Represents the largest tissue mass responsible for blood glucose storage and post-prandial lipid oxidation
Skeletal muscle
Second only to the liver, skeletal muscle is also the predominant site of
Thermogenesis
Reduced skeletal muscle mass (such as what can occur with illness and aging) is associated with an increased risk for
Cardiovascular disease, diabetes, and obesity
What are the three types of muscle tissue?
Smooth, cardiac, and skeletal
Muscle contraction falls into what two general categories?
Isometric and Isotonic
The development of tension without force
Isometric contraction
The generation of force via moving a load over a distance
Isotonic contraction
Muscle fibers are surrounded by a specialized plasma membrane containing an additional tough outer coat of collagens and polysaccharides, called the
Sarcolemma
Within each muscle fiber are bundles of
Myofibrils
Repeating units of sarcomeres that are surrounded by the sarcoplasm
Myofibrils
The sarcoplasm contains mitochondria, ions, enzymes, and the main intracellular sink (storage site) for Ca2+, which is called the
Sarcoplasmic reticulum (SR)
An important SR protein which binds Ca2+ and maintains Ca2+ in the low energy state while it is housed within the SR
Calsequesterin
Each myofibril is comprised of sarcomeres. The sarcomere is comprised of interdigitating elements
of myofilaments which each contain what three things?
- ) Actin
- ) Myosin
- ) Anchoring Z disc
Histologically speaking, the sarcomere is characterized by specific bands and is capped on each side by a Z disc. What are the three bands?
- ) A band
- ) I band
- ) H band
An overlapping region of thick (myosin) and thin (actin) elements
A band
Contains only actin filaments
I band
A centrally located light area within each sarcomere, and contains myosin
H band
Actin is anchored to
Z discs
The myosin heads are in fact connected to the tail regions by a hinged arm; collectively, the head-arm region is referred to as the
Myosin cross-bridge
In skeletal muscle, actin is in the form of a double helix of F actin, which is made up of which three things?
- ) G actin
- ) Troponin
- ) Tropomyosin
Shields active, myosin binding, sites on actin
Troponin
The myosin binding domains within actin
Tropomyosin
Troponin contains which three subunits?
- ) I (actin attachment)
- ) T (tropomyosin attachment)
- ) C (calcium binding)
Prevents actin and myosin from interacting and inducing muscle contraction during relaxed (basal) conditions
Troponin/tropomyosin complex
The process of skeletal muscle contraction begins at the juncture between the motor neuron and the
muscle tissue. This region is referred to as the
Neuromuscular junction, motor endplate, or myoneural junction
The terminus of the efferent (motor) neuron is unmyelinated and branches into several troughs on surface of the
Muscle cell
The nerve terminus contains and abundance of mitochondira as well as vesicles that house neurotransmitters, most notably
Acetylcholine (ACh)
These α motor neurons cannot synthesize choline; they can however convert choline into
Acetylcholine (ACh)
In the neuromuscular junction, ACh is the neurotransmitter, and the post-synaptic membrane belongs to the
Sarcolemma
Acetylcholine diffuses across the synaptic cleft and binds to receptors located on the post synaptic membrane called
Cholinergic-nicotinic receptors
As depolarization propagates through the sarcolemma, the ACh signal is deactivated by degradation of ACh by
Acetylcholinesterase
To pallitatively treat syndromes where ACh release and/or binding to cholinergic/nicotinic receptors is impeded, i.e. myasthenia gravis, we want to use an
Acetylcholinesterase inhibitor (will result in prolonged muscle contraction)
Skeletal muscle ACh receptors are ligand-gated ion channels, more specifically, they are
ACh-gated Na+ channels
Na+ influx induces relatively minor membrane depolarizations within the motor endplate, and these sub-threshold membrane depolarizations are known as
Endplate potentials (EPP)
Within the sarcolemma, voltage-gated Na+ channels are activated to induce membrane threshold, by the
EPPs
The spread of signal is relayed from the sarcolemma via highly conductive specialized structures known as the
Transverse tubules (T tubules)
As the AP travels down the T tubules, a conformational change occurs in voltage-gated Ca2+ channels known as
Dihydropyridine receptors (DHPR)
DHRP’s in the T tubule sit on clusters of
-embedded in the SR membrane
Ryanodine receptor Ca2+ channels (RyR)
The conformational change in DHPR alters the inhibitory interaction between DHPR and RyR, opening the pore in RyR that allows the flow of Ca2+ from
SR to the sarcoplasm
This rapid increase in sarcoplasm Ca2+ concentration, focused on the Z-disc due to the localization of the triad junction, signals
Contraction
Binds to troponin C and causes a conformational change of the troponin/tropomyosin complex
Calcium
The binding of calcium to troponin C causes a comformational change in the troponin/tropomyosin complex which reveals the
Active (myosin binding) domain in the actin molecule
The high energy myosin head/ADP + Pi complex is
maintained in
Resting Muscle
When the myosin binding domain within actin is exposed in response to elevated sarcoplasmic Ca2+ levels, the high energy myosin head binds to
Actin
The binding reaction induces a conformational change in the cocked (loaded) myosin head that drives the myosin head downward. This is called the
Power-stroke
Pulls on the actin and attempts to draw actin towards the center of the sarcomere (Z-disc to Z-disc shortening)
Power-stroke
Myosin light chains comprise the heads and contain the intrinsic
ATPase
Significant sarcomere shortening does not occur during
Isometric contraction
Muscle contraction always begins with an isometric contraction and can be followed by isotonic contraction if the muscle is more “powerful” than the
Opposing load
Crossbridge cycling will be terminated as a result of decreased
Ca2+ or sarcoplasmic ATP concentration
Experimental evidence has shown that excess extracellular Ca2+ (hypercalcemia) raises the membrane potential necessary to open motor neuron voltage-gated Na+ channels, thus inducing
Hypoexcitability
Associated with an increase in nerve and muscle excitability, i.e. hyperexcitability
Hypocalcemia (low blood calcium)
It appears that extracellular Ca2+ aids in somehow stabilizing membrane Na+channels within
Skeletal muscle and neurons
Work in concert to maintain normal calcium levels, thus a disruption can raise concerns regarding calcium homeostasis
Parathyroid hormone, bone, and the kidneys
Important for the activity of Na+/K+ ATPases, initial myosin activation, and the activity of SERCA pumps in the SR
-available for immediate use, but there is only enough for a couple seconds of contraction
Sarcoplasmic ATP
A second source of ATP is derived from the sarcoplasmic stores of
Phosphocreatrine (pCr)
Catalyzes the transfer of phosphate groups from pCr to ADP during muscle contraction
Creatine kinase
During rest, and in active muscle, pCr is re-synthesized from ATP and creatine (Cr) via the catalytic actions of
pCr kinase
During the more sustained muscle contractions, or numerous contractions over a longer period of time, ATP is produced via
Glycogen breakdown and subsequent glycolysis
-2 ATP per mole of glucose
The ultimate source of ATP production, which can provide enough ATP to sustain muscle contraction for hours
Oxidative metabolism
Has the capacity to promote the metabolism of fatty acids in order to provide the greatest proportion of ATP
Oxidative metabolism
In oxidative metabolism, one mole of glucose can produce
38 ATP
The use of fatty acids may also provide ATP during prolonged muscle activity. This mechanism is supported by the stimulatory effects of
Epinephrine and growth hormone (GH) in adipocytes
In adipocytes, epinephrine and growth hormone stimulate the conversion of triglycerides into free fatty acids. Each mole of free fatty acid can generate
129 ATP
Skeletal muscle fibers can only relax once the Ca2+ concentration in the sarcoplasm drops below the
minimal level required to allow Ca2+ to bind
Troponin C
The principal mechanism that muscle fibers use to clear Ca2+ from the cytosol
-activated immediately after sarcoplasmic [Ca2+] begins to rise
Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA)
A highly abundant protein that sits in the SR membrane and pumps Ca2+ from the sarcoplasm into the lumen of the SR
SERCA
Most of the Ca2+ is returned to the SR, however, some Ca2+ leaves the muscle fibers through Ca2+ leak channels or the
-expressed in skeletal muscle and cardiomycetes
Na+-Ca2+ exchanger (NCX) protein
A blockade in NCX function would result in
Elevated sarcoplasmic Ca2+
In muscle terms, mass means
Load
In order for concentric contraction to occur, the force generated by the muscle must overcome the
Load
Sometimes described as “lengthening contractions” since muscle fibers actually lengthen as they contract. These occur when the resistance against contraction is greater than the contractile force that can be generated by the muscle
Eccentric contraction
The propensity for muscle damage is greater during
Eccentric contraction
Determines the strength of muscle contraction, i.e. how much load a muscle can displace
Stress (stress = Force / cm^2)
Tension, strength, and stress are all intended to describe the same property of a muscle, that is,
Strength
Maximum muscle stress (i.e. greatest force generated) occurs in the range of optimal overlap between actin and myosin cross-bridges that is present only near
Normal resting length (Lo) of the sarcomere
The resistance of muscle tissue to stretch
-increases as muscle is stretched beyond its Lo
Passive tension
Tension (active and passive) is pretty high in resting muscle, and as resting muscle is stretched beyond its normal resting length (>Lo), passive tension
Increases
Generated during muscle contraction and falls as a result of stretch from Lo
-the change in tension during muscle contraction
Active tension
Peaks during the early phase of isotonic muscle contraction, when the velocity of muscle contraction is the greatest
Active tension
Active tension in fact decreases as
Isotonic muscle contraction peaks
Total tension increases somewhat within muscle fibers (increased passive tension); whereas, active tension is very low, during (remember, no displacement of load)
Isometric contraction
Maximal active tension is generated at the very beginning of the contraction when muscle fibers are very near
Lo
Is highest right near Lo, but declines if the muscle is stretched and also peaks and declines shortly after contraction begins as the muscle becomes much smaller than Lo
Active tension
A muscle fiber has the greatest potential to develop force from L0, and force declines rapidly in response to
Sarcomere shortening (isotonic muscle contraction)
A single rapid muscle contraction in response to a single action potential
Muscle twitch
Results from the simultaneous contraction of many motor units and/or the increased frequency of contraction of a motor unit per unit time
Summation of twitches
Responsible for muscle contraction as we know it
Summation of twitches
Occurs when rapid successive twitches fuse
-represents the physiologic MAXIMUM strength of contraction (i.e. further summation will not result in increased strength of contraction)
Muscle Tetany
The phenomenon whereby a stimulus is relayed to a small motor unit (more fatigue resistant), which recruits other smaller motor units until eventually large motor units are activated
Orderly recruitment principle
What are the two main types of muscle fibers in adult humans?
Type 1 and Type 2 fibers
Known as slow twitch, red, or oxidative fibers
-develop force at a slower rate but can sustain activity for longer periods of time
Type 1 fibers
Known as fast twitch, white, or glycolytic fibers
-responsible for rapid generation of force sustained over short intervals
Type 2 fibers
Type 2 fibers have been further divided into which two groups?
- ) Type 2a (low oxidative capacity)
2. ) Type 2b (almost no oxidative capacity)
Changes in the net metabolism from an individual muscle may represent variance in the relative number of different fiber types being
Activated
Physical training at high levels of resistance will result in
Hypertrophy of type 2 fibers w/ modest effect on aerobic capacity
Results in an increase in the oxidative capacity of type 1 fibers associated with a proliferation of mitochondria and an increase in capillary density
Lower intensity endurance training
Muscle protein synthesis is stimulated by resistance exercise; so long as net muscle protein synthesis
exceeds muscle protein breakdown (i.e. catabolism), the result will be
Hypertrophy
Key hormones that stimulate the intracellular signaling motifs which promote myofibrillar protein synthesis
Anabolic androgens, IGF-1, and GH
Prevent protein breakdown, increased amino acid uptake, increased lipolysis, and decreased glycogenolysis, which collectively support muscle function, growth, and repair
Growth hormone and IGF-1
Anabolic androgens such as testosterone and its pharmacologic derivatives stimulate satellite cell activity and cause
Muscle cell hypertrophy
Satellite cells are stimulated to differentiate into myoblasts, which then fuse with myotubules as part of the
Repair/hypertrophy process
Satellite cells express androgen receptor and undergo proliferation in response to
IGF-1
Blocks cell cycle progression within satellite cells, and loss-of-function is associated with enhanced muscle mass in humans and some other mammalian species
-member of TGFβ superfamily
Myostatin
Regular resistance training results in hypertrophy primarily of
Fast twitch type 2 fibers
Increases in strength result not only from muscle hypertrophy but from a better coordination of contracting
Motor units
Stimulated and mediated by several intramuscular
growth factors that are secreted in response to load
-another cause of gain of muscle
Angiogenesis (synthesis of vascular tissue) in response to load