Muscle Organization and Function PDF

Muscle Organization and Function Overview Muscles are essential for movement, stability, and heat production. Understanding their organization and function is crucial for grasping how they work in the body. Learning Objectives 1. Properties and Functions of Muscles o Role in movement, s...

Muscle Organization and Function Overview Muscles are essential for movement, stability, and heat production. Understanding their organization and function is crucial for grasping how they work in the body. Learning Objectives 1. Properties and Functions of Muscles o Role in movement, stability, and heat production. o Concept of muscle contraction. 2. Anatomical Organization o Structure of skeletal, cardiac, and smooth muscle. o Key components of a muscle fiber: § Sarcolemma § Sarcoplasm § Sarcoplasmic reticulum o Sliding filament theory of muscle contraction. o Structure and function of the sarcomere: § A band § I band § H zone § Z line § M line o Role of calcium in muscle contraction. 3. Muscle Types o Differences in structure, function, and location: § Skeletal muscle § Cardiac muscle (features: intercalated discs, autorhythmicity) § Smooth muscle (various types and functions). Muscle Overview Striated Unstriated Skeletal Cardiac Smooth Voluntary Involuntary Skeletal Muscle Tissue Properties: o Contractility: Ability to shorten. o Excitability: Capacity to respond to stimuli. o Extensibility: Ability to stretch. o Elasticity: Ability to return to original shape. Functions: o Production of movement. o Maintaining posture. o Stabilizing joints. o Generating heat. Skeletal Muscle Anatomy Components: o Epimysium: Connective tissue surrounding the entire muscle. o Fascicles: Muscle bundles. o Perimysium: Connective tissue surrounding fascicles. o Muscle Fibre: Myofibril bundles o Endomysium: Connective tissue surrounding individual fibers. o Myofibril bundles: Composed of sarcomeres Skeletal Muscle: Myofiber → Myofibril → Sarcomere → Myofilament. Myofibril Proteins: o Contractile: Generate force (e.g., Actin, Myosin). o Regulatory: Initiate/terminate contraction (e.g., Troponin, Tropomyosin). o Structural: Maintain alignment (e.g., Titin, Myomesin, Dystrophin). Muscle Fiber Types 1. Slow Oxidative (Type I) o Diameter: ↓ o Capillaries, Mitochondria, Myoglobin: ↑ o Glycogen & creatine kinase: ↓ o Color: Red o ATP Generation: Aerobic o Fatigue Resistance: ↑  o Function: Postural, endurance. 2. Fast Oxidative-Glycolytic (Type II-A) o Diameter: ↔ o Capillaries, Mitochondria, Myoglobin: ↑ o Glycogen & creatine kinase: ↔ o Color: Red-pink o ATP Generation: Aerobic & glycolysis o Fatigue Resistance: ↔ o Function: Sprinting, walking. 3. Fast Glycolytic (Type II-B) o Diameter: ↑ o Capillaries, Mitochondria, Myoglobin: ↓ o Glycogen & creatine kinase: ↑ o Color: White o ATP Generation: Glycolysis o Fatigue Resistance: ↓ o Function: Short-term. Fiber Types: I (Slow), II-A (Fast oxidative glycolytic), II-B (Fast glycolytic). Sarcomere Structure Functional Unit: Region between Z lines. Components: 1. A band: Thick & thin myofilaments overlap. § H Zone: Only thick filaments. § M Line: Contains Myomesin (stabilizes thick filaments). 2. I band: Composed of thin filaments. 3. H zone: myosin only, no overlap 4. Z line: Anchors thin actin filaments. § Composed of actinin and nebulin 5. M line: Centre of sarcomere: § Composed of myomensin 6. Sarcoplasmic Reticulum: Contains terminal cisternae and T-tubules § Traid: two terminal cisternae and T-tubule Sarcomere Structure Myofilaments Thick Filaments o Composed mainly of the protein myosin. o Myosin heads interact with actin during muscle contraction. Thin Filaments  o Composed primarily of actin, along with troponin and tropomyosin. o Actin provides the site for myosin binding. Muscle Contraction Process Overview: 1. Arrival of a nerve impulse. 2. Release of calcium ions. 3. Interaction between actin and myosin. 4. Muscle shortening and contraction. 1. Resting State (No Contraction) Troponin and Tropomyosin Block Actin Binding Sites: o Tropomyosin covers the myosin-binding sites on actin filaments Low Calcium Levels o Cytosolic calcium concentration is low 2. Nerve Impulse & Calcium Release Action Potential o A nerve impulse (action potential) travels down a motor neuron to the neuromuscular junction. Acetylcholine Release: o Acetylcholine is released into the synaptic cleft, binding to receptors on the muscle fiber membrane (sarcolemma). Depolarization: o Depolarization of the muscle membrane, triggering an action potential in the muscle fiber. Calcium Release: o Action potential spreads through the T-tubules à sarcoplasmic reticulum releases calcium ions (Ca²⁺) into the cytoplasm of the muscle cell. 3. Calcium Binding to Troponin Calcium Binds to Troponin: Conformational Change in Troponin: o Conformational change of troponin once Ca2+ binds. o Tropomyosin moves away from the myosin-binding sites so that myosin heads can bind. 4. Cross-Bridge Formation (Actin-Myosin Binding) Myosin Head Binds to Actin:  o Myosin head (bound ADP + Pi in the “cocked” position) connects to actin binding sites, forming a cross-bridge. 5. Power Stroke Release of ADP and Pi: o Once the myosin head binds to actin, ADP and Pi are released from the myosin head. o Causes myosin head to pivot and pulls the actin filament towards the M line (centre) à power stroke § Sarcomere shortens = muscle contraction 6. Detachment of Myosin from Actin Binding of New ATP: o ATP molecule binds to the myosin head, causing it to detach from the actin filament. § No ATP = muscle cramps 7. Re-cocking of the Myosin Head ATP Hydrolysis: o ATP is then hydrolyzed into ADP and Pi by myosin ATPase activity, o Results in “cocked position” of myosin head 8. Cycle Repeats (If Calcium is Present) As long as calcium remains bound to troponin and ATP is available, the cycle of actin- myosin binding, power stroke, and detachment will repeat = resulting in muscle contraction. 9. Muscle Relaxation Calcium Pumped Back into Sarcoplasmic Reticulum: o Ca2+ is actively pumped back into the sarcoplasmic reticulum by calcium pumps (using ATP) o Calsequesterin binds Ca2+ in the SR. Troponin and Tropomyosin Return to Resting Position: o As Ca2+ is pumped back, calcium dissociates from troponin, § causing tropomyosin to move back over the actin binding sites, preventing further myosin binding. Relaxation: The muscle fiber returns to its relaxed state. Muscle Physiology Sarcotubular System The sarcotubular system includes the sarcoplasmic reticulum and T-tubules. Primary Function: o Regulates calcium ion concentration, which is crucial for muscle contraction. Comparison of Muscle Types Skeletal Muscle Structure: Striated, multi-nucleated, long fibers. Function: Voluntary control, responsible for body movement. Cardiac Muscle Structure: Striated, branched, single nucleus, mitochondria, and lipid rich, intercalated discs (gap junctions). Function: Involuntary control, pumps blood throughout the body. Unique Properties: o Automaticity: Can generate its own electrical impulses. o Rhythmic contractions. o Functional syncytium – rapid synchronous contractions o Slow calcium channels – extracellular Ca2+ brought in § Rapid contraction & slow heartbeats Smooth Muscle Structure: Non-striated, spindle-shaped (fusiform), single nucleus. Function: Involuntary control, regulates internal organs, found in hollow organs Unique Properties: o Can sustain slow contractions for longer periods. o Responds to various stimuli (hormonal, neural). o No alignment/striations o No T-tubules à poor SR development § Voltage gated Ca2+ channels (caveolae) o Z-lines are referred to as dense bodies Smooth Muscle Types 1. Single Unit Smooth Muscle o Cells are connected by gap junctions. o Contracts as a single unit (e.g., walls of hollow organs) o Often hormone mediated  o Autorhythmicity – rapid transmission of stimuli via gap junctins (similar to cardiac) 2. Multi-Unit Smooth Muscle o Cells are not connected by gap junctions. o Contracts independently (e.g., eye muscles, large airways). o More individual control Muscle Physiology Overview Structural Differences 1. Nuclei o Skeletal: Multinucleated o Cardiac: Uni/bi-nucleated o Smooth: Uninucleated 2. Striations o Skeletal: Yes o Cardiac: Yes o Smooth: No 3. T-tubules o Skeletal: Yes o Cardiac: Yes o Smooth: No (caveolae instead) 4. Gap Junctions o Skeletal: No o Cardiac: Yes (intercalated discs) o Smooth: Yes (only in single-unit) Calcium Sources for Contraction Skeletal Muscle: SR Cardiac Muscle: SR and extracellular fluid Smooth Muscle: Mostly extracellular fluid Contraction Characteristics Skeletal Muscle: Rapid onset, can tetanize Cardiac Muscle: Slow onset, cannot tetanize Smooth Muscle: Slow onset, may tetanize Muscle Contraction Key Definitions Motor Unit: The smallest functional unit of muscle contraction, consisting of a single motor neuron and all the muscle fibers it innervates. Muscle Force Gradation: Nervous system control of muscle by: o Recruitment: Increasing the number of active motor units for greater force. o Frequency: Increasing the frequency of nerve impulses for greater force. All-or-None Principle: All fibers in a motor unit contract simultaneously when stimulated. Types of Muscle Fibers All fibres in a motor unit are the same fibre type 1. Slow Motor Units: o Myosin uses ATP slowly. o Many mitochondria for ATP production. o Economical maintenance for isometric contractions and efficient about repetitive slow isotonic contractions. 2. Fast Motor Units: o Myosin uses ATP quickly. o Higher power output. o Type 2A fibers: Sustained power. o Type 2B fibers: Fast, non-oxidative, and fatigue rapidly. Isometric: Muscle length sustained Isotonic: Muscle length changes Sequence of Muscle Contraction 1. Neuromuscular Junction: o Transmitter synthesized and stored in vesicles. o Action potential reaches synaptic terminal. o Depolarization opens voltage-gated Ca²⁺ channels. o Influx of Ca²⁺ causes vesicles to fuse with the synaptic membrane. o Transmitter (acetylcholine) is released into the synaptic cleft. o Binds to receptors on the postsynaptic membrane, causing excitatory/inhibitory potentials. o Ach is broken down by acetylcholinesterase to end signal à relaxation Acetylcholine Curare:  o Frogs o Blocks nicotinic receptors, preventing muscle contractions. Clostridium botulinum: o Bacteria o Produces a toxin that prevents acetylcholine release, leading to paralysis. 2. Excitation-Contraction Coupling: series of events that link an action potential to muscle contraction o Nerve impulse arrives à spreads to sarcolemma and T-tubules o T-tubules depolarize activating voltage sensitive receptors (DHP receptors) o Ca+ channels open SR o Calcium ions play a crucial role in muscle contraction. o They bind to troponin, causing tropomyosin to move and expose binding sites on actin for myosin. o Myosin heads carrying ADP and Pi bind to form cross bridges o Release of Pi causes contraction o Binding of ATP repositions head 3. Sliding Filament Theory: o Myosin heads attach to actin, pulling the filaments past each other, generating force. Types of Muscle Contractions 1. Isometric: Muscle length remains the same while tension increases to peak. 2. Isotonic: o Concentric: Muscle shortens while generating force, involved in resistance o Eccentric: Muscle lengthens while generating force, control over rate of elongation Force of contraction increases after the latent phase (post stimulus), peaks at the end of the contraction phase and beginning of relaxation phase Treppe: gradual increase in contraction force and full relaxation between stimuli o “stair like” o Gradual Ca2+ increase as SR is unable to sequester all the Ca2+ between twitches Summation: combination of multiple stimuli causing an increase in contraction strength of stimuli overlap/converge o 2nd stimulus occurs before full relaxation of the 1st o Causes increasing tension overtime o Multiple motor unit summation/recruitment: when more force is needed, more and larger units are recruited Incomplete tetanus: sustained contraction but some relaxation between stimuli occurs as maximum tension is reached Complete tetanus: sustained contraction at maximum tension with no relaxation between stimuli Muscle Fatigue Physiological basis includes depletion of energy sources, accumulation of lactic acid, and failure of neuromuscular transmission. Force/Load/Length Relationship Length-tension relationship: maximal tension is reached when there is the most actin/myosin overlap Force-Load relationship: increasing load deceases velocity of shortening “Plastic” Nature of Muscles Muscle can adapt to habitual demand Regular exercise can enhance muscle strength and endurance. Aging may result in muscle atrophy and decreased strength. Endurance training: o Cardiovascular, mitochondrial density, fuel storage Strength training: o muscle hypertrophy, neural changes, muscle fibre changes Muscle Energy Metabolism Creatine phosphate: o Form of excess energy storage in muscles o Concentration is 2-6x more than ATP o Creatine kinase is the enzyme involved in rapid synthesis o Longer/sustained energy source Glycolis o 2 ATP per glucose o Type 2B fibres (fastest and anerobic) o Glycogen utilized o Short term energy source Oxidative Phosphorylation: o Most ATP produced (~36) o Type 1 fibers o Lipids involved in prolonged endurance training Myogenesis and Nutrition Embryonic Phase of Myogenesis Key Events:  Formation of myoblasts from mesodermal cells. o Myoblasts fuse to form myotubes. o Initial muscle fiber differentiation occurs. o Nutrition Impact: o Adequate protein and energy are crucial for myoblast proliferation. o Deficiencies can lead to impaired muscle development. Phases of Myogenesis Conception to Birth o Mesoderm: The layer of cells that forms muscle develops into myotomal cells and stem cells. § Myotomal Cells: Cells that develop into early muscle. Primary Myotome: Early muscle formation. § Progenitor (Stem) Cells: Cells that can develop into various muscle types. Embryonic Myoblasts: Early muscle cells. o Primary myotubules: early muscle fibres § Primary fibres: contain sarcomeres and other structures (i.e., SR & T-tubules develop) Type 1 fibers: (& type 2 in fast muscles) Fetal Myoblasts: Later stage muscle cells. o Secondary myotubules: § Secondary fibres: during later stages of development Type 2 fibres: (Type 1 and 2 in mixed muscles) Satellite cell: regenerate muscle and also play a role in secondary myotubule formation Mesoderm Myotomal cell Progenitor/stem cell Primary myotome Embryonic myoblast Foetal myoblast Satellite cell (early muscle) Primary myotubules Secondary myotubules Primary fibres Secondary fibres Type 1 fibres Type 2 fibres  Myogenesis o Primary Myogenesis: Formation of primary muscle fibers (type 1), a bit of type 2. o Secondary Myogenesis: Formation of mainly secondary muscle fibers. o Muscle Fiber Types: § Type I Fibers: Slow-twitch fibers. § Type II Fibers: Fast-twitch fibers. o Total number of fibres fixed by ~6 months gestation § Muscle hypertrophy occurs after this mark Fetal Phase of Myogenesis Key Events: o Continued growth and maturation of muscle fibers. o Development of satellite cells, which aid in muscle repair and growth. o Muscle fibers increase in size and number. Nutrition Impact: o Nutritional support influences muscle mass and fiber type distribution. o Essential amino acids and minerals are vital for optimal growth. o Decreased nutrient intake: § during (halfway through) primary and secondary myogenesis = decreases myogenesis (# of fibres) § harder to recover from § during hypertrophy = decreased hypertrophy and birth weight § theoretically possible to recover from postnatally Skeletal Muscle Growth Hypertrophy: number of sarcomeres increase o Sarcomeres in parallel o ↑ # of sarcomeres = stronger the muscle Hyperplasia: parallel alignment of muscle fibres (early in development) o New myocytes o ↑ force produced o Can occur as an adult à tears/lacerations repaired via satellite cells Lengthening (growth): addition of sarcomeres to both sides of the length o ↑ velocity o ↑shortening capacity Summary of Myogenesis Embryonic Stage: o Paraxial mesodermal cells form myotome and progenitor cells (that further differentiate) Fetal Stage:  o Primary and secondary myogenesis à leading to muscle fiber formation (primary and secondary). Postnatal Stage: o Muscle fibers undergo hypertrophy primarily through satellite cell activity. Nutrition: o Critical during prenatal development for fiber number and mass o Affects mass postnatally. Muscle Disorders Types of Muscle Disorders Muscle Cramps/Spasms o Involuntary contractions, often painful. o Cramps last longer (up to 15 minutes) à “Charley horse”. o Causes include: § Injury § Overuse § Central Nervous System issues Muscle Strain o Tearing of muscle fibers, often at the musculotendinous junction. o Caused by overexertion or excessive stretching. o Common in large muscles (e.g., hamstrings, quadriceps) § Less common in postural muscles (slow twitch muscle, less force) Muscle Hypertrophy o Increase in muscle size due to increased sarcomeres. o Case: Double Muscling § Myostatin: plays an important role in growth regulation àinhibit muscle cell hypertrophy & hyperplasia expression limited to skeletal muscle § Mutation in myostatin = ↑ muscle mass § Causes problems in calving with affected calves Muscle Atrophy o Decrease in muscle size due to disuse or malnutrition. o Neurogenic: § Denervation: lysosomal protein degeneration = 50%↓ muscle mass + EMG abnormalities Common: pinched nerve à can be easily resolved (even if slow) § Myogenic: malnutrition, cachexia (secondary to other conditions), corticosteroid excess Slow progression, normal EMG, Only type 2 fibres Muscle Necrosis & Regeneration o Death of muscle fibers followed by regeneration. Muscle Necrosis/Rhabdomyolysis  o May affect whole fiber or subgroup of sarcomeres within a fibre o Symptoms: § Muscle pain. Contracture, increased RR, sweating § ↑ Creatine Kinase & Aspartate transaminase in serum § Myoglobinuria (oxygen storage within the muscle) is released into the bloodstream when muscle breaks down and is then filtered by kidneys into urine o Causes: § Nutrition: Vitamin E and Selenium deficiency “white muscle disease” à degeneration of cardiac and skeletal muscles Hypokalemia (low K+) toxins § Infectious § Immune related § Metabolic Muscular Dystrophy o Progressive degeneration of skeletal muscles (small mammals) & Inherited o In dogs: § Puppies: stunted growth, elbow abduction, bunny hop gait, § Adult: plantigrade stance o Due to deficiency of dystrophin (protein, anchors sarcolemma to actin of cytoskeleton) à fibre damage Altered Electrical conduction: o Altered motor neuron firing: § Hypocalcemia (cows): ↓ Ach release = ↓ neuronal firing = paresis o Altered motor end plate depolarization § Myasthenia gravis (dogs): Congenital – deficiency in the number of Ach receptors Acquired – Autoantibodies to Ach receptors § Botulism: clostridium botulism toxin à ↓Ach release = ↓ neuronal firing = paresis o Altered sarcolemma excitability: § Myotonia (dogs, horses, goats): muscle hypertrophy, stiffness, rigidity, prolonged muscle contraction Goats: autosomal dominant mutation in Cl- channel = ↓ Cl- conductance = ↑ K+ in T-tubules = ↑ contraction Muscle Disorders 2.0 (simplified) 4. Double Muscling  Defect: Myostatin gene mutation. Consequence: Increased muscle mass due to reduced inhibition of muscle growth. 5. Muscular Atrophy Defect: Loss of muscle fibers or decrease in size. Consequence: Weakness and reduced mobility due to inactivity or malnutrition. 6. Muscular Dystrophy & Malignant Hyperthermia Defect: Genetic mutations affecting muscle proteins. Consequence: Progressive muscle weakness and potential life-threatening reactions to anesthesia. 7. Botulism Defect: Toxin from Clostridium botulinum. Consequence: Muscle paralysis due to disrupted neurotransmission. 8. Hypocalcaemia & Myotonia Defect: Low calcium levels affecting muscle function. Consequence: Muscle stiffness and spasms due to impaired excitability. Muscle Disorders Study Notes Muscle Hypertrophy Definition: Increase in muscle size. Double Muscling: o Caused by mutations in myostatin, a protein that inhibits muscle growth. o Common in breeds like Belgian Blue and Piedmontese cattle. o Results in increased muscle mass and calving difficulties due to higher calf birth weight. Muscle Atrophy Definition: Decrease in muscle size. Types: 1. Neurogenic: § Caused by nerve damage (e.g., "Sweeney" in horses). § Results in significant muscle mass loss and EMG abnormalities. 2. Myogenic: § Caused by malnutrition, cachexia, or corticosteroid excess.  § Slow progression with normal EMG; affects mainly type 2 muscle fibers. Muscle Necrosis or Rhabdomyolysis Common Names: Tying up, Monday morning sickness, Azoturia. Symptoms: o Muscle pain, contracture, increased respiratory rate, sweating. o Elevated creatine kinase and aspartate transaminase in serum; myoglobinuria. Causes: o Nutritional deficiencies (e.g., Vitamin E, Selenium). o Infectious agents (e.g., Clostridial, Viral). o Immune-mediated conditions (e.g., Masticatory muscle myositis in dogs). o Metabolic disorders (e.g., Glycogenoses). Muscular Dystrophy Definition: Inherited progressive degeneration of skeletal muscle. Example: Duchenne’s muscular dystrophy in humans and similar conditions in dogs (e.g., German Shorthaired Pointers, Golden Retrievers). Symptoms: o Stunted growth, abnormal gait, plantigrade stance in adults. Cause: Deficiency of dystrophin, leading to muscle fiber damage. Altered Electrical Conduction Conditions: 1. Hypocalcemia (Milk Fever): § Decreased acetylcholine (Ach) release leads to paresis. 2. Myasthenia Gravis: § Congenital or acquired deficiency of Ach receptors. 3. Botulism: § Caused by Clostridium botulinum toxin, leading to decreased Ach release. 4. Myotonia: § Prolonged muscle contraction and stiffness due to altered ion channel function.