How is muscle categorized?
Striated vs Unstriated
Striated: skeletal and cardiac mm
Unstriated: smooth mm
Voluntary (SNS) vs Involuntary (ANS)
What is sarcopenia?
the degenerative loss of skeletal muscle mass and
strength with aging.
Changes in fiber force and power due to reduced fiber size.
What are some characteristics of skeletal muscle?
A single cell is a muscle fiber which contains bundles of myofibrils.
Muscle fibers are large, striated, and multinucleate
What makes up a myofibril?
What causes striations?
Myofibrils consist of a bundle of parallel
microfilaments called myofilaments
Myofilaments are organized into contractile units called sarcomeres (smallest functional unit of skeletal muscle)
• two myofilaments: myosin (thick) and actin (thin).
The arrangement of myofilaments causes striations.
What are the characteristics of smooth muscle?
No striations (SMOOTH)
- Filaments do not form myofibrils
– Not arranged in sarcomeres
• Spindle-shaped cells with single nucleus
• Cells usually arranged in sheets within muscle
• There are two broad groups of smooth muscle:
– single-unit (unitary)
– multi-unit Smooth Muscle
What causes skeletal muscle contraction?
How many neurons per muscle fiber? How many muscle fibers can one neuron innervate?
For skeletal muscle contraction to occur an electrical stimulus (action potential) is converted to mechanical response (contraction).
Each fiber innervated by one neuron
One neuron can branch and innervate many fibers
What are the components of a neuro-muscular junction?
A motor neuron and a motor endplate
The motor neuron contains vesicles in its active zone which contain ACh ready to be released when signaled.
The motor end plate (on muscle fiber) contains postjunctional folds to increase surface area for AChR. Highest concentrations of AChR is in the folds. Capable of End Plate Potentials (EPPs) but no action potentials (APs occur on either side after EPP)
What are the steps in neuromuscular transmission?
1. action potential in the α-motor neuron
2. Ca2+ through voltage-gated channels
3. Ach vesicle migration and fusion
4. Ach release into the synaptic cleft
5. binding of Ach to the Ach receptor and Na+ influx
6. End plate potential
7. if threshold is reached opening of voltage-gated Na+ channels and depolarization of the sarcolemma
8. Degradation of acetylcholine by acetylcholinesterase (AChE).
Note: the numbers in picture don't correspond
What are SNARE proteins?
Combination of 3 proteins in motor neuron.
2 are in the synaptic membrane, the other is attached to the synaptic vesicle (containing ACh). The proteins combine at the nerve terminus to guide the vesicle to fuse with the nerve terminus to release ACh into the synaptic cleft.
note: Botulism prevents ACh release by degrading SNARE proteins. Result in flaccid paralysis and death from respiratory paralysis.
Describe End Plate Potentials
Each vesicle release of Ach causes a miniature end-plate potential (MEPP).
• Does not cause an action potential.
• Summation of multiple MEPPs produce an EPP.
• Graded potential EPP is confined (localized) to the motor end plate.
• Magnitude depends on the amount and duration of Ach at the end plate.
How is ACh degraded? Recycled?
Binding of Ach to receptor is very brief
Acetylcholinesterase rapidly degrades Ach.
Acetylcholinesterase in junctional gap and post-synaptic folds
ACh is recycled by neurons taking up choline from cleft and uses Acetyl-SCoa enzyme to combine choline and acetate.
How can toxins/drugs affect the magnitude of the EPP?
Toxins/Drugs can alter:
- Calcium channel
- Ach Release
- Ach Breakdown
- Ach Receptors
What are two types of neuromuscular blocking drugs and how do they work?
- majority of clinically-relevant blockers
competitively block binding of Ach to receptors causing paralysis (competitive
- tubocurarine (curare)
- used during surgery as a adjunct to but not as a replacement for anesthesia.
- depolarize the sarcolemma of the muscle fiber
- prevents further activation of the muscle
succinylcholine: used to induce muscle relaxation and short term paralysis,
usually to make endotracheal intubation possible. (mimics the effect of Ach but degrades slower so not often used)
What are Thick (myosin) filaments composed of?
A single thick filament consists of many myosin molecules
Each myosin molecule is
composed of two proteins
forms a tail with two-heads
myosin has ATPase activity
What are Thin (actin) Filaments composed of?
Actin filaments, Tropomyosin Tm (w/ myosin binding site) and the Troponin complex w/ 3 enzymes: TnT, TnC, TnI
Troponin complex is the Ca2+ sensitive molecular switch, TnC: “calcium sensor”, calcium binding produces a conformational change in TnI
TnT: links Tn complex to Tm, appears to control the position of Tm on the thin filament
TnI: binds to actin and inhibits myosin ATPase
How does the Tn complex allow f-Actin to bind mysoin?
Without calcium the myosin binding site on f-actin is blocked by the Tn complex. If calcium is present, TnC will bind to it and induce a conformational change in TnI and TnT that is bound to tropomyosin moves out of the way with the rest of the complex, making the myosin binding site available.
How does Calcium concentration affect contractile force?
Ca2+ binding is cooperative.
Each molecule of Ca2+
bound increase the affinity of
troponin C for Ca2+
How is Calcium released in skeletal muscle (basic explanation)?
Depolarization of Transverse (T)-tubules causes the sarcoplasmic reticulum to release calcium.
T-tubules are a continuation of the sarcolemma (muscle plasma membrane) and carry the action potential into the muscle fiber.
The sarcoplasmic reticulum (SR) is specialized endoplasmic reticulum that stores calcium in muscle cells.
What channels/receptors are involved in Ca release from the SR?
What is a clinical correlation?
T-tubules have a voltage sensor called dihydropyridine
SR contains Ca release channels called ryanodine
receptor (RYR) which line up across from the DHPR.
Depolarization of the t-tubules causes a conformational change in the DHPR that mechanically pulls the "lid" off of the RYR, opening the RYR channel and allowing the release of calcium from the SR.
Malignant Hyperthermia is an inherited syndrome caused by a mutation in the genes for RYR, calsequestrin or DHPR. Symptoms are usualy triggered by anesthesia which results in release of Ca uncoupled from sarcolemma APs. Muscles forcefully contract w/o APs and generates tremendous heat.
How does the SR store calcium?
The SR contains a calcium binding
protein called calsequestrin (Casq)
• allows the SR to store a large
amount of calcium
• keeps free calcium concentration in
the SR low.
• prevents calcium leakage.
What is the sliding filament theory?
Theory of how muscles contract.
Contraction occurs by the sliding of thin filaments past
• Series of cyclic reactions between the myosin head and
the actin filament (cross-bridge cycling).
• Results in muscle shortening.
• Predicts that contractile force produced by the muscle
fiber is proportional to the number of myosin crossbridge-
What is the 3D arrangement of Myofilaments?
Hexagonal array of 6 thin filaments surrounding a thick filaments.
What is cross-bridge cycling? When does it begin and end?
What are the steps in cross-bridge cycling?
Each cross-bridge cycle "walks" myosin further along the actin filament. It begins when Ca is present (after AP) and bound to TnC to allow binding of myosin to actin. It ends when Ca is reaccumulated by the SR Ca-ATPase. Tetanus (muscle doesn't relax) results from a muscle being repeatedly stimulated , increasing Ca.
Steps: (from BRS)
1. At first no ATP is present and myosin is tightly bound to actin (very briefly in contracting muscle), in absence of ATP this is permanent (rigor)
2. ATP binds myosin causing it to release from actin.
3. Myosin isdisplaced towards plus end of actin. ATP is hydrolyzed and ADP remains attached.
4. Myosin attaches to new place on actin, constitutes the Power stroke. ADP is then released and returns myosin to rigor state.
5. Cycle starts over as long as Calcium is present.
Picture from lecture doesn't exactly match the steps/picture in the BRS.
What is the length-tension relationship?
Define passive and active tension.
As muscle length decreases, tension increases.
passive tension: due to stretching muscle
active tension: force from cross-bridge cycling.
Why is fascia important in skeletal muscle?
Fascia: fibrous connective
tissue that binds muscle into a
All connective tissue sheaths
are continuous with each other
and with tendon.
Force is transfered through
these connective tissues to
tendon then to bone.
What is twitch summation?
Muscle “twitch”: response to a single threshold
Summation: increased frequency of stimulation
= successive contractions with increasing force:
“piggyback”, muscle fibers don't have time to fully relax, can result in tetanus if enough Ca is present.
What is motor unit recruitment?
motor unit = motor neuron and all the fibers it innervates
recruitment = progressive activation of additional
motor units. increased motor unit recruitment =
increased force production (more fibers are active)
“all-or-none”: all fibers in a
motor unit contract
whole muscle: “graded activation”
graded muscle force development is due to
recruitment of motor units.
What are the muscle fiber types?
How does resitance training compare between fiber types?
Type I: slow twitch, high aerobic (oxidative) capacity
• lots of mitochondria, myoglobin, and capillary system, endurance
• slow contractile velocity
• smaller diameters than type IIa fibers
Type IIa: fast twitch, high anaerobic (glycolytic) capacity
• rich in enzymes for anaerobic metabolism, high SR content, high ATPase activity
• designed for power and speed but fatigue easily
• fast contractile velocity
Type IIx: really fast fiber (rare in healthy humans)
Hybrid: I/IIa, I/IIa/IIx, IIa/IIx
Resistance training: results in higher % increase in power output in type IIa than type I