able to contact between membranes, and able to contact the voltage sensors of the DHP complexthe voltage sensors of the DHP complex

Skeletal Muscle Fiber TypesSkeletal Muscle Fiber Types

not all skeletal muscle has the same not all skeletal muscle has the same biochemical or functional characteristicsbiochemical or functional characteristics

are generally classified according to their are generally classified according to their primary dependence on different metabolic primary dependence on different metabolic pathways for the production of ATP.pathways for the production of ATP.

Nomenclature based onNomenclature based on

Myosin ATPase pH lability: histochemical Myosin ATPase pH lability: histochemical stainingstaining

Glycolytic stainingGlycolytic staining

Oxidative stainingOxidative staining

Fiber sub-types:Fiber sub-types:

Type I, SO (slow oxidative), red fibers, Type I, SO (slow oxidative), red fibers, slowslow

Type IIa FOG (fast oxidative glycolytic), Type IIa FOG (fast oxidative glycolytic), intermediate fibersintermediate fibers

Type IIb FG (fast glycolytic), white, fastType IIb FG (fast glycolytic), white, fast

Type IIc rare, undifferentiated fiber, Type IIc rare, undifferentiated fiber, perhaps found during re-innervation or perhaps found during re-innervation or motor unit transformation, between I and motor unit transformation, between I and IIa on the continuum of metabolic potentialIIa on the continuum of metabolic potential

Type IIx, not classifiedType IIx, not classified

Slow twitch fibers:Slow twitch fibers:

fatigue resistant, good for prolonged fatigue resistant, good for prolonged exerciseexercise

primarily synthesized ATP via aerobic primarily synthesized ATP via aerobic energy transferenergy transfer

recruited for aerobic activities such as recruited for aerobic activities such as prolonged moderate exerciseprolonged moderate exercise

have a smaller resting membrane potential, have a smaller resting membrane potential, -50-70mv, versus 80-90mv in fast muscle-50-70mv, versus 80-90mv in fast muscle

longer latency period due to less longer latency period due to less extensive SRextensive SR

low activity of myosin ATPaselow activity of myosin ATPase

slow speed of contractionslow speed of contraction

low glycolytic capacitylow glycolytic capacity

increased size and number of increased size and number of mitochondriamitochondria

higher levels of myoglobinhigher levels of myoglobin

higher concentrations of mitochondrial higher concentrations of mitochondrial enzymesenzymes

increased blood flow -- increased increased blood flow -- increased capillarizationcapillarization

Fast twitch fibers:Fast twitch fibers:

activated in short-term, sprint activities, and activated in short-term, sprint activities, and forceful contractions which rely primarily on forceful contractions which rely primarily on anaerobic metabolism for energyanaerobic metabolism for energy

important in stop and go and change of important in stop and go and change of pace activitiespace activities

more extensive SRmore extensive SR

greater capability for electrochemical AP greater capability for electrochemical AP transmission (due to increased SR)transmission (due to increased SR)

high activity level of myosin ATPasehigh activity level of myosin ATPaserapid SR calcium release and uptakerapid SR calcium release and uptakehigh rate of cross-bridge turnover high rate of cross-bridge turnover development development intrinsic speed of contraction and tension intrinsic speed of contraction and tension is 2-3 times that of ST fibersis 2-3 times that of ST fibersprimarily use the glycolytic system for primarily use the glycolytic system for energy transferenergy transfer