5.Muscle physiology

PART 1 — Big picture: what “muscle” is + the 3 muscle types (core logic)

1) What muscle cells do (vs neurons)

• Like neurons: can be excited chemically / electrically / mechanically → generate an action potential (AP) that spreads along the membrane.
• Unlike neurons: their main response is activation of a contractile system → force + shortening.
• Main structural/work proteins:
• Myosin (motor/contractile)
• Actin (cytoskeletal + contractile partner)

2) The 3 muscle types (key contrasts)

A) Skeletal muscle

• Biggest mass of body muscle (somatic).
• Cross-striations present (microscopic bands).
• Needs nerve stimulation to contract (doesn’t normally “auto-beat”).
• Each fiber is independent: no anatomic/functional bridges between fibers (not syncytial).
• Usually voluntary control.

B) Cardiac muscle

• Cross-striations present.
• Functionally syncytial (cells electrically linked).
• Can contract rhythmically without external nerves because of pacemaker cells in myocardium.
• Autonomic nerves mainly modulate rate/force (not required for basic rhythm).

C) Smooth muscle (not one uniform thing)

• No cross-striations.
• Two broad functional types:
• Unitary / visceral smooth muscle
• Found in most hollow organs
• Functionally syncytial
• Pacemakers present, discharge irregularly
• Multiunit smooth muscle
• Found in eye (iris) + some other locations
• Not spontaneously active
• More like skeletal muscle in being able to do graded, fine contraction

PART 2 — Skeletal muscle morphology: “how it’s built” (from whole fiber → sarcomere)

1) Organization (whole muscle → fiber → myofibril → myofilaments)

• Skeletal muscle is made of muscle fibers (the “building blocks” like neurons are for NS).
• Most skeletal muscles start/end in tendons.
• Fibers arranged parallel between tendons → forces add up (summation of units).
• Muscle fiber (one cell) is:
• Long, cylindrical
• Multinucleated
• Wrapped by membrane = sarcolemma
• No syncytial bridges between fibers
• Inside: many myofibrils → divisible into myofilaments (contractile machinery).

2) Core contractile proteins (the “must know set”)

• Main contraction system relies on:
• Myosin-II (thick filament motor)
• Actin (thin filament track)
• Tropomyosin (thin-filament “cover strip”)
• Troponin (thin-filament Ca²⁺ sensor complex)
• Troponin subunits
• TnT: anchors troponin to tropomyosin
• TnI: inhibits actin–myosin interaction
• TnC: binds Ca²⁺ to start contraction
• There are also many structural proteins keeping everything aligned and linked to ECM.

3) Striations = banding pattern explained by filament geometry

• Striations come from different refractive indices (how they bend light).
• Bands/lines (know names + what they mean):
• I band (light): thin filaments only
• Has the Z line (dark) in its center
• A band (dark): length of thick filaments (plus overlap zone)
• Center has H band (lighter) = thick only (when relaxed, no overlap)
• M line in middle of H band
• Pseudo-H zone = M line + narrow light areas on each side (term sometimes used)
• Sarcomere = region between two Z lines
• Filament arrangement:
• Thick filaments (myosin) align → form A band
• Thin filaments (actin + tropomyosin + troponin) extend from Z line into A band, and also create the I band
• In relaxed muscle, H zone is where thin doesn’t overlap thick
• Z line anchors thin filaments
• EM cross-section at A band:
• Each thick filament surrounded by 6 thin filaments (hexagonal pattern)

4) Thick filament details (myosin-II)

• Myosin-II structure: 2 globular heads + long tail
• Heads form cross-bridges with actin.
• Composition:
• Heavy chains + light chains
• Head = light chains + N-terminal parts of heavy chains
• Each head has:
• Actin-binding site
• ATPase catalytic site (hydrolyzes ATP)
• Myosin arranged symmetrically around sarcomere center → contributes to light areas near the M region
• M line is where polarity reverses in thick filaments; cross-connections keep thick filaments aligned.
• Each thick filament contains several hundred myosin molecules.

5) Thin filament details

• Thin filament = polymer of two actin chains → double helix
• Tropomyosin lies in the groove between actin chains.
• Counts per thin filament (approx):
• 300–400 actin
• 40–60 tropomyosin
• Troponin = small globular units at intervals along tropomyosin.

6) Extra structural proteins (high-yield support + elasticity)

• α-actinin (actinin): binds actin to Z lines
• Titin:
• Largest known protein (~3,000,000 Da)
• Connects Z line → M line
• Acts as scaffold + spring
• Stretch behavior: low resistance initially (domains unfold) → then resistance rises sharply (protects sarcomere)
• Desmin:
• Reinforces Z line structure
• Links Z lines to plasma membrane

PART 3 — Skeletal muscle “wiring”: T-tubules, SR, dystrophin complex

1) Sarcotubular system = T system + sarcoplasmic reticulum (SR)

A) T system (transverse tubules)

• Continuous with sarcolemma
• Forms a grid around myofibrils
• Space inside T tubule is essentially extracellular space extension
• Function: carries the AP rapidly from surface → deep to all fibrils

B) Sarcoplasmic reticulum (SR)

• Wraps each myofibril like an irregular curtain
• Has enlarged terminal cisterns
• Terminal cisterns sit near T tubules at A–I junction
• SR is major Ca²⁺ store and supports metabolism

C) Triad

• At A–I junction: 1 T tubule + 2 SR terminal cisterns
• This three-part arrangement = triad

2) Dystrophin–glycoprotein complex (mechanical reinforcement system)

• Dystrophin (~427 kDa) forms a rod linking:
• Actin (thin filaments) → to sarcolemma via:
• cytoplasmic proteins syntrophins
• transmembrane β-dystroglycan
• Outside the cell:
• β-dystroglycan connects to merosin/laminin-α2–containing laminins in ECM through α-dystroglycan
• Also linked to sarcoglycan complex (4 transmembrane glycoproteins):
• α, β, γ, δ sarcoglycan
• Role: adds strength + scaffolding, ties cytoskeleton to extracellular matrix
• Disruption → multiple muscular dystrophies

PART 4 — Skeletal muscle electrophysiology + contraction mechanics (AP → twitch → sliding)

1) Electrical characteristics (numbers you should be able to quote)

• Resting membrane potential: ~ −90 mV
• AP duration: 2–4 ms
• Conduction velocity along fiber: ~ 5 m/s
• Absolute refractory period: 1–3 ms
• After-polarizations + threshold changes: relatively prolonged
• Ion basis (same “idea” as nerve):
• Depolarization: mainly Na⁺ influx
• Repolarization: mainly K⁺ efflux

2) Electrical vs mechanical events (don’t mix them)

• AP starts at motor endplate
• AP spreads along fiber + into T-system
• This triggers mechanical contraction, but electrical and mechanical timings differ.

3) Muscle twitch

• One AP → brief contraction + relaxation = twitch
• Twitch begins ~ 2 ms after depolarization starts (before repolarization finished)
• Twitch duration depends on fiber type:
• Fast fibers: as short as ~7.5 ms (fine, rapid, precise)
• Slow fibers: up to ~100 ms (strong, gross, sustained)

4) Molecular basis = sliding filament (what changes + what doesn’t)

• Contraction = thin slides over thick
• Filaments themselves do not shorten
• What changes during contraction:
• Z lines move closer
• Overlap increases
• What stays constant:
• A band width stays constant

5) Cross-bridge cycle (sequence, in plain logic)

Resting state

• TnI helps keep actin sites blocked (with tropomyosin covering myosin-binding sites)
• Myosin head holds ADP (tightly bound)

After AP → Ca²⁺ rises

1. Ca²⁺ binds TnC
2. This weakens TnI’s inhibitory hold → binding sites exposed
3. Myosin binds actin → cross-bridge forms
4. ADP released → myosin head shape changes → power stroke
5. ATP binds myosin → myosin detaches from actin
6. ATP hydrolyzed → Pi released → head “re-cocks” ready again

• Continues as long as:
• Ca²⁺ remains elevated
• ATP is available
• Quantitative points:
• Each power stroke shortens sarcomere ~10 nm
• Each thick filament has ~500 heads
• Each head cycles ~5 times/sec in rapid contraction

6) Excitation–contraction coupling (how AP causes Ca²⁺ release)

• AP travels via T system
• At terminal cisterns, triggers Ca²⁺ release
• Key proteins:
• DHPR (dihydropyridine receptor)
• voltage-gated Ca²⁺ channels in T-tubule membrane
• acts as voltage sensor
• RyR (ryanodine receptor)
• Ca²⁺ release channel on SR (ligand-gated, Ca²⁺ as natural ligand)

Skeletal vs Cardiac difference (must separate)

• Cardiac: Ca²⁺ influx through DHPR is required to trigger SR release (calcium-induced calcium release).
• Skeletal: extracellular Ca²⁺ entry via DHPR is not required; DHPR mechanically interacts with RyR to “unlock” SR Ca²⁺ release; then Ca²⁺ release is amplified via CICR.

7) Relaxation + ATP roles

• Ca²⁺ removed from cytosol mainly by SERCA (SR Ca²⁺-ATPase)
• pumps Ca²⁺ back into SR using ATP
• ATP is needed for:
• Contraction (cross-bridge cycling)
• Relaxation (SERCA pumping Ca²⁺ back)
• If Ca²⁺ reuptake is blocked → relaxation fails → sustained contraction = contracture

PART 5 — Skeletal muscle mechanics: isometric/isotonic, tetanus, length–tension–velocity, fiber types

1) Types of contraction

• Isometric: tension develops but whole muscle length ~ constant (elastic/viscous elements absorb shortening)
• Isotonic: constant load + muscle shortens → does work
• Work = force × distance
• Isotonic does work
• Isometric essentially does not
• Muscle can also do negative work when lengthening against constant weight

2) Summation + tetanus

• Muscle membrane is refractory during spike rise and part of fall — but contractile machinery has no refractory period
• If stimulated again before relaxation ends → added force = summation
• High-frequency stimulation → fused contraction = tetanus
• Incomplete tetanus: some relaxation between stimuli
• Complete tetanus: no relaxation between stimuli
• Complete tetanus tension ≈ 4× single twitch tension
• Frequency for summation depends on twitch duration:
• twitch 10 ms → <100/s gives separate twitches; >100/s gives summation

3) Length–tension relationship (active vs passive vs total)

• Passive tension: tension from stretch of non-contractile elements
• Total tension: passive + active after stimulation
• Active tension: total − passive
• Active tension maximal at resting length (term comes from many muscles resting near that length)
• Sliding-filament explanation:
• Too stretched → overlap ↓ → cross-bridges ↓ → active tension ↓
• Too short → thin filament travel limited → active tension ↓

4) Force–velocity

• Velocity of shortening varies inversely with load
• At a given load, velocity maximal at resting length
• Velocity decreases if muscle shorter or longer than resting length

5) Fiber types (slow vs fast; 3 major categories)

• Muscles contain mixtures of:
• Type I (SO) = slow oxidative
• Type IIA (FOG) = fast oxidative-glycolytic
• Type IIB (FG) = fast glycolytic
• Differences come largely from protein isoforms (multigene families):
• 10 myosin heavy chain isoforms (MHC)
• light chain isoforms
• actin mostly one form
• multiple isoforms of tropomyosin + all troponin subunits

Key comparative properties (from the table you pasted)

• Type I (SO): red, slow ATPase, moderate SR Ca²⁺ pump, small diameter, moderate glycolysis, high oxidative, motor unit = S
• Type IIA (FOG): red, fast ATPase, high SR Ca²⁺ pump, large diameter, high glycolysis, moderate oxidative, motor unit = FR
• Type IIB (FG): white, fast ATPase, high SR Ca²⁺ pump, large diameter, high glycolysis, low oxidative, motor unit = FF
• Resting membrane potential noted again: −90 mV

PART 6 — Energy + heat + rigor (how skeletal muscle powers contraction)

1) ATP is the immediate energy source

• Muscle = converter of chemical energy → mechanical work
• ATP regenerated mainly from carbs + lipids

2) Phosphorylcreatine (PCr) = quick buffer system

• ATP can transfer phosphate to creatine in mitochondria → builds PCr stores
• During exercise:
• PCr hydrolyzed at actin–myosin region → phosphate used to turn ADP → ATP
• Supports short bursts before slower pathways catch up

3) Fuel selection with exercise intensity

• Rest/light exercise: mainly free fatty acids
• Higher intensity: fat too slow → carbohydrate becomes dominant

4) Aerobic vs anaerobic glycolysis (core logic)

• Glucose enters cell → becomes pyruvate
• Sources of glucose:
• blood glucose
• glycogen (liver + skeletal muscle storage polymer)
• If O₂ adequate:
• pyruvate → TCA + respiratory chain → CO₂ + H₂O + lots of ATP
• (text calls this aerobic glycolysis in the broad sense)
• If O₂ insufficient:
• pyruvate → lactate
• fewer ATP, but doesn’t require O₂

5) Oxygen debt mechanism (why you breathe hard after)

• Very heavy exertion:
• aerobic ATP production can’t keep up
• PCr used + anaerobic glycolysis produces lactate
• Limitation: lactate accumulates → buffers overwhelmed → pH drops → enzymes inhibited
• Example proportions (illustrative):
• 100 m dash (10 s): ~85% anaerobic
• 2-mile race (10 min): ~20% anaerobic
• 60-min long distance: ~5% anaerobic
• After exercise, extra O₂ used to:
• clear lactate
• restore ATP + PCr
• replace small O₂ released from myoglobin
• Oxygen debt measured by post-exercise O₂ consumption above baseline; can be up to ~6× basal O₂ consumption.

6) Rigor

• If ATP + PCr fully depleted → rigid state = rigor
• After death: rigor mortis
• Mechanism: myosin heads attach to actin in a fixed, resistant way → stiffness

7) Heat production categories

• Energy output appears as:
• work
• energy stored (small)
• heat (large)
• Mechanical efficiency:
• up to ~50% when lifting weight isotonic
• ~0% in isometric contraction
• Heat types:
• Resting heat: basal metabolism
• Initial heat during contraction:
• activation heat (whenever contracting)
• shortening heat (∝ distance shortened)
• Recovery heat after contraction (can last up to ~30 min); ≈ initial heat
• Relaxation heat: extra heat when muscle is returned to previous length after isotonic contraction (external work done on muscle)

PART 7 — Muscle in the intact body + cardiac + smooth muscle + clinical boxes

A) Skeletal muscle in the intact organism

1) Motor unit

• Smallest functional contractile “unit” in vivo:
• one motor neuron + all fibers it innervates
• Innervation ratio varies:
• fine control muscles (eye/hand): ~3–6 fibers per motor unit
• leg muscles: up to ~600 fibers per motor unit
• Motor unit fibers can be intermixed, not necessarily neighbors.
• One motor neuron innervates one fiber type, so motor unit fibers are same type.

2) Motor unit types + size principle

• Motor units classified by twitch duration / fatigue:
• S (slow)
• FR (fast, fatigue-resistant)
• FF (fast, fatigable)
• Tendency:
• S fibers → low innervation ratio (small units)
• FF fibers → high innervation ratio (large units)
• Recruitment usually follows size principle:
1. S first (controlled, low force)
2. then FR
3. then FF for maximal demand
• Example leg:
• standing → S
• walking → more FR
• running/jumping → FF added

3) Fiber properties can change with activity pattern

• Not fully “fixed”:
• Cross-innervation experiments show slow muscle can become fast if reinnervated by fast nerve (activity pattern drives protein isoform shifts)
• Exercise/inactivity:
• increased activity → hypertrophy (strength ↑), especially IIA/IIB
• inactivity → atrophy, type I most susceptible (used most often)

4) Electromyography (EMG)

• EMG records electrical activity using:
• surface electrodes or needle/fine wire electrodes
• At rest: normally little/no spontaneous skeletal activity
• Increasing voluntary effort:
• more motor units recruited + firing frequency increases
• Smooth force depends on:
• motor unit number
• firing frequency (tetanic > twitch)
• muscle length
• asynchronous firing between units → smooth whole-muscle contraction
• EMG helps detect abnormal electrical activity patterns.

5) Strength numbers + body mechanics examples

• Skeletal muscle tension: ~3–4 kg/cm² cross-section
• Examples:
• gastrocnemius resists forces several times body weight during running impacts
• gluteus maximus can exert ~1200 kg tension
• total possible if all muscles pulled together ~22,000 kg (~25 tons)
• Body mechanics often keeps muscles near resting length for max tension.
• Multi-joint example: hamstrings (hip + knee) → motion at one joint can offset length change at the other → near-isometric → high force.
• Walking:
• stance + swing phases; two double-support periods each cycle
• brief burst of leg flexor activity at start → swing mostly passive
• comfortable pace ~80 m/min, power ~150–175 W per step
• people naturally choose speed minimizing energy cost

B) Cardiac muscle (structure → AP → contraction)

1) Morphology

• Has striations + Z lines like skeletal
• Many elongated mitochondria close to myofibrils
• Fibers branch and interdigitate; each is a separate cell with membrane
• Intercalated discs (at Z lines):
• folded membranes forming strong end-to-end unions → transmit pull
• Gap junctions along sides near discs:
• low-resistance electrical bridges → spread excitation cell-to-cell
• makes heart function like a syncytium without cytoplasmic bridges
• Cardiac T tubules located at Z lines (vs A–I junction in mammalian skeletal)

2) Electrical properties (ventricular myocyte example)

• Resting potential ~ −90 mV
• AP has:
• rapid depolarization + overshoot (phase 0)
• plateau then repolarization
• Timing:
• depolarization ~ 2 ms
• plateau + repolarization ~200 ms or more
• repolarization not complete until contraction half over
• Ion channel phases:
• Phase 0: fast voltage-gated Na⁺ channels open
• Phase 1: Na⁺ channels close; a K⁺ channel type opens → initial repolarization
• Phase 2 (plateau): prolonged opening of voltage-gated Ca²⁺ channels (mainly L-type)
• Phase 3: Ca²⁺ channels close + delayed ↑ K⁺ efflux
• Phase 4: resting baseline
• External ions:
• extracellular K⁺ affects resting potential
• extracellular Na⁺ affects AP magnitude
• Channel dysfunction mutations → major pathology

3) Mechanical properties

• Contraction begins just after depolarization and lasts ~1.5× AP duration
• E-C coupling:
• Ca²⁺ influx via DHPR in T tubules triggers SR release via RyR (CICR)
• Recovery Ca²⁺ handling:
• greater role for plasma membrane Ca²⁺ ATPase + Na⁺/Ca²⁺ exchanger (because net Ca²⁺ influx occurs)
• Refractory period:
• absolute refractory spans phases 0–2 and ~half of phase 3 (until ~−50 mV)
• relative refractory until phase 4
• therefore no tetanus (protective; sustained tetanus would be fatal)

4) Isoforms

• Cardiac muscle is generally “slow” with lower ATPase; relies on oxidative metabolism + continuous O₂
• Human heart has α and β MHC
• β MHC has lower ATPase than α
• both in atria (α predominates)
• ventricles: β predominates
• This distribution supports coordinated contraction

5) Length–tension + Starling + catecholamines

• Similar resting length concept, but in vivo initial length depends on diastolic filling
• Ventricular pressure ∝ end-diastolic volume (Starling law)
• Tension increases with filling to max then may decrease at extreme dilation
• not because cross-bridges decrease like skeletal (dilated hearts not stretched that far)
• rather due to beginning fiber disruption
• Catecholamines increase force without length change (positive inotropy):
• via β₁ receptors (innervated), cAMP, Ca²⁺ handling
• also β₂ receptors (non-innervated), smaller effect, maximal in atria
• cAMP → PKA
• phosphorylates Ca²⁺ channels → more open time
• increases Ca²⁺ uptake into SR → faster relaxation → systole shorter (helps filling at high HR)

6) Cardiac metabolism

• High blood supply, many mitochondria, high myoglobin
• Normally < 1% energy anaerobic; hypoxia up to ~10%
• Basal substrate use (typical):
• ~35% carbs
• ~5% ketones + amino acids
• ~60% fat
• Shifts:
• after high glucose intake → more lactate/pyruvate use
• starvation → more fat
• diabetics untreated → carb use ↓, fat use ↑
• Circulating free fatty acids contribute ~50% of lipid used

C) Smooth muscle (structure → types → electrical behavior → contraction/relaxation)

1) Morphology essentials

• No striations because actin/myosin not in regular sarcomeres
• Has actin + myosin-II sliding
• Anchoring system:
• instead of Z lines → dense bodies (cytoplasmic + membrane-attached)
• α-actinin links actin to dense bodies
• Contains tropomyosin
• Troponin absent
• SR present but less extensive
• Few mitochondria; depends largely on glycolysis
• Actin/myosin isoforms differ from skeletal

2) Types (unitary vs multiunit)

• Unitary (visceral)
• large sheets
• many gap junctions → syncytial behavior
• in hollow viscera: intestine, uterus, ureters
• Multiunit
• individual units, few/no gap junctions
• iris etc; fine graded contraction
• not voluntary but functionally similar to skeletal in some ways
• Innervation pattern:
• multiunit: each cell gets en passant nerve endings
• unitary: fewer cells directly innervated; excitation spreads via gap junctions
• Vessels can have both types

3) Electrical + mechanical activity (tone + slow coupling)

• Unitary smooth muscle:
• membrane potential unstable
• continuous irregular contractions independent of nerves
• maintained partial contraction = tone (tonus)
• “resting” potential varies; during quiescence ~ −20 to −65 mV
• electrical patterns can include:
• slow wave oscillations
• spikes (may or may not overshoot 0)
• some have prolonged plateau like cardiac
• channels involved: K⁺, Na⁺, Ca²⁺, plus Na⁺/K⁺ ATPase (details vary by tissue)
• Excitation–contraction coupling is slow
• in some preparations delay can be up to 500 ms
• compared with <10 ms in skeletal/cardiac
• Multiunit:
• not syncytial; contraction stays local and discrete

4) Molecular basis of smooth muscle contraction (the key difference: phosphorylation)

• Ca²⁺ can rise by multiple routes:
• influx via voltage-gated or ligand-gated channels
• release from stores via RyR
• release via IP₃ receptor (IP3R)
• combinations of the above
• No troponin → Ca²⁺ does not activate via troponin binding
• Instead:
1. Ca²⁺ binds calmodulin
2. Ca²⁺–calmodulin activates MLCK (calmodulin-dependent myosin light chain kinase)
3. MLCK phosphorylates myosin light chain at Ser19
4. myosin ATPase activity ↑ → contraction
• MLCP (myosin light chain phosphatase) dephosphorylates myosin
• But dephosphorylation doesn’t always instantly relax:
• Latch bridge idea: cross-bridges can stay attached after Ca²⁺ falls → sustained force with low energy (important in vessels)

5) Special behaviors + autonomic chemicals

• Unitary smooth muscle contracts to stretch even without nerves:
• stretch → membrane potential falls → spike frequency ↑ → tone ↑
• Intestinal smooth muscle in vitro:
• NE/Epi typically hyperpolarize (membrane potential becomes larger), spikes ↓, relaxation
• ACh does opposite: depolarize, spikes ↑, tonic tension ↑ + rhythmic contractions ↑
• ACh effect mediated by PLC → IP₃ → Ca²⁺ release via IP₃ receptors
• Multiunit smooth muscle:
• highly sensitive to circulating substances
• activated by ACh/NE from motor nerves
• NE can persist → repeated firing after one stimulus → irregular tetanus more than single twitch
• if single twitch seen, duration ~10× skeletal twitch

6) Relaxation pathway (NO → cGMP)

• Endothelium releases NO (EDRF = NO)
• NO diffuses into smooth muscle → activates soluble guanylyl cyclase
• ↑ cGMP → activates cGMP-dependent protein kinases
• Leads to relaxation via effects on:
• ion channels
• Ca²⁺ handling
• phosphatases (often combined effects)

7) Function of nerve supply (unitary)

• Nerves mainly modify activity, not initiate it
• Usually dual autonomic supply:
• one division ↑ activity, other ↓ (can reverse depending on organ)

8) Force economy + plasticity

• Smooth muscle can generate similar force per area despite:
• ~20% myosin content vs skeletal
• ~100-fold less ATP use vs skeletal
• Trade-off: much slower contraction
• Plasticity:
• stretch → tension rises initially
• if held stretched → tension gradually falls (can drop to baseline or below)
• so no fixed “resting length” like skeletal
• behaves partly like viscous material
• Human bladder example: tension rises little at first with filling (plasticity) until threshold where strong contraction occurs.

PART 8 — Clinical boxes re-expressed (every point preserved, in your words)

Clinical Box 5–1: Structural & metabolic disorders

• Muscular dystrophy = progressive skeletal muscle weakness (many forms; some also affect heart).
• Many due to mutations in dystrophin–glycoprotein complex genes.
• Dystrophin gene is huge → many possible mutation sites.
• Duchenne MD
• X-linked
• dystrophin absent
• severe; often fatal by ~age 30
• Becker MD
• dystrophin present but reduced/abnormal
• milder
• Limb-girdle dystrophies
• mutations in sarcoglycans or other complex components
• Titin mutations
• shorter titin forms linked to dilated cardiomyopathy
• other mutations linked to hypertrophic cardiomyopathy
• tibialis muscular dystrophy: titin mutation predicted to destabilize folded domains
• muscle-specific phenotypes despite titin being in all striated muscle → shows titin has multiple roles
• Desmin-related myopathies
• rare, heterogeneous; desmin aggregates
• symptoms: distal lower-limb weakness/wasting → later other areas
• desmin knockout mice show defects in skeletal/smooth/cardiac, especially diaphragm/heart
• Metabolic myopathies
• enzyme gene mutations in metabolism of carbs/fats/proteins → ATP production impaired
• example: McArdle syndrome
• common theme: exercise intolerance + risk of muscle breakdown from toxic metabolite buildup
• Therapy highlights:
• acute soreness: rest + anti-inflammatory drugs
• genetic disorders: aim to slow progression, relieve symptoms
• monitoring + physiotherapy + drugs (incl corticosteroids) may slow progression
• assistive devices + surgery often needed as disease advances

Clinical Box 5–2: Muscle channelopathies

• Channelopathies = ion-channel dysfunction disorders affecting excitable cells incl muscle.
• Myotonias: delayed/prolonged relaxation after contraction.
• Myotonia dystrophy: autosomal dominant mutation → overexpression of a K⁺ channel (mutation not in K⁺ channel gene itself)
• Other myotonias:
• Na⁺ channel mutations: hyperkalemic periodic paralysis, paramyotonia congenita, Na⁺ channel congenita
• Cl⁻ channel mutations: dominant or recessive myotonia congenita
• Congenital myasthenia
• inherited defects in channels needed for neuronal → muscle signaling
• can involve Ca²⁺ channels for transmitter release or ACh receptor cation channels
• Myasthenia gravis
• autoimmune
• antibodies to nicotinic ACh receptor → functional receptor presence ↓ up to ~80% → weak muscle response
• RyR mutations can cause malignant hyperthermia
• normal baseline function, but triggers (certain anesthetics; rarely heat/exertion) → abnormal SR Ca²⁺ release → sustained contraction + heat production → can be fatal
• Therapy highlights:
• symptoms may look similar but treatments vary; drugs targeted to specific defect
• avoid movements/triggers that worsen condition

Clinical Box 5–3: Muscle rigor

• When ATP + PCr are depleted → rigidity
• After death = rigor mortis
• In rigor, most myosin heads bind actin in a fixed resistant way → muscles lock and feel stiff

Clinical Box 5–4: Denervation

• Normal skeletal muscle contracts only when motor nerve stimulates it.
• Denervation → atrophy
• Also → abnormal excitability + ↑ sensitivity to circulating ACh (denervation hypersensitivity)
• Produces fibrillations: fine irregular contractions of individual fibers (usually not grossly visible)
• Classic lower motor neuron lesion picture
• If nerve regenerates → fibrillations disappear
• Don’t confuse with fasciculations (visible jerky contractions of groups of fibers from abnormal spinal motor neuron discharge)

Clinical Box 5–5: Long QT syndrome

• LQTS = prolonged QT on ECG → risk arrhythmias → syncope/seizure/cardiac arrest/death
• Can be drug-induced, but often genetic channel mutations
• Most mutation-based cases (~90%) from K⁺ channel genes:
• KCNQ1 or KCNH2
• Also Na⁺ channel gene SCN5A or Ca²⁺ channel gene CACNA1C
• Key point: different channels can all prolong QT because AP shape depends on channel interplay
• Therapy highlights:
• avoid QT-prolonging drugs; correct low K⁺/Mg²⁺
• β-blockers used to reduce arrhythmia risk
• best targeted therapy once cause identified; treating asymptomatic patients can be controversial, but congenital LQTS generally considered for intervention

Clinical Box 5–6: Digitalis glycosides (ouabain etc)

• Used in failing hearts to increase contractile strength
• Working mechanism idea:
• inhibit Na⁺/K⁺ ATPase in cardiomyocytes → intracellular Na⁺ ↑
• reduces Na⁺ gradient → less Na⁺ entry driving Na⁺/Ca²⁺ exchanger
• Ca²⁺ efflux via exchanger ↓ → intracellular Ca²⁺ ↑ → stronger contraction
• Toxicity risks:
• too much Na⁺/K⁺ ATPase inhibition → depolarization → conduction slowed or abnormal automaticity
• too much Ca²⁺ ↑ → harmful effects on cardiomyocyte physiology

Clinical Box 5–7: Drugs acting on smooth muscle

• Asthma bronchoconstriction = smooth muscle overactivity in airways
• “Rescue” inhalers act fast by relaxing airway smooth muscle:
• β-agonists: albuterol/ventolin, sambuterol etc
• rapid relief but don’t fix all asthma components (eg inflammation/mucus)
• NO–cGMP pathway downregulated by PDE (breaks cGMP → GMP)
• PDE-5 inhibitors: sildenafil, tadalafil, vardenafil
• block PDE-5 (mainly in corpus cavernosum smooth muscle)
• increase local blood flow → treat erectile dysfunction