Muscle System

Muscle does more than move limbs—it regulates body temperature, helps push blood back to the heart, and keeps organs in rhythmic motion. The high-yield payoff is that one core mechanism—excitation–contraction coupling—underlies everything from a bicep curl to a heartbeat. Master it once, apply it everywhere.

Priority labels: Must know = cold; Know the logic = mechanism not names; Passage-level = recognize, don't memorize; Optional = skippable.

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Important Functions

The MCAT tests not just contraction mechanics but the integrative roles of muscle.

Mobility and Support

Must know

Skeletal muscle generates the forces that move bones at joints. Muscles work in antagonistic pairs—when the agonist (prime mover) contracts, the antagonist relaxes (e.g., biceps flexes the elbow, triceps extends it). Beyond movement, skeletal muscle maintains postural tone: continuous low-level partial contraction that holds you upright against gravity.

Quick check: If a patient loses voluntary control of their skeletal muscles, why might they also lose the ability to maintain upright posture, even without moving?

Answer: Postural tone requires continuous low-level motor neuron input. Without motor commands, the muscles cannot maintain the partial contractions that hold the skeleton in alignment.

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Peripheral Circulatory Assistance

Must know

The skeletal muscle pump: contracting leg muscles compress nearby veins, pushing blood centrally against gravity (one-way venous valves prevent backflow). This is why prolonged immobility (long flights, bed rest) raises the risk of deep vein thrombosis (DVT)—blood pools without the pump.

Quick check: A person stands still for hours. Why do their legs swell, and what underlying mechanism explains the risk of clot formation?

Answer: Without muscle contractions, venous blood pools in the lower extremities. Elevated hydrostatic pressure drives fluid into tissue (edema), and stasis promotes coagulation, increasing DVT risk.

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Thermoregulation and the Shivering Reflex

Must know

Muscle contraction is metabolically inefficient—most energy from ATP hydrolysis is released as heat. The body exploits this: when core temperature drops, the hypothalamus triggers shivering—rapid, involuntary, asynchronous skeletal-muscle contractions that generate heat without net movement.

Passage-level

Shivering is a somatic reflex (skeletal muscle, somatic motor neurons), distinct from non-shivering thermogenesis in brown fat.

Quick check: Why does shivering generate heat rather than useful movement?

Answer: Many motor units fire asynchronously, so contractions in opposing groups largely cancel mechanically. But each ATP hydrolysis cycle still releases heat, warming the body.

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Structure of the Three Basic Muscle Types

The MCAT expects you to compare skeletal, cardiac, and smooth muscle across several dimensions (table below).

Skeletal (Striated) Muscle

Must know

Skeletal muscle is voluntary, multinucleated (nuclei pushed to the periphery), and striated. Each fiber is a single huge cell formed by fusion of many myoblasts during development.

Structural hierarchy: muscle → fascicles → muscle fibers (cells) → myofibrils → sarcomeres. The whole muscle blends into the tendon that attaches it to bone.

Striations arise because the sarcomeres of adjacent myofibrils are aligned in register, creating alternating light (I) and dark (A) bands.

Quick check: Why do skeletal muscle fibers appear striated but smooth muscle fibers do not?

Answer: Striations require sarcomeres aligned side-by-side across the cell. Skeletal (and cardiac) muscle have this; smooth muscle has contractile proteins in an oblique lattice without discrete aligned sarcomeres.

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Cardiac Muscle

Must know

Cardiac muscle is involuntary, striated, and made of cardiomyocytes—usually uninucleate cells joined end-to-end by intercalated discs, which contain:

• Gap junctions: electrically couple cardiomyocytes so the action potential spreads rapidly and each chamber contracts as a functional syncytium.
• Desmosomes: mechanical anchors that keep cells from pulling apart.

Cardiac muscle is autorhythmic (intrinsic pacemaker activity), branched, fatigue-resistant (dense mitochondria, relies on oxidative phosphorylation), and cannot be tetanized (see refractory period below).

Quick check: What structural feature of cardiac muscle allows the atria to contract as a unit before the ventricles?

Answer: Gap junctions in intercalated discs electrically couple cardiomyocytes within each chamber. The fibrous AV ring insulates atria from ventricles, so the impulse must pass through the AV node, creating the delay.

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Smooth Muscle

Must know

Smooth muscle is involuntary, non-striated, and uninucleate (central nucleus). It lines hollow organs—blood vessels, GI tract, bladder, uterus, airways. Actin and myosin are arranged in a non-sarcomeric lattice attached to dense bodies (analogous to Z-discs), letting smooth muscle shorten much more than skeletal—useful for organs that change volume (e.g., bladder).

Smooth muscle contracts slowly but sustains contraction far longer with much less ATP (tonic contraction)—good for maintained vascular tone. It is regulated by the autonomic nervous system, hormones, and local signals, and uses calmodulin/MLCK rather than troponin (see Common Confusions).

Feature	Skeletal	Cardiac	Smooth
Striated	Yes	Yes	No
Nuclei per cell	Multiple (peripheral)	1–2 (central)	1 (central)
Control	Voluntary (somatic)	Involuntary (autonomic + intrinsic)	Involuntary (autonomic/hormonal)
Intercalated discs	No	Yes	No
Autorhythmicity	No	Yes (SA node)	Some (GI pacemaker cells)
Fatigue	Yes	Resistant	Very resistant
Contraction speed	Fast	Intermediate	Slow
Regulation	Troponin/tropomyosin	Troponin/tropomyosin + CICR	MLCK/calmodulin

Quick check: Why can't cardiac muscle be tetanized the way skeletal muscle can?

Answer: Cardiac muscle has an extremely long refractory period lasting nearly as long as the contraction itself, so a second action potential can't arrive until the muscle has begun relaxing. This prevents tetany, which would stop the heart from filling.

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Muscle Structure and Control of Contraction

This is the most mechanistically rich—and most tested—section. Build the mental movie.

Sliding-Filament Mechanism (Recap)

Must know

At the molecular level, each sarcomere (the contractile unit between two Z-discs) shortens when its thin filaments (actin) slide inward over its thick filaments (myosin), driven by myosin cross-bridges cycling on ATP. The filaments themselves do not shorten; their increasing overlap pulls the Z-discs closer. A rise in cytoplasmic Ca²⁺ is the on/off trigger that exposes actin's myosin-binding sites and starts the cycle.

Cross-reference: The full molecular contractile detail—sarcomere bands/lines (A/I/H/Z/M), the cross-bridge cycle step-by-step, and the troponin/tropomyosin Ca²⁺ switch—is covered in the Specialized Cell – Muscle Cell guide. Here we focus on how that machinery is triggered and controlled at the whole-muscle and system level.

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The Length-Tension Relationship

Know the logic

Force depends on the overlap between thick and thin filaments—there is an optimal resting length with maximal cross-bridge formation, and force falls off if the muscle is over-stretched or over-shortened. This underlies the Frank-Starling mechanism: greater diastolic filling stretches cardiomyocytes toward optimal overlap, increasing stroke volume.

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The T-Tubule System

Must know

How does a surface action potential reach myofibrils deep inside a large fiber almost instantly? Via the transverse tubule (T-tubule) system—deep invaginations of the sarcolemma that carry depolarization into the fiber interior so every myofibril is reached simultaneously.

Each T-tubule sits between two terminal cisternae of the SR, forming a triad where the electrical signal is converted into Ca²⁺ release: a voltage sensor in the T-tubule membrane is coupled to a Ca²⁺-release channel on the SR.

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Sarcoplasmic Reticulum

Must know

The sarcoplasmic reticulum (SR) is specialized smooth ER wrapping each myofibril; its job is Ca²⁺ storage and regulated release.

• At rest: Ca²⁺ is pumped into the SR by SERCA (ATP-dependent), keeping cytoplasmic Ca²⁺ very low.
• Upon stimulation: the Ca²⁺-release channel opens, flooding the cytoplasm with Ca²⁺.

This Ca²⁺ spike is the on/off switch for contraction: rising Ca²⁺ binds troponin C, shifting tropomyosin off actin's myosin-binding sites so cross-bridges can cycle; when SERCA pumps Ca²⁺ back into the SR, the sites are re-covered and the muscle relaxes (the troponin/tropomyosin detail is in the Specialized Cell – Muscle Cell guide). The full system-level sequence ties this together below.

Quick check: A drug permanently opens the SR Ca²⁺-release channels in isolated skeletal muscle. What happens?

Answer: Cytoplasmic Ca²⁺ stays elevated, tropomyosin stays open, cross-bridges keep cycling, and the muscle stays in sustained contraction (spasm)—until ATP depletes and it enters a rigor-like state.

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Full Excitation–Contraction Coupling Sequence (Skeletal Muscle)

Must know

1. Motor neuron action potential reaches the neuromuscular junction (NMJ).
2. ACh released → binds nicotinic receptors → end-plate potential → action potential along the sarcolemma.
3. Action potential travels down T-tubules.
4. T-tubule depolarization triggers the SR to release Ca²⁺.
5. Ca²⁺ binds troponin C → tropomyosin shifts → actin binding sites exposed.
6. Cross-bridge cycle proceeds → fiber shortens.
7. Motor neuron stops → ACh cleared → sarcolemma repolarizes.
8. SERCA pumps Ca²⁺ back into the SR (ATP) → tropomyosin re-covers sites → muscle relaxes.

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Fiber Types

Must know

Property	Type I (Slow oxidative)	Type II (Fast glycolytic)
Speed	Slow	Fast
Fatigue resistance	High	Low
Metabolism	Oxidative (aerobic)	Glycolytic (anaerobic)
Mitochondria / Myoglobin	Many / High (red)	Few / Low (white)
Use	Posture, endurance	Explosive bursts

Optional

(Type IIa is an intermediate fast oxidative-glycolytic type.)

Memory hook: A chicken's breast (white) = fast glycolytic for rare explosive flapping; the leg (dark) = slow oxidative for continuous walking.

Passage-level

Myoglobin is the O₂-storage protein giving red muscle its color; its binding curve is hyperbolic (high affinity, no cooperativity), so it holds O₂ at low pO₂ and releases it to working mitochondria. Type II fibers cycle cross-bridges faster (faster myosin ATPase isoforms); Type I sustain activity longer via oxidative ATP.

Quick check: An elite marathon runner's calf muscles would have a higher proportion of which fiber type than a sprinter's, and why?

Answer: More Type I (slow oxidative) fibers—fatigue-resistant from high mitochondrial density and aerobic capacity, ideal for prolonged effort. Sprinters rely more on Type II fast glycolytic fibers for short bursts.

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Regulation of Cardiac Muscle Contraction

Must know

Cardiac muscle uses the same troponin/tropomyosin system as skeletal muscle, but Ca²⁺ delivery differs—a favorite MCAT distinction:

• The T-tubule channel is an L-type Ca²⁺ channel, so depolarization lets a small amount of Ca²⁺ enter.
• That entering Ca²⁺ triggers a much larger SR Ca²⁺ release—calcium-induced calcium release (CICR).
• The amount of external Ca²⁺ entering tunes the force of contraction (inotropy).

This is why sympathetic stimulation (norepinephrine on β₁ receptors) increases contractility—more Ca²⁺ entry and faster cycling. The cardiac action potential's long plateau phase (Ca²⁺ influx) produces a prolonged refractory period that prevents tetany, ensuring the heart relaxes and refills between beats.

Quick check: Why does cardiac muscle need extracellular Ca²⁺ to contract while skeletal muscle does not?

Answer: In skeletal muscle, mechanical coupling between the T-tubule voltage sensor and the SR channel releases all needed Ca²⁺ without any entry. Cardiac muscle uses CICR, so extracellular Ca²⁺ entering via L-type channels triggers SR release—making cardiac force tunable by external Ca²⁺ and autonomic input.

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Oxygen Debt and Muscle Fatigue

Energy Sources for Muscle Contraction

Must know

A hierarchy of ATP sources:

1. Phosphocreatine (PCr): creatine kinase transfers a phosphate to ADP → ATP. Fastest; lasts ~10 s (fuels a 100-m sprint).

$\ce{PCr + ADP -> Creatine + ATP}$

2. Anaerobic glycolysis: glucose → pyruvate → lactate + ATP. Rapid but limited (2 ATP/glucose net); causes fatigue.

3. Aerobic oxidative phosphorylation: glucose/fats/amino acids → acetyl-CoA → TCA → ETC → ~30–32 ATP/glucose. Slow to ramp up; sustains prolonged exercise.

Oxygen Debt (EPOC)

Must know

During intense exercise, ATP demand outpaces aerobic supply, so anaerobic glycolysis fills the gap and produces lactate. Afterward the body keeps consuming oxygen above rest—the oxygen debt (EPOC)—to restore PCr, convert lactate back to glucose (Cori cycle in the liver), re-oxygenate myoglobin/hemoglobin, and restore ion gradients.

Muscle Fatigue

Must know

Muscle fatigue is the inability to maintain expected force.

Know the logic

• Pᵢ accumulation inhibits the power stroke and SR Ca²⁺ release.
• Acidosis (lactate/H⁺) interferes with troponin-Ca²⁺ binding and cross-bridge kinetics.
• K⁺ accumulation in the T-tubule impairs excitability; Ca²⁺ depletion and glycogen depletion also contribute.

Quick check: Why does intense short-burst exercise leave you breathing hard for minutes after stopping?

Answer: You're repaying the oxygen debt (EPOC)—continued elevated O₂ consumption restores PCr, clears lactate, re-oxygenates myoglobin, and restores normal metabolic conditions.

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Nervous Control of Muscle

Motor Neurons

Must know

A motor unit = one motor neuron + all the muscle fibers it innervates—the smallest contractile unit the nervous system can recruit. Small motor units (few fibers) give precise control (e.g., eye muscles); large units (many fibers) give power but less precision (e.g., quadriceps).

Force is graded two ways:

1. Recruitment: activating more motor units.
2. Rate coding (temporal summation): firing already-active units faster, summing twitches into tetanus (smooth, sustained, maximal contraction).

Passage-level

A twitch has a latent period → contraction → relaxation phase; if stimuli come fast enough twitches summate into fused (complete) tetanus.

Henneman's size principle: motor units are recruited smallest-first (Type I, low threshold) to largest (Type II, high threshold), scaling force smoothly from fine movement to maximal effort.

Quick check: Why can you hold a coffee cup gently without crushing it, even though your hand muscles can produce tremendous force?

Answer: Selective recruitment (Henneman's size principle). Only small, low-threshold motor units fire for delicate tasks; large, powerful units stay silent unless much greater force is needed.

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Proprioceptors and Reflexes

Must know

Two sensory receptors feed back to the nervous system:

• Muscle spindles — parallel to fibers; sense muscle length and rate of stretch.
• Golgi tendon organs (GTOs) — in tendons, in series with fibers; sense muscle tension.

The stretch (myotatic) reflex is the classic monosynaptic reflex (knee-jerk): stretch excites the spindle → sensory neuron synapses directly on the alpha motor neuron → the same muscle contracts (with reciprocal inhibition of the antagonist). The Golgi tendon reflex is protective: dangerously high tension activates an inhibitory interneuron that relaxes the muscle, preventing damage.

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The Neuromuscular Junction and Motor End Plate

Must know

The neuromuscular junction (NMJ) is the synapse between a motor neuron and a skeletal muscle fiber—one of the most MCAT-tested synapses.

Structure: the presynaptic terminal holds vesicles of acetylcholine (ACh); across the synaptic cleft, the motor end plate has junctional folds densely packed with nicotinic ACh receptors (nAChR)—ligand-gated Na⁺/K⁺ channels.

Transmission sequence:

1. Action potential reaches the terminal → opens voltage-gated Ca²⁺ channels.
2. Ca²⁺ influx → exocytosis of ACh vesicles.
3. ACh binds nAChR → Na⁺ in, K⁺ out → net depolarization = end-plate potential (EPP).
4. The EPP is always large enough to trigger a sarcolemmal action potential (the NMJ is a fail-safe 1:1 synapse).
5. Acetylcholinesterase (AChE) in the cleft rapidly degrades ACh, terminating the signal; choline is recycled.

Passage-level

How the NMJ fails:

• Botulinum toxin: blocks ACh release → flaccid paralysis.
• Curare: competitively blocks nAChR → paralysis (anesthesia).
• AChE inhibitors: ACh accumulates → overstimulation; mild inhibition treats myasthenia gravis.
• Myasthenia gravis: autoimmune destruction of nAChR → weakness worsening with use.

Quick check: Why does myasthenia gravis cause weakness that worsens with repeated use?

Answer: Antibodies destroy nAChR, so each ACh release generates a smaller EPP. Repeated firing depletes the readily releasable ACh pool faster than it's replenished, so weakness accumulates with use.

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Sympathetic and Parasympathetic Innervation

Must know

Skeletal muscle receives NO direct autonomic innervation for contraction—it's controlled entirely by somatic motor neurons (the autonomic system affects it only indirectly, via blood flow and adrenal epinephrine).

Cardiac and smooth muscle are autonomically innervated:

• Cardiac — Sympathetic (β₁): ↑ heart rate (chronotropy), conduction velocity, and contractility (inotropy). Parasympathetic (M₂): ↓ heart rate by increasing K⁺ conductance → hyperpolarizing the SA node.
• Smooth: highly variable by organ—the same neurotransmitter can excite or relax depending on receptor type. General pattern: sympathetic relaxes GI/bronchial smooth muscle (β₂) but constricts blood vessels (α₁); parasympathetic increases GI peristalsis and contracts the bladder.

Quick check: Why would a non-selective β-blocker decrease heart rate AND cause bronchospasm?

Answer: β₁ blockade reduces SA-node stimulation → lower heart rate. β₂ blockade prevents bronchodilation, letting parasympathetic tone constrict the airways. This is why non-selective β-blockers are contraindicated in asthma.

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Voluntary vs. Involuntary Muscles

Must know

A clean MCAT distinction: Voluntary = skeletal (somatic motor neurons, cell bodies in the ventral horn or brainstem). Involuntary = cardiac and smooth (autonomic, plus intrinsic for cardiac).

Nuance: Some skeletal-muscle behaviors are reflexive (stretch reflex, shivering) and thus involuntary, but the tissue is still skeletal muscle run by somatic motor neurons—not the autonomic system.

Muscle type	Voluntary?	Innervation	Neurotransmitter at effector
Skeletal	Yes (+ reflexes)	Somatic motor neuron	ACh → nicotinic
Cardiac	No	Autonomic (+ intrinsic)	NE / ACh → adrenergic/muscarinic
Smooth	No	Autonomic (+hormones)	NE / ACh (receptor-dependent)

Quick check: Is the diaphragm voluntary or involuntary? How can you both hold your breath consciously AND breathe automatically during sleep?

Answer: The diaphragm is skeletal muscle—technically voluntary. The motor cortex can override breathing temporarily, but the medullary respiratory centers drive automatic rhythmic breathing during sleep. Both pathways converge on the same somatic (phrenic) motor neurons, making the diaphragm a rare skeletal muscle under both voluntary and automatic control.

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Common Confusions & Tricks

1. A band vs. I band during contraction.
Remember: "A band—Always the same; I band—I shrink; H zone—H shrinks." The A band equals the thick-filament length, which doesn't change. Only the non-overlap zones (I band, H zone) change.

2. Skeletal vs. cardiac Ca²⁺ entry.
Skeletal: no extracellular Ca²⁺ needed—the T-tubule voltage sensor mechanically opens the SR channel. Cardiac: L-type Ca²⁺ channel lets Ca²⁺ in to trigger CICR. A passage about Ca²⁺-channel blockers reducing cardiac contractility works on cardiac channels, not skeletal.

3. Troponin is only in striated muscle.
Smooth muscle uses calmodulin + MLCK (phosphorylating myosin light chains), not troponin-tropomyosin. A drug acting on troponin affects skeletal and cardiac, not smooth.

4. Rigor mortis = no ATP, NOT excess Ca²⁺.
Without ATP, myosin can't release actin (ATP binding is needed). It is not caused by Ca²⁺ flooding.

5. Botulinum toxin = flaccid; too much AChE inhibition = spastic/rigid.
Botox blocks ACh release → no EPP → flaccid. Organophosphates block AChE → ACh accumulates → continuous stimulation → spastic paralysis. Don't reverse these.

6. Motor unit vs. sarcomere vs. muscle fiber.
A sarcomere is molecular, a muscle fiber is a cell, a motor unit is one neuron plus its fibers. Recruitment = adding motor units; rate coding = firing the same unit faster.

7. "Voluntary" ≠ "skeletal" always, but on the MCAT it effectively does.
Cardiac and smooth = involuntary. Skeletal = voluntary (with reflex exceptions).

8. Myoglobin vs. hemoglobin oxygen binding.
Myoglobin: hyperbolic curve, single subunit, no cooperativity, higher O₂ affinity than hemoglobin at most physiological pO₂. It stores O₂ in muscle. This is a binding curve, NOT Michaelis-Menten kinetics.

9. Tetanus (physiological) vs. tetanus (disease).
Physiological tetanus = smooth sustained contraction from high-frequency stimulation. Tetanus disease (Clostridium tetani toxin) blocks inhibitory neurotransmitter release → loss of motor inhibition → spastic paralysis ("lockjaw").

10. Parasympathetic slows heart via hyperpolarization, not troponin.
M₂ activation increases K⁺ conductance → hyperpolarizes SA node → slower spontaneous depolarization → slower heart rate. A pacemaker effect, not a contractile-protein effect.

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Key Takeaways

Muscle Types at a Glance

• Skeletal: Voluntary, multinucleate, striated, somatic control, ACh→nAChR at NMJ, fatigue-prone, troponin regulation.
• Cardiac: Involuntary, 1–2 nuclei, striated, intercalated discs with gap junctions, autorhythmic, CICR, troponin regulation, long refractory period (no tetany).
• Smooth: Involuntary, uninucleate, non-striated, autonomic/hormonal control, MLCK/calmodulin regulation, very fatigue-resistant, greatest shortening.

Sarcomere and Cross-Bridge Cycle

• Sarcomere = Z-disc to Z-disc; A band constant; I band and H zone shorten during contraction.
• Sliding filament theory: actin slides over myosin; filaments don't shorten.
• Cross-bridge cycle: ATP binding releases myosin; hydrolysis cocks the head; Pᵢ release = power stroke; ADP released.
• No ATP → rigor.

Excitation–Contraction Coupling

• Skeletal: action potential → T-tubule → mechanical coupling → SR Ca²⁺ → TnC → tropomyosin shifts → cross-bridges.
• Cardiac: same + L-type Ca²⁺ channel → CICR.
• Relaxation: SERCA pumps Ca²⁺ back into SR (ATP).
• Troponin: TnC binds Ca²⁺, TnI inhibitory, TnT anchors to tropomyosin.

Fiber Types

• Type I = slow, oxidative, fatigue-resistant, high myoglobin (red), endurance.
• Type II = fast, glycolytic, fatigues quickly, low myoglobin (white), explosive power.

NMJ

• ACh → nAChR → EPP → action potential → contraction; AChE terminates signal.
• Botox: blocks ACh release (flaccid). Curare: blocks nAChR (flaccid). AChE inhibitors: accumulate ACh.

Oxygen Debt and Fatigue

• PCr → anaerobic glycolysis → oxidative phosphorylation.
• Oxygen debt (EPOC): post-exercise O₂ consumption to restore PCr, clear lactate, re-oxygenate tissues.
• Fatigue: Pᵢ, H⁺/lactate, K⁺ in T-tubule, Ca²⁺ depletion.

Autonomic Innervation

• Sympathetic → β₁ on heart: ↑ HR, ↑ contractility, ↑ conduction.
• Parasympathetic → M₂ on heart: ↓ HR (hyperpolarizes SA node).
• Skeletal muscle: no direct autonomic innervation; somatic motor neurons only.

Key Integrations

• Shivering = involuntary skeletal contraction → heat (thermoregulation).
• Skeletal muscle pump aids venous return.
• Henneman's size principle: small → large recruitment order.
• Force graded by recruitment + rate coding.