Muscle (5), full

What percentage of lean body mass (magere Körpermasse) does skeletal muscle comprise?

Skeletal muscle comprises approximately 40% of lean body mass, significantly affecting overall metabolism

How does muscle influence metabolism and what factors cause muscle remodeling?

• Muscle has a major effect on overall metabolism

• Muscle undergoes massive remodeling depending on:

  • Use/activity level

    • Endurance training

    • Resistance training

    • Immobilization

  • Metabolic state

    • Obesity

    • Malnutrition

  • Age

  • Disease

What can cause muscle wasting, and what are its consequences?

• Causes of muscle wasting:

  • Cancer

  • Sepsis

  • Disuse / immobilization

  • Aging

• Consequences of muscle wasting:

  • Loss of muscle strength

  • Major reduction in quality of life

  • Can lead to loss of ambulation (ability to walk)

  • Severe cases may cause early death due to impaired respiratory function

How is skeletal muscle formed?

• Skeletal muscle forms a syncytium (multinucleated structure)

• Mononucleated myoblasts fuse to form myotubes

• Proven by chicken–quail chimera experiments

• Muscle fusion involves:

  • Transcription factors:

    • Myf5

    • MyoD

  • Extracellular signaling / induction events:

    • Wnt

    • Shh (Sonic hedgehog)

  • Growth factors:

    • FGF

What triggers myotube formation from myoblasts?

• Myoblast proliferation must stop first

• After proliferation stops, specific cell–cell interactions occur

• These interactions trigger the fusion of non-dividing myoblasts

• Fusion results in the formation of myotubes

What are satellite cells and what is their role in skeletal muscle?

• Satellite cells are mononucleated cells present in adult skeletal muscle

• They are normally quiescent (inactive)

• They become activated when muscle fibers are damaged or destroyed

• After activation, satellite cells can:

  • Proliferate

  • Form new muscle fibers (via fusion into multinucleated fibers)

• This process is essential for muscle regeneration after injury

What is the epimysium?

• Epimysium = layer of connective tissue surrounding the muscle

• Continuous with tendons

• Functions:

  • Protects the muscle from friction

  • Reduces friction between bones and other muscles

Why must skeletal muscle fibers be connected to the nervous system?

• Skeletal muscle is responsible for voluntary movement

• Therefore, individual muscle fibers must be connected to the nervous system

• This connection allows neural control of muscle contraction

From which embryonic germ layer (Keimblatt) do muscles originate?

All muscles originate from the mesoderm (Mesoderm)

From which specific mesodermal structure do the heart and smooth muscles form?

They form from the lateral plate mesoderm (Seitenplattenmesoderm)

From which specific mesodermal structure do most skeletal muscles (except head muscles) derive?

They derive from the paraxial mesoderm (paraxiales Mesoderm), specifically from the somites (Somiten)

Into which three structures do somites differentiate?

Somites differentiate into the sclerotome (Sklerotom: skeleton), myotome (Myotom: skeletal muscle), and dermatome (Dermatom: dermis)

What term describes a muscle fiber because it contains multiple nuclei in one shared cytoplasm?

A muscle fiber is a true syncytium (Synzytium)

What mono-nucleated cells fuse together to form myotubes during development?

Myoblasts (Myoblasten) fuse to form myotubes

Which transcription factors (Transkriptionsfaktoren) are involved in the muscle fusion process?

Myf5 and MyoD are key transcription factors in this process

Which extracellular signaling events and growth factors (Wachstumsfaktoren) regulate muscle development?

Wnt, Shh, and FGF are key regulators

What specific trigger in a cell culture dish induces myoblasts to stop proliferating and start fusing?

The withdrawal of growth factors or fetal calf serum (fötales Kälberserum) triggers this

What are the quiescent, mono-nucleated cells in adult muscle called that are essential for repair?

They are called satellite cells (Satellitenzellen), which activate and proliferate when fibers are damaged

How is skeletal muscle connected to bone (Knochen)?

Skeletal muscle is connected to bone via tendons (Sehnen)

What connective tissue layer separates individual muscles from each other and is continuous with tendons?

The epimysium (Epimysium)

What is a collection of 10-100 individual muscle fibers called?

It is called a muscle fascicle (Muskelfaszikel)

Which connective tissue (Bindegewebe) surrounds a muscle fascicle?

The perimysium (Perimysium)

What is the smallest unit of a muscle and what tissue surrounds it?

The muscle fiber (Muskelfaser) is the smallest unit, surrounded by the endomysium (Endomysium)

Where are myonuclei (Zellkerne) normally located in a healthy muscle fiber?

They are localized in the periphery (Peripherie) of the fiber

What does it indicate if myonuclei are found in the center (Zentrum) of a muscle fiber?

Centralized nuclei are a sign of recent regeneration (Regeneration)

What is the basic contractile unit (kontraktile Einheit) of skeletal muscle?

The sarcomere (Sarkomer)

What are the structural borders of a sarcomere called?

They are called Z-discs (Z-Scheiben)

Which two bands are distinguished in skeletal muscle under polarized light (polarisiertes Licht)?

The A-bands (anisotropic, dark) and I-bands (isotropic, light)

Which protein is a major component of the Z-disc and can be used for antibody staining?

Alpha-actinin (Alpha-Aktinin)

Where are the cell bodies (Zellkörper) of the motor neurons that innervate skeletal muscle located?

They are located in the spinal cord (Rückenmark)

What is the simplest neural circuit (Nervenschaltkreis) involved in muscle movement?

The monosynaptic reflex (monosynaptischer Reflex), such as the knee-jerk response

What is the primary purpose of the monosynaptic reflex?

To keep the length and tonus (Tonus: muscle tension) constant for proper locomotion.

• Reflex based on a sensory neuron that measures the length of the muscle and feeds this information back to the motor neuron.

How does synaptic area relate to quantal content at the neuromuscular junction?

• Synaptic area has a linear correlation with quantal content

• Larger neuromuscular junctions (NMJs):

  • Release more neurotransmitter per action potential

• Smaller neuromuscular junctions:

  • Release less neurotransmitter per action potential

Why are postsynaptic folds increased at the neuromuscular junction?

• Exact reason is not fully understood

• Most likely function:

  • To ensure each presynaptic action potential reliably causes contraction of the postsynaptic muscle fiber

How does the neuromuscular junction ensure that each presynaptic action potential leads to muscle contraction?

• Unlike neuron–neuron synapses, NMJs do not rely on integration for decision-making

• In NMJs, each presynaptic action potential → muscle contraction

• This reliability is ensured by:

  • Voltage-gated Na⁺ channels located close to acetylcholine receptors (AChRs)

  • Rapid local depolarization near AChRs

  • Depolarization easily reaches threshold

  • This triggers opening of voltage-gated Na⁺ channels

• Result: consistent generation of muscle action potential → contraction

How do postsynaptic folds contribute to reliable neuromuscular transmission?

• Postsynaptic folds increase surface area of the muscle membrane

• This ensures high concentration of voltage-gated Na⁺ channels

• Even when little acetylcholine is released presynaptically:

  • Local depolarization is still sufficient

  • Threshold is reached reliably

• Result: consistent activation of muscle action potentials → contraction

What is the role of T-tubules in skeletal muscle?

• Skeletal muscle fibers are very large, so surface action potentials do not reach deep inside the fiber

• Without deeper signal spread, deep myofibrils would not contract effectively

• T-tubules (transverse tubules) solve this problem by:

  • Penetrating from the surface into the entire muscle fiber

  • Allowing action potentials to spread deep inside the cell

• This ensures uniform activation of myofibrils → maximal muscle contraction

What is the specific site where a motor neuron innervates a muscle fiber?

The neuromuscular junction (neuromuskuläre Endplatte), which covers only about 0.1% of the fiber surface

What is the linear correlation between the presynaptic area and neurotransmitter release?

Synaptic area correlates linearly with quantal content (Quantengehalt: amount of neurotransmitter)

How do human neuromuscular junctions (NMJ) compare to frogs in terms of size and folds?

Human NMJs are smaller and release fewer quanta (~20) but have much deeper postsynaptic folds (Faltungen)

What does the folding index (Faltungsindex) represent and how does it correlate with synaptic area?

It represents the factor by which folding increases postsynaptic area, and it inversely correlates with synaptic area size

What is a key functional difference between neuron-to-neuron synapses and the NMJ?

NMJ has high efficacy, where every presynaptic action potential (Aktionspotential) results in a muscle contraction

Where are voltage-gated sodium channels (spannungsabhängige Natriumkanäle) located in the postsynaptic folds?

They are localized in the trough (Mulde) of the folds

Where are acetylcholine receptors (Azetylcholin-Rezeptoren) located on the postsynaptic membrane?

They are located at the crest (Gipfel) of the folds

How does an action potential reach deep inside a large muscle fiber to trigger contraction?

Via transverse tubules or T-tubules (T-Tubuli) that penetrate the entire fiber

What is the ion gradient (Ionengradient) of T-tubules?

• High sodium (Natrium) outside and high potassium (Kalium) inside.

• Their ion gradient is as in all other cell membranes because they are connected to the extracellular environment.

How does an action potential lead to calcium release in skeletal muscle?

• Action potential activates DHPR (voltage sensor in T-tubule membrane)

• DHPR opening activates RyR1 (ryanodine receptor) on sarcoplasmic reticulum

• RyR1 opens → Ca²⁺ is released into the sarcoplasm

• Result: increase in intracellular Ca²⁺ triggers muscle contraction

What is the clinical relevance of malignant hyperthermia and how is it managed in at-risk patients?

• Patients with a family history of malignant hyperthermia can be tested before surgery

• Testing helps identify susceptible individuals

• In clinical practice, non-depolarizing muscle relaxants are used

  • These do not trigger malignant hyperthermia

• This reduces the risk of malignant hyperthermia during anesthesia

Why is muscle force maximal at an intermediate muscle length?

• Force is maximal at intermediate muscle stretch

• At high contraction (too short muscle length):

  • Sliding filament inhibition occurs

  • Reduced effective force generation

• At maximal extension (too long muscle length):

  • Low overlap between actin and myosin

  • Fewer cross-bridges can form

• Result: optimal actin–myosin overlap at intermediate length → maximal force

What is temporal summation and tetanic contraction in skeletal muscle, and what is their molecular basis?

• If time between action potentials is shorter than a single twitch duration:

  • Twitches overlap → temporal summation

  • Leads to increased force production

• At higher stimulation frequency:

  • Twitches fully fuse

  • Produces tetanic contraction

• Molecular basis:

  • Accumulation of Ca²⁺ in the sarcoplasm

  • Repeated excitation–contraction coupling prevents full Ca²⁺ removal between stimuli

What is the size principle in motor unit recruitment?

• Small motor units (few muscle fibers) are recruited first and faster

• Large motor units (many muscle fibers) are recruited later and require stronger input

• Cause: differences in motor neuron size → different thresholds for action potential generation

• Result: graded force production

  • From low to high force via sequential recruitment of increasingly larger motor units

What are fast fatigue-resistant motor units?

• A third class of motor units with intermediate properties

• Properties lie between slow and fast-fatigable motor units

• Produce about 2× more force than slow motor units

• Are resistant to fatigue

• Combine higher force output + endurance

How does motor unit recruitment produce graded muscle force (Henneman’s size principle)?

• Muscle force is regulated by changing the number of active motor units

• Increasing synaptic input to a motor neuron pool → progressive recruitment of motor units

• Recruitment follows a fixed size order (Henneman’s size principle):

  • Small, low-threshold motor units (slow) recruited first

  • Then fast fatigue-resistant motor units

  • Finally large, fast-fatigable motor units at highest activity

• Result: graded increase in muscle tension from weak to strong contraction

How do motor neuron firing frequency and asynchrony regulate smooth muscle force?

• Motor neuron firing frequency also regulates muscle tension

• At very high firing rates:

  • Muscle fibers reach fused tetanus

  • Constant, maximal tension in active motor units

• Normally:

  • Motor neuron firing rate is below fused tetanus level

• Asynchronous firing of different motor neurons:

  • Ensures steady overall input to muscle

  • Smooths out individual contraction–relaxation cycles

• Result: stable force output and smooth movements

What happens when an action potential arrives at the T-tubules?

Voltage-gated calcium channels called dihydropyridine receptors (DHPR) open

To which receptor in the sarcoplasmic reticulum is the DHPR coupled?

The ryanodine receptor 1 (RyR1)

Where is calcium (Kalzium) stored within the muscle fiber?

In the terminal cisternae (terminale Zisternen) of the sarcoplasmic reticulum (sarkoplasmatisches Retikulum)

What is the concentration change of calcium in the sarcoplasm during activation?

It increases from 10^-7 mol/l to up to 10^-5 mol/l

What specific proteins regulate the interaction between actin and myosin?

Troponin and tropomyosin (Tropomyosin)

How is calcium removed from the sarcoplasm (Sarkoplasma) to stop contraction?

It is removed by calcium pumps (Kalziumpumpen) that move it back into the SR

What disease is triggered by mutations in DHPR or RyR1 when exposed to certain anesthetics?

Malignant hyperthermia (maligne Hyperthermie), causing muscle rigidity and high body temperature

Which drug is used to treat malignant hyperthermia by acting as a RyR1 antagonist?

Dantrolene (Dantrolen)

At what sarcomere length is force generation (Kraftentwicklung) maximal?

At an intermediate degree of stretching (Dehnung), where there is optimal overlap between myosin and actin

What is a single mechanical response to a single action potential called?

A single twitch (Einzelzuckung)

Which muscle is a classic example of a slow-twitch (langsam zuckend) muscle?

The soleus muscle (M. soleus)

Which muscle is a classic example of a fast-twitch (schnell zuckend) muscle?

The gastrocnemius muscle (M. gastrocnemius)

What happens when the interval between action potentials is shorter than the twitch duration?

Temporal summation (Summierung) occurs, increasing force

What is the state of constant muscle tension produced by high-frequency stimulation called?

Tetanic contraction or tetanus (Tetanus)

Define a motor unit (motorische Einheit).

A motor neuron and all the muscle fibers it innervates

What is the "size principle" (Größenprinzip) in motor unit recruitment?

Small motor units (lower threshold) are recruited first, followed by progressively larger ones

Why are small motor neurons easier to excite than large ones?

They have a smaller surface area and fewer channels, leading to higher overall resistance (Widerstand), allowing threshold to be reached easier

Describe slow motor units (langsame Einheiten).

Small "red" fibers, high myoglobin (Myoglobin), many mitochondria, fatigue-resistant, used for posture

Describe fast fatigable motor units (schnell ermüdbare Einheiten).

Large "pale" fibers, sparse mitochondria, generate large force but fatigue quickly, used for sprinting

Describe fast fatigue-resistant motor units (schnelle, ermüdungsresistente Einheiten).

Intermediate properties, generating about twice the force of slow units while resisting fatigue

What is the most prevalent autoimmune disease affecting neuromuscular transmission?

Myasthenia gravis (Myasthenia gravis)

• Rare and heterogenous neuromuscular disease.

• Patients very prone to fatigue and they are therefore also weak.

• Ptosis.

What is the primary cause of Myasthenia gravis?

Auto-antibodies (Autoantikörper) against acetylcholine receptors or MuSK

What is the medical term for the drooping of the eyelid seen in myasthenia gravis?

Ptosis (Ptose)

What mechanism causes receptor loss in Myasthenia gravis?

Antibody-mediated endocytosis (Endozytose) of the receptors, lowering their half-life

How is myasthenia gravis treated?

• Treatment is either symptomatic or immunological (empiric)

• Symptomatic treatment:

  • Acetylcholinesterase inhibitors (increase ACh availability)

• Immune-targeting treatments:

  • Immunosuppressive therapy

  • Plasma exchange (removes antibodies)

  • Intravenous immunoglobulins (IVIG)

  • Thymectomy (removal of thymus)

What are congenital myasthenic syndromes (kongenitale myasthene Syndrome)?

Rare genetic diseases caused by mutations in genes like rapsyn, Dok-7, or sodium channels

How does nerve gas (Nervengas) like "Senfgas" affect the NMJ?

It blocks acetylcholine esterase, causing constant activation

Which poisons bind to and block acetylcholine receptors?

Alpha-bungarotoxin (Schlangengift) and curare (Pfeilgift).

• They block acetycholine receptors thereby preventing neuromuscular transmission.

What is the lethal dose of Botulinum neurotoxins (Botulinumtoxin)?

Approximately 10^-9 g/kg, making them the most potent acute lethal toxins

How does Botulinum toxin affect the muscle?

It cleaves proteins (SNAREs) required for neurotransmitter release, causing chemical denervation (Denervierung)

What are the three distinct muscle fiber types in humans?

Type I, Type IIa, and Type IIx

Which human fiber type is the most oxidative and fatigue-resistant?

Type I (often called "red meat" or rotes Fleisch)

How does tetanus toxin act in the nervous system and what is its molecular target?

• Tetanus toxin does not act directly at the neuromuscular junction

• It is:

  • Endocytosed at motor neuron terminals

  • Transported retrogradely to the soma

• Then released and taken up by inhibitory interneurons in the spinal cord via TRANSCYTOSIS

• In inhibitory neurons, it:

  • Cleaves VAMP/synaptobrevin (vesicle fusion protein)

• Mechanism of transport is highly specific but not fully understood

Which human fiber type has the largest diameter and uses low oxidative metabolism?

Type IIx

Which methods are used to analyze muscle fiber metabolic properties?

• ATPase activity measurement at different pH

• Oxidative capacity assessment using succinate dehydrogenase (SDH) activity assay

• Glycogen content measurement using periodic acid–Schiff (PAS) staining

Can muscle fiber composition change, and what influences it?

• Yes, muscle fiber composition is adaptable

• It depends on:

  • Innervation (type of nerve input)

  • Environmental changes such as exercise/training

• Result: muscle fibers can shift their functional/metabolic properties

What is Duchenne muscular dystrophy (DMD) and its main consequences?

• Duchenne muscular dystrophy (DMD) causes loss of muscle integrity

• Leads to:

  • Progressive inability to ambulate (loss of walking ability)

  • Severe muscle weakness

• Eventually results in:

  • Respiratory failure due to diaphragmatic muscle failure

  • Death

What are cachexia and sarcopenia in relation to muscle loss?

• Cachexia:

  • Secondary muscle wasting condition

  • Associated with:

    • Cancer

    • AIDS

    • Chronic obstructive pulmonary disease (COPD)

    • Renal disease

    • Sepsis

• Sarcopenia:

  • Age-related loss of muscle mass

What are the key features and progression of muscular dystrophies?

• Caused by >30 different genes linked to muscular dystrophies

• Late-stage features:

  • Loss of muscle due to fiber degeneration

  • Fibrosis (connective tissue replacement)

• Common disease mechanism:

  • Muscle attempts to compensate via regeneration

• Early/ongoing process:

  • Repeated cycles of muscle degeneration and regeneration (apoptosis/necrosis)

• Histological/biochemical signs:

  • Centralized myonuclei in regenerating fibers

  • Increased muscle-specific proteins (e.g., creatine kinase) in blood

Where can the products of mutated genes causing muscular dystrophies be localized?

• Mutated gene products can be found in all cell compartments, including:

  • Basement membrane

  • Sarcolemma

  • Sarcoplasm

  • Nucleus

Which mutations in the dystrophin–glycoprotein complex cause muscular dystrophies?

• Mutations in components of the dystrophin–glycoprotein complex lead to muscular dystrophies, including:

  • LAMA2 (α2 chain of laminin-211) → MDC1A (congenital muscular dystrophy)

  • Sarcoglycans → limb-girdle muscular dystrophies

  • α-dystroglycan glycosylation defects → congenital muscular dystrophies

  • Dystrophin mutations → Duchenne or Becker muscular dystrophy

What is the role of the dystrophin complex in DMD and how does its loss lead to muscle fiber damage?

• The dystrophin–glycoprotein complex provides mechanical stability during muscle contraction

• In DMD, loss of this stability leads to:

  • Detachment of muscle fibers from the basement membrane

  • Small tears in the sarcolemma

  • Disruption of linkage to the F-actin cytoskeleton

• Consequences of sarcolemma damage:

  • Unregulated Ca²⁺ influx into muscle fibers

  • Activation of Ca²⁺-dependent proteases

  • Triggering of downstream damage pathways

• Final outcome: muscle fiber necrosis

What are the main adaptations of skeletal muscle to endurance training?

• Increased oxidative capacity of muscle

• Increased blood supply (capillarization)

• Metabolic adaptations:

  • Increased glycogen stores

  • Glycogen sparing at submaximal workloads

  • Increased fat oxidation

  • Improved lactate kinetics

• Morphological changes:

  • Higher proportion of type I fibers per muscle area

  • Increased capillary density

  • Increased mitochondrial density

• Key mechanism:

  • Mitochondrial biogenesis → increased enzyme activity and fatigue resistance

What is the primary genetic cause of Duchenne muscular dystrophy (DMD)?

Mutations in the dystrophin (Dystrophin) gene, which is the largest gene in the human genome

What is the incidence of DMD and who does it primarily affect?

1 in 3,500 boys, as it is an X-linked recessive (X-chromosomal-rezessiv) disorder

How does Becker muscular dystrophy (BMD) differ from DMD?

BMD is milder because there is residual expression of a truncated (verkürzt) form of dystrophin