Physiology: Skeletal Muscle Physiology (Part I and 2) (together)

Myotatic reflex (stretch) whats the four step process Inverse myotatic reflex four steps

Stretch spindles type Ia spinal cord Direct synapse to α motor neurons Function: rapid motor output corrections - posture, picking your head up as you dose off... Contraction GTO type Ib spinal cord Direct synapse to inhibitory neurons Function: tension feedback - posture

sacromere structure thick and thin

Thin filament- predominantly actin Thick filament- predominantly myosin type II

Tropomyosin-troponin regulation what does each do and also how do they work

Tropomyosin: Dimer Wraps around F-actin Troponin: trimeric complex of TnT: binds Tropomyosin TnC: binds Ca2+ TnI: Inhibits by binding actin inhibitier basically? Troponin is attached to the protein tropomyosin and lies within the groove between actin filaments in muscle tissue. In a relaxed muscle, tropomyosin blocks the attachment site for the myosin crossbridge, thus preventing contraction. When the muscle cell is stimulated to contract by an action potential, calcium channels open in the sarcoplasmic membrane and release calcium into the sarcoplasm. Some of this calcium attaches to troponin, which causes it to change shape, exposing binding sites for myosin (active sites) on the actin filaments. Myosin's binding to actin causes crossbridge formation, and contraction of the muscle begins.

Skeletal muscle fiber types 3 types Fatigue color metabolism mitochondria glycogen Muscle adaptation (remodeling) Endurance training: Stress training: what happens during both these processes Muscle remodeling over time

Type 1 (always engaged), 2a (intermdiate) and 2x(rapid fire, eyes) (SLOW, FAST, FAST) resistant, resistant, fatigable red, red, white oxidative, oxidative, glycolytic high, higher, fewer low, abdundant, high muscle has a combo of all 3 Endurance training: capillary # , mitochondria # Type IIx fibers Type IIa Stress training: Type IIa Type IIx Hypertrophy of Type IIx Type I fibers cannot be converted to fast twitch fibers basically to make these work has to be over a long time not one trip to the gym

Duchenne muscular dystrophy

X-linked Presents 3-6 yrs of age Difficulty walking, running, waddling gate, Gowers' sign Early-calf hypertrophy followed by pseudohypertrophy Serum CK values Death: cardiac and respiratory failure Dystrophin loss or absence

Functions of sarcomere proteins α-actinin- Nebulin- Titin- Desmin- Dystrophin- Dystrophin-glycoprotein complex dystrophin: Duchenne muscular dystrophy, Becker muscular dystrophy sarcoglycans: limb-girdle muscular dystrophy

Z disk, Connects actin to Z disk Ruler, Binds actin, determines length huge, orients thick filaments (spring mechanism) IF connect myofibrils-sacrolemma Glycoprotein Comlex

myasthenia gravis

a chronic autoimmune disease that affects the neuromuscular junction and produces serious weakness of voluntary muscles Symptoms: Ptosis Blurred vision Muscle weakness Dysphasia Becomes worse with activity No muscle damage Autoimmune disease Antibodies to AChR Reduced availability

ryanodine receptor

calcium-release channel found in the lateral sacs of the sarcoplasmic reticulum in skeletal muscle cells Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum and endoplasmic reticulum, an essential step in muscle contraction.[1] In skeletal muscle, activation of ryanodine receptors occurs via a physical coupling to the dihydropyridine receptor (a voltage-dependent, L-type calcium channel), whereas, in cardiac muscle, the primary mechanism of activation is calcium-induced calcium release, which causes calcium outflow from the sarcoplasmic reticulum.[3]

A Band

dark area; extends length of the thick filaments

excitation-contraction coupling

events that link the action potentials on the sarcolemma to activation of the myofilaments, thereby preparing them to contract basically saying first has to be the peak of the AP then the Caclcium then the contraction.

Z disk

filamentous network of protein. Serves as attachment for actin myofilaments

Muscle mechanics Normal activity of intact muscle is a combination of both contraction types

isometric vs isotonic

Myotube development Derived from which germ layer? Skeletal muscle metabolism conversion of blank to blank need high blank and other stoargae molecules skeletal muscle is 30% of metabolism at rest

mesoderm->paraxial mesoderm->epaxial/hypaxial epaxial is for back and hypaxial is for limbs or body wall High metabolic tissue Conversion of chemical energy to work ATP Glucose, glycogen, liver glucose, FFA

DHP receptor

nonconducting calcium channels in the T-tubule membranes of skeletal muscle cells, which act as voltage sensors in excitation-contraction coupling

Muscle spindles

receptors sensitive to change in length of the muscle and the rate of that change Inform about muscle length and velocity of stretch Higher density in muscles responsible for fine movement Contractile elements innervated by gamma motor neurons streching

Cross-bridge cycle 5 step process

repeated sequential interactions between myosin and actin filaments at cross-bridges that cause a muscle fiber to contract rigor relax resting binding power stroke back to begin

H band

thick filaments only

I band

thin filaments only

Muscle regeneration Rare stem cell population in adult skeletal muscle Cells can differentiate and fuse with damaged myofibrils. External lamina must be intact otherwise fibroblast induced repair with scar tissue which cells do it

-limited capacity to regenerate itself -sometimes replaced with fibrous connective tissue instead of this tissue satelitte cells

myosin structure

-two protein strands twisted together -globular heads (myosin crossbridges)

Review the excitation-contraction coupling.

1 action potential in muscle membrane 2a depolarization of t tubules 2b opens SR Ca2+ realease channels (ryandoine recpetors) 3 IC Ca rises 4. CA2+ binds troponin C 5 Tropomyosin moves and allows interation of actin and myosin 6 cross bridge cycling and force generation 7 ca2+ reaccuulated by SR-> relaxation

Lateral and longitudinal transmission LATERAL MAKES WHAT PERCENT

Costamere complexes: Dystrophin-glycoprotein Integrin-vinculin-talin 70 30 is longitudual so any issue in desmin is bad

Triad: SR cisterna and T-tubule does what

Crosses sarcomere at A-I junction Allow signal integration externally with internal membranes

Desmin also connects myofibrils what does it do

Desmin aligns sarcomeres at each z-disk and to the sarcolemma via costameres Mutations lead to myofibrillar myopathy or cardiomyopathy

Desmin

Desmin is a protein that in humans is encoded by the DES gene.[5][6] Desmin is a muscle-specific, type III[7] intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture.[8]

Receptor interaction at the Triad

In the histology of skeletal muscle, a triad is the structure formed by a T tubule with a sarcoplasmic reticulum (SR) known as the terminal cisterna on either side.[1] Each skeletal muscle fiber has many thousands of triads, visible in muscle fibers that have been sectioned longitudinally. (This property holds because T tubules run perpendicular to the longitudinal axis of the muscle fiber.) In mammals, triads are typically located at the A-I junction;[1] that is, the junction between the A and I bands of the sarcomere, which is the smallest unit of a muscle fiber. Triads form the anatomical basis of excitation-contraction coupling, whereby a stimulus excites the muscle and causes it to contract. A stimulus, in the form of positively charged current, is transmitted from the neuromuscular junction down the length of the T tubules, activating dihydropyridine receptors (DHPRs). Their activation causes 1) a negligible influx of calcium and 2) a mechanical interaction with calcium-conducting ryanodine receptors (RyRs) on the adjacent SR membrane. Activation of RyRs causes the release of calcium from the SR, which subsequently initiates a cascade of events leading to muscle contraction. These muscle contractions are caused by calcium's bonding to troponin and unmasking the binding sites covered by the troponin-tropomyosin complex on the actin myofilament and allowing the myosin cross-bridges to connect with the actin.

actin filament structure

Made of single protein (actin) a smaller globular protein placed end to end kinda like bricks. 7 nm across, a plus and minus end.

M line

Middle of sarcomere, holds thick filament in place

Potential for muscle regeneration or cell therapies

Muscle atrophy: from disuse or denervation Treatment of muscular dystrophy Sarcopenia: muscle fiber # with age

Disruption at NMJ Myasthenia Gravis: Botulism: toxin (also Botox) Dantrolene: Dihydropyridines: Ryanodines: Succinylcholine:

Myasthenia Gravis: Autoimmune disease, antibodies target ACh nicotinic receptors Botulism: toxin (also Botox) from Clostridium botulinum interferes with ACh release Dantrolene: RyR antagonist- malignant hyperthermia Dihydropyridines: calcium channel blockers-hypertension Ryanodines: plant alkaloid, insecticide Succinylcholine: muscle relaxant, agonist of ACh nicotinic receptors

Succinylcholine action

NACHR->Depolarization->Ca2+pulse->tension->serca cant pump-> relaxation Phase 1 blocking has the principal paralytic effect. Binding of suxamethonium to the nicotinic acetylcholine receptor results in opening of the receptor's monovalent cation channel; a disorganized depolarization of the motor end-plate occurs and calcium is released from the sarcoplasmic reticulum. In normal skeletal muscle, acetylcholine dissociates from the receptor following depolarization and is rapidly hydrolyzed by the enzyme acetylcholinesterase. The muscle cell is then ready for the next signal. Suxamethonium has a longer duration of effect than acetylcholine, and is not hydrolyzed by acetylcholinesterase. By maintaining the membrane potential above threshold, it does not allow the muscle cell to repolarize. When acetylcholine binds to an already depolarized receptor, it cannot cause further depolarization. Calcium is removed from the muscle cell cytoplasm independent of repolarization (depolarization signaling and muscle contraction are independent processes). As the calcium is taken up by the sarcoplasmic reticulum, the muscle relaxes. This explains muscle flaccidity rather than tetany following fasciculations. The results are membrane depolarization and transient fasciculations, followed by paralysis

PhosphoCreatine buffer system what does it do

PCr has higher energy than ATP 2-5X more PCr than ATP in muscle Pi transfer happens quickly Provides enough energy for 100M run helps to keep atp level high so we can move not die Phosphocreatine, also known as creatine phosphate (CP) or PCr (Pcr), is a phosphorylated creatine molecule that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and the brain to recycle adenosine triphosphate, the energy currency of the cell.

Types of tension

Passive tension: unstimulated stretch Active tension: by cross-bridge formation and contraction after stimulation Preload refers to muscle length

Muscle spindle sensory neurons Primary (type Ia): Secondary (type II): Both respond to stretch, generate action potentials to CNS

Primary (type Ia): wrap around middle of both nuclear bag and nuclear chain fibers. Larger neurons, faster conductive velocities, dynamic, speed of strech Secondary (type II): Innervate mostly chain fibers along contractile apparatus ,static, degree of strech Both respond to stretch, generate action potentials to CNS

Force-velocity relationship relates to which one Increase load beyond maximal load results in negative velocity (stretching) Power is maximal at intermediate loads

Relates to isotonic contraction Inverse relationship between velocity and load Max velocity only dependent upon cross-bridge cycling Zero velocity all cross-bridges engaged

Twitch Stimulation in single muscle fiber Twitch 25-200ms Action potential only a few ms Temporal/Frequency summation Tetanus

Remember, twitch 25-200ms Action potential only a few ms Increases tension frequency is changing so this Remember, twitch 25-200ms Action potential only a few ms Not enough time for relaxation, little increase in tension temporal is the best way to build up things and lift by slowing increasing

Removal of Ca2+ from sarcoplasm Serca what?

SR membrane contains ATP dependent Ca2+ pumps (SERCA) SR contains low-affinity Ca2+ binding proteins Ca2+ conc. kept low in sarcoplasm until depolarization

Motor unit fine vs large motors spatial summation

A motor neuron and all of the muscle fibers it innervates Multiple fibers innervated by a single motor neuron Fine motor movement- units tend to be small Larger movement- units larger Spatial summation: recruitment of motor units to increase force

Acetylcholine

A neurotransmitter that enables learning and memory and also triggers muscle contraction

Troponin regulation by Ca2+ Ca2+ binds TnC Occupies 2 Low affinity sites Results in conformation change blank moved off of myosin binding sites

Ca2+ binds TnC Occupies 2 Low affinity sites Results in conformation change Tropomyosin moved off of myosin binding sites

Malignant hyperthermia what is this and why is it bad

Ca2+ leakage into sarcoplasm Can be induced by some inhaled anesthetics Symptoms: Hyperthermia Muscle rigidity Tachycardia Tachypnea Mutations in ryanodine receptors

dystrophin

Dystrophin is a protein located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber). It is a cohesive protein, linking actin filaments to other support proteins that reside on the inside surface of each muscle fiber's plasma membrane (sarcolemma). These support proteins on the inside surface of the sarcolemma in turn links to two other consecutive proteins for a total of three linking proteins. The final linking protein is attached to the fibrous endomysium of the entire muscle fiber. Dystrophin supports muscle fiber strength, and the absence of dystrophin reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils. This has been shown in recent studies where biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus were measured,[9] and helps to prevent muscle fiber injury. Movement of thin filaments (actin) creates a pulling force on the extracellular connective tissue that eventually becomes the tendon of the muscle. The dystrophin associated protein complex also helps scaffold various signalling and channel proteins, implicating the DAPC in regulation of signalling processes.[ The lethal muscle-wasting disorder, Duchenne muscular dystrophy, is caused by mutations or deletions in the dystrophin gene. In skeletal and cardiac muscle, dystrophin associates with various proteins to form the dystrophin-associated protein complex (DAPC). The DAPC is thought to play a structural role in linking the actin cytoskeleton to the extracellular matrix, stabilizing the sarcolemma during repeated cycles of contraction and relaxation, and transmitting force generated in the muscle sarcomeres to the extracellular matrix ( Petrof et al., 1993). There is also evidence that the DAPC is involved in cell signalling via its interactions with calmodulin, Grb2 and nNOS ( Rando, 2001). Various members of the DAPC, such as the sarcoglycans, have already been implicated in a number of muscle diseases, illustrating the vital role this complex plays in the maintenance of muscle integrity. This brief review offers a glimpse of the major known proteins that constitute the DAPC and the defects caused by their absence. ⇓

Fatigue 3 factors

Factors involved in muscle fatigue: ATP low Lactic acid high Glycogen low Fatigue: protective mechanism to maintain ATP and viability

Golgi tendon organs (GTO) function

Feedback regarding contraction Type Ib afferent neuron Stretch induces action potential to CNS to provide input about force of contraction info about contraction

length-tension relationship relates to which mechanic

The resting length of a muscle and the tension the muscle can produce at this resting length. Relates to isometric contraction Force (tension) determined by actin-myosin overlap has to do with actin and myosin heads (as we have a longer length there is less heads interacting with the myosin and less force, as we get closer to ideal legnth all the heads are touching, too close and start to miss heads again) Why is there so little change in force despite change in length?

gamma motor neurons

The sensitivity of the muscle spindle is maintained by help maintain them (specifically 1a motor neurons)

sliding filament model Where does Ca2+ come from?

The theory explaining how muscle contracts, based on change within a sarcomere, the basic unit of muscle organization, stating that thin (actin) filaments slide across thick (myosin) filaments, shortening the sarcomere; the shortening of all sarcomeres in a myofibril shortens the entire myofibril Sarcoplasmic reticulum- modified sER Ca2+ storage Interacts with invaginated sarcolemma (Transverse-tubule). (cell memembrene)