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Muscle Physiology
Muscle Physiology Skeletal Muscle Anatomy: Muscle fibers (= individual muscle cells):
- Multi-nucleated (mitosis sans cytokinesis)
- Sarcolemma (= plasma membrane + collagen fibers)
- Sarcoplasm (= cytoplasm; mitochondria)
- Myofibrils (contractile elements):
- Actin filaments (thin)
- Myosin filaments (thick) Sarcomere Z Z Bare zone M Filamentous structural^ Titin: protein (“springy”) I band Isotropy (Gr.) A band Anisotropy (Gr.) Dystrophin: Anchors myofibril arrays to cell membrane Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10.2 / 10.3 dystrophy^ Muscular
Sliding Filament Theory (Huxley and Huxley – 1954):
Contraction results from sliding action of inter-digitating actin and myosin filaments Evidence? Myosin head interacts with actin (cross-bridging) Each cross-bridge generates force independent of other cross-bridges Thus Total tension developed by sarcomere proportional to number (proportional^ of cross to filament overlap)-bridges Muscle Physiology Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10. Length relationship-tension Muscle Physiology
Sliding Filament Theory (Huxley and Huxley – 1954):
Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10.8 / 10. Muscle Physiology Length relationship-tension Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10.8 / 10.
Sliding Filament Theory (Huxley and Huxley – 1954):
Muscle Physiology Length relationship-tension Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10.8 / 10.
Sliding Filament Theory (Huxley and Huxley – 1954):
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Muscle Physiology Length relationship-tension Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10.8 / 10.
Sliding Filament Theory (Huxley and Huxley – 1954):
Maximum Contraction Strength: ~ 50 lbs. / inch 2 Normal resting length of skeletal muscle Muscle Physiology Length relationship-tension Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10.8 / 10.
Sliding Filament Theory (Huxley and Huxley – 1954):
The geometry of myofilaments in a sarcomere strongly affects the contractile properties of the muscle Muscle Physiology Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Spotlight 10.
- Myosin:
- Two heavy chains (tail)
- Four light chains (head)
- Actin-binding sites
- ATPase activity
- Myosin filament composed of 200+ individual myosin molecules (~1.6 m in length)
- Actin:
- Two double-stranded helixes of G-actin polymers woven to form F-actin (~ 1 m in length)
- ADP attached to G-actin (active site)
- Tropomyosin: Spiral around F-actin; cover active sites
- Troponin: Attaches tropomyosin to F-actin Muscle Physiology Myofilament Anatomy: Guyton & Hall (Textbook of Medical Physiology, 12th^ ed.) – Figure 6.
- Myosin:
- Two heavy chains (tail)
- Four light chains (head)
- Actin-binding sites
- ATPase activity
- Myosin myosin filament composed of 200+ individualmolecules (~1.6 m in length)
- Actin: Muscle Physiology Myofilament Anatomy: Guyton & Hall (Textbook of Medical Physiology, 12th^ ed.) – Figure 6. Troponin (sub-units): 1 ) Troponin C: Binds calcium (up to 4 Ca++)
- Troponin T: Binds tropomyosin
- Troponin I: Binds actin (covers active site on actin) Walk-Along Theory: Ca++^ enters sarcoplasm; tropomyosin shifts Muscle Physiology
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ATP ATPATP ADP Muscle Physiology Myosin head “cocked” (ATP^ Hydrolysis ADP + P i) Myosin head releases
ATP
(ATP bound)
POWER STROKE
Myosin head attaches to actin (active site) Walk-Along Theory: Ca++ tropomyosin^ enters sarcoplasm shifts; Re-cock ATPATP ADP P Muscle Physiology Myosin head “cocked” (ATP^ Hydrolysis ADP + P i) Myosin head releases
ATP
(ATP bound)
POWER STROKE
Myosin head attaches to actin (active site) Walk-Along Theory: Ca++ tropomyosin^ enters sarcoplasm shifts; ATP ATP (^) ADP P ADP ATP (^) ADP P ATP Re-cock ATP^ ADP P Muscle Physiology Myosin head “cocked” (ATP^ Hydrolysis ADP + P i) Myosin head releases
ATP
(ATP bound)
POWER STROKE
Myosin head attaches to actin (active site) Walk-Along Theory: Ca++^ enters sarcoplasm; tropomyosin shifts (^) State of contracture followingRigor Mortis: death (~ 12 – 24 hours) Process will continue until: 1 ) Full overlap of actin and myosin
- Load on muscle becomes too great
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Neuromuscular Junction: Neuron Muscle fiber Motor Neuron Muscle Fiber Subneural ( surface area) cleft Synaptic cleft (^20) – 30 nm
STEP 1:
Secretion of acetylcholine by nerve terminals Muscle Physiology Excitation – Contraction Coupling: 1 connection / muscle fiber Motor End Plate Guyton & Hall (Textbook of Medical Physiology, 12th^ ed.) – Figure 7. Neuromuscular Junction: Motor Neuron Muscle Fiber Muscle Physiology Excitation – Contraction Coupling: ~ 300, A) Small vesicles formed in stoma of neuron; shuttled to axon terminal B) Acetylcholine (ACh) synthesized in terminal; transported into vesicles (~ 10,000 Ach / vesicle) C) Action potential travels down axon; activates voltage-gated Ca++^ channels at terminal Ca++ Ca++ D) Ca++^ influx triggers vesicles to fuse with membrane (~ 125 vesicles / AP); ACh released E) ACh mouth of binds with subneural ACh - cleftsgated ion channels (muscle fiber) at Choline + Acetyl CoA Acetylcholine acetyltransferase^ choline Nicotinic receptors ACh-gated Ion Channel:
- 5 sub-units (2 alpha , 1 beta , 1 gamma , 1 delta ); form tubular channel 40 0
- 40
- 80 mV 0 15 30 45 60 75 mSec
- Opening produces of Ach end plate potential-gated ion channels (EPP) Safety Factor:^ •^ Strong sodium^ EPP triggers voltage channels (AP generation)-gated Each AP arriving junction causes ~ 3x at neuromuscular end plate potential necessary muscle fiber to stimulate Acetylcholinesterase (AChE): Deactivates (synaptic cleft) ACh Muscle Physiology MEPPACh = 0.4 mV Excitation – Contraction Coupling: Guyton & Hall (Textbook of Medical Physiology, 12th^ ed.) – Figure 7.
- Activation = 2 ACh molecules (bind to alpha units)
- Primarily Na+^ channel:
- (-) charge restricts anions
- (-) RMP of muscle fiber favors Na+^ influx vs. K+^ efflux Pathophysiology: Various drugs / toxins / diseases exist that are capable of enhancing or blocking neuromuscular junction activity Neurophysiology normal Drugs / Toxins - Inhibitors: Botulism (bacterial toxin - ACh release) Curare (plant toxin – blocks ACh receptors) Nicotine (plant derivative – mimics ACh) Sarin Gas (synthetic – deactivates AChE) Drugs / Toxins - Stimulants: (“grave muscle weakness”)^ Myasthenia Gravis Autoimmune; destruction ACh-gated Na+ (^) receptors of Treatment = Anti-AChE drugs Result = Paralysis (Weak EPPs) Rare Condition: 1 / 20, (diaphragm paralysis)^ Can be fatal Role of Calcium: Ringer’s Solution beating if Ca^ Isolated^ Frog heart stopped++^ omitted from bath
- Interacts thin filament: with troponin in^ When Ca ++ (^) binds: (uncovers active sites)
- Troponin I / actin bond weakens
- Troponin T / I / C bonds strengthen 10 -^4 Muscle Physiology Excitation – Contraction Coupling: Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10. Sidney Ringer (1836 – 1910) Solution: Sarcoplasmic Reticulum For a muscle contraction to occur, there must be a link between electrical excitation and increased intracellular Ca++^ levels… Problem 1: (~ 25^ Rate of diffusion from Ca – 50 m) several orders of magnitude too++^ to interior of cell slow to explain observed latent period plasma membrane which flood cell with Ca^ AP triggers voltage-gated Ca++^ channels in++… Hollow collars around^ Terminal^ cisterna: myofibril; neighbor Z lines
- Specialized ER; stores Ca++ The only source of regulatory Ca skeletal muscle is from the SR++^ in
- SR membrane contains Ca++^ pumps
- Maintain < [10-^7 M Ca++]
- Calsequestrin: Binds Ca++^ in SR
- Reduces [gradient] Muscle Physiology Excitation – Contraction Coupling: Randall et al. (Eckert: Animal Physiology, 5th^ ed.) – Figure 10.12 / 10.
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Muscle Mechanics:
- Cross-bridge detachment rate (fast detachment = fast contraction)
- Chemical nature of myosin head (Vmax of ATPase)
- Density of Ca++^ pumps (affects clearance of Ca++)
- Mitochondria # / vasculature (affects oxidative ATP production capacities) Fast Glycolytic Fibers:
- Rapid cross-bridge cycling
- Rapid Ca++^ clearance
- Low endurance (anaerobic respiration)
- () glycolytic enzyme content
- () glycogen reserves Large diameter (powerful) Muscle Physiology Muscle fibers can be divided into two primary types based on anatomical and physiological properties Marieb & Hoehn (Human Anatomy and Physiology, 9th^ ed.) – Figure 9. Slow Oxidative Fibers:
- Slow cross-bridge cycling
- Slow Ca++^ clearance
- High endurance
- () mitochondria / capillaries
- () myoglobin content Small diameter Muscle Physiology Muscle Mechanics:
- Cross-bridge detachment rate (fast detachment = fast contraction)
- Chemical nature of myosin head (Vmax of ATPase)
- Density of Ca++^ pumps (affects clearance of Ca++)
- Mitochondria # / vasculature (affects oxidative ATP production capacities) Muscle fibers can be divided into two primary types based on anatomical and physiological properties Marieb & Hoehn (Human Anatomy and Physiology, 9th^ ed.) – Figure 9. White Muscle: Muscle dominated (e.g. chicken breast)^ by fast fibers Red Muscle: Muscle dominated by slow fibers (e.g. chicken leg) Most human muscles contain both of muscle fibers; proportions differ types Fast Fibers Slow Fibers Marathon 18% 82% Runners Swimmers 26% 74% Avg. Human 55% 45% Weight 55% 45% Lifters Sprinters 64% 37% Jumpers 63% 37%
- Genetically determined
- No alters evidence that proportions training significantly Muscle Physiology Muscle Mechanics: Muscle fibers can be divided into two primary types based on anatomical and physiological properties Muscle Remodeling: Muscle Hypertrophy: Increase in total mass of muscle b) Fiber Hypertrophy (most common)
- Increase in myofilament number
- Trigger = Near maximal force generation
- Increase in muscle fiber number
- Trigger: Extreme muscle force generation c) Hyperplasia (rare) a) Lengthening (normal growth)
- Sarcomeres added to existing myofilaments Loss of muscle performance ( contractile proteins = force / velocity) Causes: Plaster cast Muscle Atrophy: Decrease in total mass of muscle Weeks Years Muscle Physiology Sedentary lifestyle Denervation / neuropathy Space flight (zero gravity)
- Discrete muscle fibers
- Nervous control (single innervation / fiber)
- Location: Iris, piloerector muscles Unitary smooth muscle
- Sheets / bundles of muscle fibers
- Electronically-coupled (gap junctions)
- Multiple controls (e.g., hormonal / spontaneous) Multi-unit smooth muscle Muscle Physiology Types of Smooth Muscle:
- Form muscular walls of hollow organs Guyton & Hall (Textbook of Medical Physiology, 12th^ ed.) – Figure 8.1^ •^ Location: Walls of viscera Smooth Muscle:
- Produce mobility (e.g., gastrointestinal tract)
- Maintain tension (e.g., blood vessels)
- Mono-nucleated cells (20 – 500 m length / 1- 5 m width) Properties of Smooth Muscle: Contraction occurs via actin / myosin interaction (ATP) Smooth Muscle – How Does it Differ from Skeletal Muscle?
- Physical Organization: Dense-bodies: Analogous Z lines to Intermediate Filaments (structural backbone) Gap Junction Mechanical Junction Smooth muscle can over large range of lengths operate (~ 75% shortening possible)
- Dispersed / attached to cell membrane Muscle Physiology HOWEVER Smooth muscle appears non-striated
- Anchor actin filaments Marieb & Hoehn (Human Anatomy and Physiology, 9th^ ed.) – Figure 9.
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Properties of Smooth Muscle: Smooth Muscle – How Does it Differ from Skeletal Muscle? 2 ) Neuromuscular Junction:
- Mechanical Operation:
- Slow cycling of myosin cross-bridges (1/10 – 1/300 of skeletal)
- ATPase activity ( = energy required: ~ 1% of skeletal muscle)
- Slow onset of contraction / relaxation (0.2 – 30 sec.)
- Slow cross-bridge action; Slow Ca++^ influx / efflux
- Prolonged contraction periods (hours / days / weeks)
- “Latch” mechanism (poorly understood…) Muscle Physiology Diffuse junctions present in smooth muscle Varicosities: Bulbous swellings along innervating neuron Properties of Smooth Muscle: Smooth Muscle – How Does it Differ from Skeletal Muscle?
- Ca++^ Source:
- Activation Mechanism: Muscle Physiology
- Primarily extracellular (poorly developed SR)
- More extensive SR = More rapid contraction
- Caveolae (T.T. analogs)
- Ca++^ pumps (S.R. / plasma membrane) clear Ca++^ (slow-acting) 10 -^3 M 10 -^7 M Guyton & Hall (Textbook of Medical Physiology, 12th^ ed.) – Figure 8.
- Regulation is myosin-based (not actin-based)
- Troponin complex absent
- Myosin must be phosphorylated before it can hydrolyze ATP (become activated)
- Regulatory chain = Myosin light chain phosphorylated
- Latent period = 200 – 300 ms (50x longer than skeletal muscle)
- Force of contraction dependent on [extracellular Ca++]
Ca++
Calmodulin Myosin light chain kinase (^ MLC active phosphorylated) MLC inactive (dephosphorylated) Contraction Excitation – Contraction Coupling: Events:
- Voltage-gated Ca++^ channels open
- Ca++^ binds with calmodulin (^) Similar in structure
- Ca++^ - calmodulin complex activates^ to^ troponin^ C myosin light chain kinase
- When Ca++^ levels fall; myosin phosphatase deactivates myosin Relaxation phosphatase the time required for relaxation^ Amount of active myosin can greatly affect phosphatase^ Myosin
Ca++
Muscle Physiology Excitation – Contraction Coupling: Muscle Physiology Additional Sources of Ca++: coupled system^ G-protein coupled system^ G-protein Costanzo (Physiology, 4th^ ed.) – Figure 1.
