Muscle Physiology 2024 PDF

의료인공지능 융합인재양성 사업 Muscular System - 근육생리 - Dept of Physiology Ajou University School of Medicine  Muscle (근육) - Soft tissue found in most animals: composed of cell (muscle cell) and connective tissue - Comprise ~45% of body w...

의료인공지능 융합인재양성 사업 Muscular System - 근육생리 - Dept of Physiology Ajou University School of Medicine  Muscle (근육) - Soft tissue found in most animals: composed of cell (muscle cell) and connective tissue - Comprise ~45% of body weight - Function to produce force and motion 1. Types of Muscles 1) Classification by morphology (histology) (1) striated muscle (줄무늬근): skeletal muscle (골격근), cardiac muscle (심근) (2) non-striated muscle (민무늬근): smooth muscle (평활근) 2) Classification according to innervation (신경지배에 따른 구분) (1) voluntary muscle (수의근): skeletal muscle (2) involuntary muscle (불수의근): smooth muscle, cardiac muscle 2. General Functions of Muscles  energy converter, transducer (에너지 변환기) - muscle contraction: chemical energy  mechanical-, heat energy ex) ▪ skeletal muscle: movement, locomotion (개체이동), body heat control ▪ smooth muscle: control internal diameter of blood vessels and the bronchi  resistance control (저항조절)  control blood and air flow ▪ cardiac muscle: generates blood pressure  provide energy for blood flow I. Skeletal Muscle (골격근) - striated muscle (횡문근, 橫紋筋) - about 40% of body weight, approximately 400 skeletal muscles in the body - innervated by central nervous system, effector for supporting and moving skeleton 1. Structure of skeletal muscle (골격근의 구조) 1) Organization of Skeletal Muscle (골격근의 구성) (1) Tendon (腱, 힘줄) (2) Fascia (근막) (3) Muscle (근육) 1) Organization of Skeletal Muscle (골격근의 구성) (1) Tendon (腱, 힘줄) (2) Fascia (근막) (3) Muscle (근육) ∙ epimysium (근외막) ∙ perimysium (근다발막, 근주위막) ∙ fascicle, muscle bundle (근속 (筋束), 근다발)  endomysium (근내막)  muscle fiber (근섬유) = muscle cell (근세포) (근다발) (근형질막, 근초) (근주위막) (근섬유) (건, 힘줄) (근외막) (근원섬유) (근막) (근내막) ▪ Muscle fiber (근섬유) - sarcolemma (근형질막) - nuclei (핵): multi-nucleated - sarcoplasm (근형질) - myofibril (근원섬유) ∙ thin filament (actin) ∙ thick filament (myosin) ; distinct series of alternating light and dark bands (∵ A band and I band  striated muscle)  Organization of Skeletal Muscle Myofilament Myofibril Muscle fiber Whole Muscle (근필라멘트) (근원섬유) (근섬유) (근육)  Cytoskeletal elements  shows parallel arrangement in sarcoplasm - Thick filament (myosin)  specialized intracellular structure a cell an organ - Thin filament (actin) Myofilament Myofibril Muscle fiber Fascicle Skeletal muscle (근필라멘트) (근원섬유) (근섬유, 근세포) (근다발) (골격근) Proteins Cells Tissue 2) Structure of Muscle Fiber (근섬유의 미세구조) - Muscle fiber: basic structure of skeletal muscle; has myofibrils (筋原纖維) in sarcoplasm → myofibrils are composed of myofilaments (1) Sarcolemma (근형질막, 근초 筋鞘) - plasma membrane of muscle fiber; has excitability and conductivity (2) Transverse tubule (T-tubule, T-세관) - part of the sarcolemma is deeply inserted into muscle fiber - excitable changes from sarcolemma can be easily transmitted into muscle fiber (3) Sarcoplasmic reticulum (SR, 근형질내 세망, 근소포체, 근장(筋臟) 그물) - same as endoplasmic reticulum of ordinary cells - enclose each of the myofibril. arranged at right angles to T-tubules - lateral sac (외측낭) or terminal cisternae (종조, 終槽): an inflated area adjacent to the T-tubule; Ca2+ storage site * Triad (삼인조): 1 T-tubule and adjacent 2 terminal cisterni (cytoplasm) (Sarcolemma)  Triad 1 T-tubule, 2 terminal cisterni (lateral sac) (4) Myofilament (근 필라멘트) - contractile protein; components of myofibril - thick filament (굵은 미세섬유): Myosin (100~200Å) - thin filament (가는 미세섬유): Actin (60~70Å) ▪ Striation (횡문, 가로무늬)  A-band (anisotropic band; 암대, 어두운 띠) - a band corresponding to the length of myosin filament (thick filament) - both ends of myosin are overlapped with some actin, but middle site is not.  H-zone: area looks relatively light because myosin is not overlapped with actin  M-line: attachment site for the thick filaments  I-band (isotropic band; 명대; 밝은 띠) - a band corresponding to the length of actin filament (thin filament) which is not overlapped with myosin - I-band is shortened as the superposition of actin and myosin increases  Z-line (or A-disk): actin attachment site; centerline of I-band  Sarcomere (근절 筋節) - functional unit of muscle contraction (2~3m) - Z-line to Z-line (the section between the attachment sites of the actin grid) ▪ Contractile proteins (수축성 단백질)  Myosin filament - a polymer of about 200 myosin molecules on the axis  Myosin head: bumps of about 20nm - actin-binding site: upon binding to actin, forms actin-myosin cross-bridge - enzymatic site: ATPase activity  Myosin neck: acts as hinge (경첩기능) → utilize ATP energy  Actin filament - 3 protein components: actin, tropomyosin, troponin (a) Actin (globular actin monomer; G actin, 구슬모양) - connected in a row to form two spiral chains (actin chain; F-actin)  Cross-bridge binding site (active site) - binding site for myosin head - located in the furrow between actin chains and is covered with tropomyosin actin. (b) Tropomyosin - arranged like a thread along the spiral furrows of actin filament - by binding to troponin T1 and T2, stabilize filament structure - opening and closing of cross bridge binding site by positional movement ∙ muscle relaxation: located where it covers the cross-bridge binding site ∙ muscle contraction: upon binding of Ca2+ to Troponin, it moves deep into the spiral furrows and exposes the cross-binding site, allowing the myosin head to bind (c) Troponin - attached on tropomyosin at regular interval - Troponin C, Troponin I, Troponin T ∙ Troponin C: Ca2+-binding site ∙ Troponin I: inhibit response of myosin and actin ∙ Troponin T1, T2: binding to tropomyosin 2. Contraction of Skeletal Muscle (골격근의 수축) 1) Sliding-Filament Mechanism (1) Operation of the cross-bridge (연결팔의 작용) - Cross bridge cycle: closely related to the ATP consumption at myosin head  Formation of Cross-bridge Binding of Ca2+ to the Ca2+-binding site in Troponin C  dislocation of tropomyosin  expose cross-bridge binding site of actin  binding of actin-binding site of myosin head and cross-bridge binding site of actin  formation of actin-myosin cross-bridge (in the binding step, ATP is not consumed)  Cross-bridge movement  ATP degradation at enzymatic site (ATPase activity) of myosin head  released energy causes repetitive flexing movement of myosin head (hinge movement): cross-bridge movement (rowing motion); power stroke  sliding of myosin filament into the actin grid : increase overlapping of actin and myosin; decrease in lengths of I-band and H-band (H-zone)  shortening of sarcomere  muscle contraction  Uncoupling of Cross-bridge - New ATP + myosin head  uncouples cross-bridge * Rigor mortis (사후강직) - due to ATP depletion - a phenomenon in which the muscle contraction continues due to the failure of the cross-bridge uncoupling - begins at 3~4 hrs after death, is completed in about 12 hrs and disappears after 48~60 hrs 2) Molecular mechanism of contraction (1) Excitation-contraction coupling - Step-wise response from the electrical excitation of sarcolemma (AP) to the formation of cross-bridge in the myofilament - AP of muscle fiber sustains 1~2 ms and disappears before muscle contraction - Excitation-contraction coupling: Neurostimulation on muscle fiber → action potential (membrane excitation) → transmitting excitation via T-tubule → Ca2+ release from SR → action of Ca2+ on myofibril → contraction of contractile protein (2) Role of Ca2+ in the muscle contraction mechanism - AP propagation (neuron) → end plate potential → depolarization of sarcolemma → opening L-type Ca2+-channel (DHP receptor; sarcolemma) → Ca2+ influx into the cytosol → Ca 2+ release from SR (Ryanodine R) (Ca2+ induced Ca2+ release) → Ca2+ binding to troponin C → formation of cross bridge between + 2+ Na -Ca exchanger myosin head and actin → crossbridge cycle → muscle contraction → outflux of Ca2+ SERCA (Na+-Ca2+ exchanger, Ca2+-pump) → restoration of Ca2+ concentration → cross bridge uncoupling → muscle relaxation (3) Energy for muscle contraction - Role of ATP ① binding to myosin head causes decoupling of cross-bridge ② provide energy for cross-bridge stroke ③ Ca2+-pump operation 3. Neuromuscular Junction (신경-근 접합부) 1) Structure of Neuromuscular junction - neuromuscular junction: junction of motor nerve ending (운동신경 말단) and motor end plate (운동종판); synaptic cleft (연접부 간격) 2) Transmission of excitation at NM junction ▪ Excitation of motor neuron → increased Ca2+ influx at nerve ending → release acetylcholine-containing synaptic vesicles → binding to ACh R on motor end plate → increase in Na+, K+ influx → depolarization, generate end plate potential (EPP, 종판(終板) 전압) → generate action potential → Muscle contraction ▪ Acetylcholine esterase: breaks down ACh into choline and acetic acid → recycling ▪ Differences from excitement transmission in interneural synapse ① use only acetylcholine as neurotransmitter ② a single EPP can go beyond the threshold cf) EPSP can go threshold via summation ③ IPSP (억제성 전압) does not occur 4. Mechanics of Muscle Contraction (근수축의 역학) - muscle tension (근장력) vs load (하중): ∙ muscle contraction: the force exerted on an object by muscle contraction ∙ load: the force exerted on the muscle by an object 1) Types of muscle contraction (1) Twitch (연축 攣縮) - single contraction in muscle fibers caused by a single action potential - Twitch curve (연축곡선): chronological record of twitch ∙ latent period (잠복기), contraction period (수축기), relaxation period (이완기) (1) Twitch (연축 攣縮) -- contin’d  isotonic contraction (등장성 수축, 等張性 收縮, 등력성 수축, 等力性 收縮)  isometric contraction (등척성 수축, 等尺性 收縮, 등장성 수축, 等長性 收縮)  all-or-none rule (실무율 悉無率) Isotonic contraction Isometric contraction  isometric twitch (등장성 연축) ; characteristics vary depending on the magnitude of the load - the heavier the load,  longer latent period  slow down the shortening velocity  shorter duration of twitch  decrease in shortening length - Shortening does not take place until the muscle tension exceeds the load (2) Summation (가중 加重) - Temporal summation (시간적 가중): a phenomenon in which muscle tension increases due to series of action potential ; action potential (1~2 ms), twitch (100 ms) ∙ cf: spatial summation (공간적 가중) Complete dissipation of elastic tension between subsequent stimuli. S3 occurred prior to the complete dissipation of elastic tension from S2. S3 occurred prior to the dissipation of ANY elastic tension from S2. (2) summation (가중 加重) – contin’d  Tetanus (강축 强縮) - contraction with greater and sustaining force during repeated short intervals of stimulation (than twitch) - incomplete tetanus (불완전 강축), complete tetanus (완전 강축) Incomplete tetanus: partial dissipation of elastic tension between subsequent stimuli. Complete tetanus: no time for dissipation of elastic tension between rapidly recurring stimuli. Temporal summation vs spatial summation 1) Multiple motor unit summation ; Spatial summation 2) Frequency summation; Temporal summation  Staircase effect, Treppe (계단효과) - a phenomenon in which contraction strength increases with repeated stimuli of the same intensity; there is a relaxation cf) Summation (가중) * cause: increased availability of Ca2+ and accumulation of heat → basis of “warm up” (3) Contracture (경축 痙縮) - persistent contraction (지속성 수축), reversible, but does not propagate (= rigor, 강직 剛直) - can be induced without action potential ex) Caffeine, rigor mortis (사후강직 死後剛直) 2) Length-tension relationship (길이-장력 관계) - length-tension diagram (길이-장력 곡선): magnitude of maximum tension is dependent on the length of muscle before contraction Short sarcomere: actin filaments lack room to slide, so little tension can be developed. Optimal length Optimal-length sarcomere: (최적길이) lots of actin-myosin overlap and plenty of room to slide. 장력(%) Long sarcomere: actin and myosin do not overlap much, so little tension can be developed. 근길이 (%) 3) Control of muscular strength (근력의 조절) - Motor unit (운동단위): is made up of a motor neuron and all of the skeletal muscle fibers innervated by the neuron's axon terminals, including the neuromuscular junctions between the neuron and the fibers - Size of motor unit (운동 단위의 크기): innervation ratio (지배비율) ex) extraocular eye muscle (외안근) 1:5, general muscle (일반근육) 1:500 - Muscle strength increases as a large number of motor units are activated (spatial summation); the smaller size of each motor unit, the more accurate control is possible. 5. Miscellaneous topics with muscle contraction 1) Energy for muscle contraction In skeletal muscle, ATP production via substrate phosphorylation is supplemented by the availability of creatine phosphate. Skeletal muscle’s capacity to produce ATP via oxidative phosphorylation is further supplemented by the availability of molecular oxygen bound to intracellular myoglobin. 2) Types of skeletal muscle fiber - classification according to the shortening velocity (fast, slow fiber) and metabolic pathways for ATP generation (oxidative, glycolytic fiber) ① slow-oxidative fiber, type I (느린 산화대사형 섬유) ② fast-oxidative fiber, type IIa (빠른 산화대사형 섬유) ③ fast-glycolytic fiber, type IIb (빠른 당원질분해형 섬유) - oxidative fiber: red muscle fiber; glycolytic fiber: white muscle fiber Myosin ATPase activity Note: Because fast-glycolytic fibers have significant glycolytic capacity, they are sometimes called “fast oxidative-glycolytic [FOG] fibers. 3) Exercise effect (운동효과) - Strength training (근력운동): hypertrophy (근섬유비대), increase in contractile protein contents, increase of anaeorobic glycolytic enzyme contents cf. muscle atrophy (근위축) - disuse atrophy (비활동성 위축): decrease in contractile protein contents, increase of lipid contents in muscle fiber - Endurance training (지구력 훈련): no change in the size of muscle fiber, but increases of the number of capillary vessel and mitochondrial enzyme contents in the skeletal muscle - no changes in the type of muscle fiber 4) Skeletal muscle tone (골격근의 긴장도) - muscle tension due to nerve excitement from the spinal cord. It can be controlled by muscle spindle (근방추) or descending regulation from brain stem to spinal motor neuron 5) Electromyography (근전도) - measures muscle response or electrical activity in response to a nerve's stimulation of the muscle. - Muscular activity (근육활성도): increase during muscle contraction activities; decrease in cases of neuronal injury and muscular atrophy 6) Muscle fatigue (근 피로) - a phenomenon in which muscle tension cannot be maintained at a certain level. accompanying muscle discomfort, pain. - muscular factor (근육성 요인): depletion of energy source, accumulation of inorganic phosphate and H+, inappropriate blood supply - neuronal factor (신경성 요인): defects in release or generation of acetylcholine at NM junction ☞ neuromuscular fatigue In skeletal muscle, repetitive Rest overcomes fatigue, but stimulation leads to fatigue, fatigue will reoccur sooner if evident as reduced tension. inadequate recovery time passes. Slow-oxidative skeletal muscle Most skeletal muscles include all three types. responds well to repetitive stimulation without becoming fatigued; muscles of body posture are examples. Fast-oxidative skeletal muscle responds quickly and to repetitive stimulation without becoming fatigued; muscles used in walking are examples. Fast-glycolytic skeletal muscle is used for quick bursts of strong activation, such as muscles used to jump or to run a short sprint. 7) Sore muscle (근육통) - due to connective tissue injury and histamine release 8) Pathophysiology of neuromuscular junction - Acetylcholine esterase (AChE) inhibitor: nerve gas (신경가스), organophosphate pesticide (유기인계 살충제: malathion, parathion) - Blocking the Acetylcholine-ACh receptor interaction: curare (D-tubocurarine) ∙ Myasthenia gravis (중증근무력증): autoimmune disease (antibody for ACh R) ; treatment: AChE inhibitor (neostigmine, physostigmine) Myasthenia gravis Eyes, eyelids and face Most people with myasthenia gravis have weakness in the muscles of the eyes, eyelids and face  droopy eyelids– affecting 1 or both eyes  double vision  difficulty making facial expressions Swallowing, speaking and breathing If the weakness affects the muscles in the mouth, throat and chest, it can cause:  difficulty chewing  slurred speech  a husky, quiet or nasal-sounding voice  difficulty swallowing  choking and accidentally inhaling bits of food, which can lead to repeated chest infections  shortness of breath, particularly when lying down or after exercise Some people with myasthenia gravis also experience severe breathing difficulties, known as a "myasthenic crisis". Limbs and other parts of the body The weakness caused by myasthenia gravis can also spread to other parts of the body, including the neck, arms and legs. This can cause:  difficulty holding the head up  difficulty with physical tasks, such as lifting, getting up from sitting to standing, climbing stairs, brushing teeth or washing hair  a waddling walk  aching muscles after using them The weakness tends to be worse in the upper body than in the legs and feet. [Source: NHS] 9) Muscular dystrophy (근무력증) - Duchenne muscular dystrophy (뒤시엔느 근무력증): defects in dystrophin Duchenne muscular dystrophy weakens the hip and trunk muscles, thus altering the lever-system relationships of the muscles and bones that are used to stand up. II. Smooth Muscle (평활근) 1. Characteristics of Smooth Muscle (평활근의 특성) 1) Structural Characteristics of Smooth Muscle  size: smaller than skeletal muscle (diameter 2-10 m, length 20-500 m)  no striation: ∙ no A and I band is identified ∙ irregular arrangement of actin and myosin → no sarcomere (근절), and does not form myofibril (근원섬유) ∙ myofilament: actin, myosin (mainly actin); scattered through the cell and converged to membrane and dense body (치밀소체) ∙ Dense body (치밀소체) cf) z-line of skeletal muscle, intercalate disc of cardiac muscle  lacks troponin C: Ca2+ binds to Calmodulin  poorly developed SR and T-tubule  abundant gap junction and mechanical junction (adherens junction)  contains lots of pinocytotic vesicle  neuromuscular junction structure: varicosity (팽대부); different from skeletal muscle Other differences compared with skeletal muscle  mitotic ability  action potential: generated by Ca2+ current; duration 10 -100 msec; long latent period → sufficient time for Ca2+ diffusion from cell surface; subjected to autonomic neural, hormonal or drug influences  Inputs Influencing Smooth Muscle Contractile Activity 1. Spontaneous electrical activity in the plasma membrane of the muscle cells 2. Neurotransmitters released by autonomic neurons 3. Hormones 4. Locally induced changes in the chemical composition (paracrine agents, oxygen, acidity, osmolarity, ion concentrations) of the extracellular fluid surrounding the cell 5. Stretch  2) Electrical Characteristics of the Smooth Muscle (전기적 특성) - resting membrane potential (안정막 전압, RMP): -50 ~ -60mV - slow wave (서파, 徐波): generated in some smooth muscles (ex, GI smooth muscle), periodic changes of RMP; it is not the action potential inducing muscle contraction → when excitatory signals overlaps, membrane potential could shoot over the threshold potential (활동전압 역치) → generates spike potential (가시전압) - some smooth muscle cells can spontaneously contract without external stimuli: due to slow wave (pacemaker potential, 박동원 전위)에 기인 - duration of action potential is longer than skeletal muscle and neurons (a) (b) Slow wave potential Pacemaker potential 2. Types of Smooth Muscles (평활근의 분류)  Classification according to anatomical and physiological characteristics ▫ Single unit smooth muscle (단단위성 평활근) - small number of innervated neurons per muscle fiber; shows pace-maker potential - aggregated into sheets or bundles (membranes are intimately linked each other) → rapid conduction of excitation through gap junction → functional syncitium (기능적 공동체) ☞ visceral smooth muscle (장기성 평활근): intestine, blood vessels, bile ducts, uterus ▫ multi unit smooth muscle (다단위성 평활근) - each fiber can contract independent of the others; shows no-pacemaker potential → large number of innervated neurons per muscle fiber ☞ pilomotor muscle (기모근), iris (홍채), ciliary muscle (모양근), muscle of nictitating membrane (깜빡막 근육), large vascular smooth muscle (대혈관 평활근) 3. Mechanism of Smooth Muscle Contraction (평활근의 수축기전) - Sliding mechanism of actin and myosin filament is largely similar to skeletal muscle  Differences in detailed mechanism (세부적 기전상의 차이) ① most of Ca2+ is recruited from outside of the cell. ② myosin is the acting site of Ca2+: Ca2+ → binds to calmodulin → activates myosin light chain kinase → upon phosphorylation of myosin, cross bridge of myosin head and actin is formed ③ most of cytosolic Ca2+ are pumped out of the cell by Ca2+ pump ④ slow cycling of cross-bridge cycle: cross-bridge heads have far less ATPase activity · contraction responses are very slow compared with skeletal muscle: slow interaction between Ca2+ influx process and actin-myosin → longer latent period to contraction; slow degradation of ATP causes longer duration of contraction · maintain prolonged tonic contraction with very little use of energy (Latch) Contraction Mechanism of Smooth Muscle Ca2+ bind with calmodulin ↓ Calmodulin-calcium combination with and activation of myosin light chain kinase (MLCK) ↓ Regulatory chain phosphorylation (main for attachment-detachment cycling) ↓ Actin-Myosin attachment ↓ Contraction 4. Regulation of Smooth Muscle Contraction (평활근의 수축조절) 1) Autonomic nervous system (자율신경계); diffuse junctions, multiple varicosities Neurotransmitters (in ANS); acetylcholine, norepinephrine 2) Hormones: angiotensin, vasopressin, endothelin, bradykinin 3) Local factors: paracrine agents, acidity, oxygen concentration, osmolarity, ion composition of the extracellular fluid - Paracrine factors: NO, eicosanoids - Stretch: stretch activated (mechano-sensitive) Ca2+ channel IP3 AC EDCF: endothelial derived EDHF: endothelial derived constriction factor hyperpolarizing factor III. Cardiac Muscle (심장근) 1. Morphological Characteristics (형태적 특성) - has both skeletal muscle and smooth muscle characteristics: striated muscle, gap-junction - cells are connected together to form electrical syncytium - intercalated disk: gap junction and desmosome 2. Electrical Characteristics (전기적 특성) - pacemaker potential: Sinoatrial node (SA node, 동방결절) → periodic and spontaneous firing of action potential - conduction systems: SA node, atrioventricular node (AV node, 방실결절), bundles of His, Purkinje cells - electrical syncytium: gap junction: rapidly propagate action potential between cells 3. Functional Characteristics (기능적 특성) - main function: blood circulation - contraction mechanism: similar to skeletal muscle; abundant SR and T-tubule, troponin C is the acting point of Ca2+ - highly dependent on extracellular Ca2+; respond to hormones; spontaneous excitation - Excitation-contraction can be modulated by autonomic nervous system  Myocardial Action Potential (심장세포들의 활동전위) SA node: 동방결절 AV node: 방실결절  Cardiac Muscle Contraction Ca2+ release-induced Ca2+ release Na+/Ca2+ exchanger SERCA: Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase The prolonged refractory period of cardiac muscle prevents tetanus, and allows time for ventricles to fill with blood prior to pumping. Cardiac Control by Autonomic Nervous System (자율신경계의 심장조절) Chronotropy: 변주기작용; heart rate Dromotropy: 변전도작용; 전도속도 Inotropy: 변력작용; 수축력 Lusitropy: 심실이완속도