MECHANISM OF MUSCLE CONTRACTION Ginus Partadiredja The Department

MECHANISM OF MUSCLE CONTRACTION Ginus Partadiredja The Department of Physiology UGM, Yogyakarta

• Muscle = neuron excited chemically, electrically, mechanically to produce action potentials • Muscle neuron contractile mechanism activated by action potentials

Skeletal muscle: • cross-striations • does not contract without innervation • lacks anatomic & functional connections between fibers • voluntary control Cardiac muscle: • cross-striations • functionally syncytial • contracts rhythmically in the absence of external innervation • contains pacemaker Smooth muscle: • Lacks cross-striations • functionally syncytial • contains pacemaker

• Skeletal muscle fibers myofibrils • Muscle fiber: multinucleated, long, cylindrical, single cell surrounded by sarcolemma (cell membrane)

• Skeletal muscle fibers myofibrils filaments

Hexagonal pattern

• Filaments = contractile proteins: • Myosin II (thick filament) • Actin • Tropomyosin • Troponin: - Troponin I thin filament - Troponin T - Troponin C

Thick filaments A bands Thin filaments I bands

• Myosin 2 globular heads & long tail • Head of myosin contains actin-binding site & catalytic site that hydrolize ATP

• Thin filaments two chains of actin • Tropomyosin in the groove of actin • Troponin: T binds other troponin to tropomyosin I inhibits the interaction of myosin & actin C contains the binding sites for Ca+2

• Sarcotubular system = T system + sarcoplasmic reticulum • T system of tubules + adjacent terminal cisternae = triad • T system rapid transmission of action potentials from the cell membrane to the fibrils

• The resting membrane potential of muscle = -90 m. V • The action potential = 2 – 4 ms • The speed along the muscle = 5 m/s • The absolute refractory period = 1 – 3 ms • The distribution of ions nerve cells • Depolarization = Na+ influx • Repolarization = K+ efflux • Depolarization starts at motor end plate transmitted along the fiber contractile response

Sequence of events during transmission from the motor nerve the muscles = transmission in synapses between neurons

Sequence of Events in Contraction and Relaxation of Skeletal Muscle Steps in Contraction: 1. Discharge of motor neuron end of motor neuron Ca+2 enters the endings

2. Release of transmitter (acetylcholine) at motor end-plate 3. Binding of acetylcholine to nicotinic acetylcholine receptors (concentrated at the tops of the junctional folds)

Junctional folds

4. Increased Na+ and K+ conductance in end-plate membrane 5. Generation of end-plate potential 6. Generation of action potential in muscle fibers

7. Inward spread of depolarization along T tubules excitation – contraction coupling 8. Release of Ca+2 from terminal cisterns of sarcoplasmic reticulum and diffusion to thick and thin filaments

9. Binding of Ca+2 to troponin C, uncovering myosin-binding sites on actin (at resting, troponin I is tightly bound to actin and tropomyosin covers the sites where myosin heads bind to actin) • ATP is then split ADP + Pi contraction

10. Formation of cross-linkages between actin and myosin and sliding of thin on thick filaments, producing movement

Steps in Relaxation: 1. Ca+2 pumped back into sarcoplasmic reticulum diffuses into the terminal cisterns, ready to be released by next action potential 2. Release of Ca+2 from troponin 3. Cessation of interaction between actin and myosin

Muscular Contraction • The width of A bands is constant • Z lines move closer

Production of ATP in Muscle Fibers (Tortora & Derrickson, 2006) • 3 ways of ATP production: 1. From creatine phosphate 2. Anaerobic cellular respiration (ATP-producing reactions not requiring oxygen) 3. Aerobic cellular respiration (ATP-producing reactions requiring oxygen, in mitochondria)

1. Creatine Phosphate • Creatine: small amino acid-like molecule formed in liver, kidneys, pancreas transported to msucles • Relaxed muscles creatine phosphate 3 -4 x > ATP • Relaxation: ATP + creatine phosphate + ADP (by creatine kinase) • Contraction: creatine phosphate + ADP ATP + creatine (by creatine kinase) • For 15 seconds contraction (100 -m dash)

2. Anaerobic Cellular Respiration • Creatine phosphate is depleted then: • Glucose (from blood or from the breakdown of glycogen in muscles) glycolysis 2 pyruvic acid + 2 ATP (produces 4 ATP but net gain of 2 ATP) • Pyruvic acid mitochondria, aerobic respiration ATP • No oxygen (anaerobic) in cytosol: 80% Pyruvic acid lactic acid blood (becomes acid) liver convert back into glucose • For 30 - 40 seconds activity (400 -m race)

3. Aerobic Cellular Respiration • Sources of ATP: pyruvic acid, fatty acid (breakdown of triglycerides; yields > 100 ATP), amino acids (breakdown of proteins) • Sufficient oxygen: Pyruvic acid mitochondria oxydized ATP + CO 2 + H 2 O + heat • Slower than glycolysis, but yields 36 ATP • Sources of oxygen: hemoglobin & myoglobin • For > 10 minutes activity (marathon race)

Energy Sources (Ganong, 2005) ATP + H 2 O ADP + H 3 PO 4 + 7. 3 kcal Phosphorylcreatine + ADP ↔ Creatine + ATP Rest & light exercise: FFA CO 2 + H 2 O + ATP Increased intensity of exercise Glucose + 2 ATP (or glycogen + 1 ATP) 2 Lactic acid + 4 ATP (anaerobic) Glucose + 2 ATP (or glycogen + 1 ATP) 6 CO 2 + 6 H 2 O + 40 ATP (aerobic)

• 100 -m dash (10 seconds) 85% of energy is derived anaerobically • 2 -mile race (10 minutes) 20% of energy is derived anaerobically • long-distance race (60 minutes) 5% of energy is derived anaerobically

• Muscle fatigue: The inability of muscle to maintain force of contraction after prolonged activity, caused by: • Inadequate release of Ca+2 from sarcoplasmic reticulum • Depletion of creatine phosphate • ATP levels = resting levels • Insufficient oxygen • Depletion of glycogen • Buildup of lactic acid & ADP • Failure of action potentials in releasing ACh

Oxygen Consumption after Exercise • Oxygen debt added oxygen, over and above the resting oxygen consumption, taken into the body after exercise 1. Convert lactic acid glycogen stores in liver (small amount) 2. Resynthesize creatine phosphate & ATP 3. Replace the oxygen removed from myoglobin • Much of lactic acid pyruvic acid for ATP production (heart, liver, kidneys, skeletal muscles) • Better term: recovery oxygen uptake ( chemical reactions, heart & muscles still working, recovery processes)

Types of Contraction Isotonic (A) and isometric (B) contraction

Types of Contraction • Isometric (“same length”) contraction: Contraction occurs without an appreciable decrease in the length of the whole muscle do not work (work = force x distance)

• Isotonic (“same tension”) contraction: Contraction against a constant load do work

Isotonic contraction Cause more damage

Muscle twitch: brief contraction followed by relaxation of all muscle fibers in a motor unit caused by a single action potential in its motor neuron • “Fast” muscle fibers: fine movements (7. 5 ms) • “Slow” muscle fibers: gross movements (100 ms)

Summation of Contractions • No refractory period such as in neurons in muscle fibers • Repeated stimulation summation of contractions • Tetanus (tetanic contraction) continuous contraction: • Fused (complete) tetanus • Unfused (incomplete) tetanus

Types of Muscle Fibers Type II Other names Slow, oxidative, red muscles Fast; glycolytic; white muscles Myosin isoenzyme ATPase rate Slow Fast Ca+2 pumping capacity of sarcoplasmic reticulum Moderate High Diameter Moderate Large Glycolytic capacity Moderate High Oxidative capacity (content of mitochondria, capillary density, myoglobin content) High Low Examples Long muscles of the back Estraocular

Type I (Red muscles) Charateristics Functions Examples Type II (White muscles) Slow response; long latency; adapted for long, slow contractions Posture maintenance Short twitch durations Long muscles in the back Extraocular muscles, hand muscles Fine, skilled movements

Slow Oxidative Fibers Fast Oxidative. Glycolytic Fibers Fast Glycolytic Fibers Fiber diameter Smallest Intermediate Largest Myoglobin content Large amount Small amount Mitochondria Many Few Capillaries Many Few Color Red-pink White (pale) Structural Characteristic

Slow Oxidative Fibers Fast Oxidative. Glycolytic Fibers Fast Glycolytic Fibers Functional Characteristic Capacity of High; aerobic Intermediate; generating ATP respiration aerobic & anaerobic (glycolysis) Rate of ATP Slow Fast hydrolysis Low; anaerobic (glycolysis) Contraction velocity Slow Fast Fatigue resistance High Intermediate Low Fast

Slow Oxidative Fibers Creatine kinase Lowest amount Fast Oxidative. Glycolytic Fibers Intermediate amount Fast Glycolytic Fibers Highest amount Glycogen stores Low Intermediate High Order of recruitment First Second Third Location Postural Lower limb muscles (e. g. neck) Upper limb

Slow Oxidative Fibers Fast Oxidative. Glycolytic Fibers Primary Maintaining Walking, functions posture; aerobic sprinting endurance (running a marathon) Fast Glycolytic Fibers Rapid, intense movement of short duration (weight lifting; throwing a ball)

Disorders and Abnormalities • Myasthenia gravis: skeletal muscles are weak and tire easily; caused by autoantibodies destroying nicotinic acetylcholine receptors • Lambert-Eaton syndrome: muscle weakness; caused by antibodies against Ca+2 channels in the nerve endings • Denervation hypersensitivity • Contracture: No relaxation due to the inhibition of Ca+2 transport into the reticulum

Disorders and Abnormalities • Hypotonia: decreased or lost muscle tone • Flaccid paralysis loss of muscle tone, loss/ reduction of tendon reflexes, atrophy, degeneration of muscles (disorders of nervous system; electrolytes imbalances (Na+, Ca+2, Mg+2) • Hypertonia: increased muscle tone • Spastic paralysis increased muscle tone, tendon reflexes, pathological reflexes (Babinski sign) • Rigidity increased muscle tone, not reflexes (tetanus)

Disorders and Abnormalities • Muscular dystrophy: progressive weakness of skeletal muscle caused by mutations in genes for muscle proteins • Duchene’s muscular dystrophy dystrophin protein is absent from muscle; X-linked; fatal by 30 y/o • Metabolic myopathies (e. g. Mc. Ardle’s syndrome) mutations in genes of enzymes involved in carbohydrates, fats, and proteins, metabolism • Myotonia muscle relaxation is prolonged after contraction; abnormal genes in chromosomes 7, 17, or 19, which produce abnormalities of Na+ or Cl- channels

References 1. Ganong WF (2005). Review of Medical Physiology, 22 nd ed. Chapter 3, Pages: 65 -78; Chapter 4, Pages: 116120 2. Tortora GJ & Derrickson B (2006). Principles of Anatomy and Physiology, 11 th ed. Chapter 10, Pages: 290 -314.