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April 4, 2007
Lecture 34
MUSCLE: STRUCTURE-FUNCTION
All movement at cellular and organismal levels is dependent on one of two basic
contractile systems. The two basic contractile systems in eucaryote cells are dependent
on either microtubules or microfilaments. The cytoskeletal elements form protein strands
and accessory proteins utilize ATP hydrolysis to move along the protein strands. Earlier
we mentioned the organization of microtubules in axonemes for cilia and flagella
movements (Fig. 6.24). Microfilaments can also be organized into protein arrays and the
accessory motor protein, myosin, can through ATP hydrolysis move along the
microfilaments. The coupling of ATP hydrolysis and motor protein movement is through
allosteric regulation (Fig. 8.11) by the nucleotide and inorganic phosphate group. The
structure and function of myosin is progressively modified through a cycle of allosteric
regulation. We will first focus on skeletal muscle contraction and then look at cardiac
and smooth muscles.
The action of all animal muscles is to contract. Muscles extend only passively, thus to
move any part of the body in opposite directions, muscles have to be attached in
antagonistic pairs (Fig. 49.27). In order to understand how skeletal muscles contract, we
first need to understand its structure. A skeletal muscle consists of a number of parallel
muscle fiber cells (Fig. 49.28). Each muscle fiber cell is multi-nucleated because
embryonic myofibrils fused together during development and each myofibril gives rise
to a longitudinal array of contractile units called a sarcomere, which is the basic
contractile unit of the muscle. Thus a muscle fiber cell contains a bundle of myofibrils
and each myofibril is a longitudinal series of sarcomeres (Fig. 49.28). Each sarcomere
contains two kinds of myofilaments: thin filaments and thick filaments. Each thin
filament is a microfilament of two strands of actin (Table 6.1) with an additional strand
of regulatory proteins associated with each actin strand (Fig. 49.31). Each thick filament
is a staggered array of myosin motor proteins (Fig. 49.30). The myosin heads with an
attachment site for actin project out from the thick filament towards the neighboring thin
filaments.
Skeletal muscle is also called striated muscle because of the regular arrangement of the
thick and thin filaments in each sarcomere create a pattern of light and dark bands (Fig.
49.28). The borders of each sarcomere are called the Z-lines and are aligned in adjacent
myofibrils. The thin filaments are attached to the Z-line on both side and project toward
the center of each sarcomere. The thick filaments lie between the thin filaments and are
centered in the sarcomere. At rest, the thick and thin filaments partially overlap and the
region around the Z-line, which contains only the thin filaments is called the I band. The
A band is the entire length of the thick filament within each sarcomere. Since thin
filaments do not extend entirely to the center of the sarcomere, there is a central zone of
just thick filaments, which is called the H zone. The M line extends down the middle of
each sarcomere.
Muscle contraction is explained by the sliding filament model, where thick and thin
filaments length is constant, but contraction occurs with shortening of each sarcomere by
the filaments "sliding" past each other (Fig. 49.29), rather than a shortening of the thick
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and thin filaments. The proposal of the sliding filament model was originally based on
light microscopy observations of striated muscle contraction. During contraction the two
zones of either just thin filaments (I band) and just thick filaments (H zone) shrink. A
muscle is fully contracted when the I band and H zone fully disappear.
We now understand the molecular interactions between myosin and actin for the sliding
filament model. Each thick filament consists of nearly 350-400 myosin molecules
forming a bipolar filament with staggered arrays at either end of the myosin heads (Fig.
49.30) projecting outward to the thin filaments. The globular myosin head contains an
actin binding site and is an ATPase, which hydrolyzes ATP to ADP and inorganic
phosphate. The myosin head structure-function is regulated by the binding of ATP, then
ADP + Pi, then ADP and finally no nucleotide bound. Thus the allosteric regulation of
myosin is a complex four-step event, which controls the structure of myosin and its
binding to actin (Fig. 49.30). When myosin can bind actin, it forms a cross-bridge, which
pulls the thin filament toward the M line or the center of the sarcomere. In this way the
filaments slide past each other, the sarcomere shortens and the muscle contracts by the
sum of all the sarcomere shortening.
Typically a muscle contracts only when stimulated by a motor neuron. While the muscle
is at rest, the myosin-binding sites of actin are blocked by the regulatory protein,
tropomyosin (Fig. 49.31). For the myosin-actin crossbridges to form, the tropomyosin
has to be moved to expose the myosin-binding sites. This happens when the level of Ca2+
rises (Fig. 49.31b) due to release of Ca2+ from the sarcoplasmic reticulum, which are
specialized structures of the smooth endoplasmic reticulum (Fig. 49.32). The motor
neuron action potential releases acetylcholine, which binds to its receptors in the muscle
membrane and cause a depolarization of the muscle fibers. An action potential is
stimulated and the action potential spreads into the muscle along the infoldings of the
plasma membrane called, T-tubules. The T-tubules connect to the sarcoplasmic
reticulum, which releases its Ca2+ content with t-tubule depolarization. Ca2+ binding to
the troponin complex causes an allosteric change that displaces the tropomyosin and
expose the myosin-binding sites of actin for myosin-actin cross-bridge formation and
muscle contraction. Muscle contraction ceases and the muscle relaxes when the
depolarization of the T-tubules cease, the sarcoplasmic reticulum re-sequesters the Ca2+,
the troponin complex relaxes back to resting, tropomyosin covers the myosin-binding
sites, cross-bridging ends and the muscle relaxes back to resting state (Fig. 49.33).
Each skeletal muscle fiber responds to neuronal stimulation with a brief, all-or-none
contraction, called a twitch. However the contraction of an entire muscle is graded
because we can alter the extent and strength of a muscle contraction. A graded
contraction can occur by varying the number of muscle fibers that contract OR by
varying the rate of muscle stimulation. Each skeletal muscle fiber is innervated by a
single motor neuron, but each motor neuron may stimulate a pool of muscle fibers, which
constitutes a motor unit (Fig. 49.34). The nervous system can regulate the strength of
contraction by determining how many motor units are stimulated at any moment. The
force of contraction increases as more motor units are activated. Each nerve action
potential produces a muscle twitch that last 100 milliseconds or more. If a second action
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potential arrives before the effects of the first action potential have completely ceased,
then the second stimulation will initiate a twitch, which sums with the first and produces
a greater force (Fig. 49.35). Further stimulations will cause further summation of muscle
contraction until the stimulation frequency is such that the muscle is unable to relax at all
between stimuli and the twitches fuse into one long continuous contraction called
tetanus.
Muscle fibers can be classified according to their speed of contraction as slow or fast
(Table 49.1). The difference is mainly due to the rate the myosin heads can hydrolyze
ATP and cycle through their cross-bridging with actin (Fig. 49.30). Fast fibers are used
for brief, rapid, powerful contractions. In contrast the slow fibers have less sarcoplasmic
reticulum and Ca2+ pumps, thus Ca2+ is released for a long period and a longer lasting
twitch. Muscle fibers also differ in production of ATP. Some fibers rely mainly on
aerobic respiration and are called oxidative fibers, while others depend mainly on
glycolysis and called glycolytic fibers. The oxidative fibers have large numbers of
mitochondria, rich blood supply and oxygen-storing protein, myoglobin. Oxidative
fibers can be fast or slow. All glycolytic fibers are fast and tend to fatigue rapidly when
the ATP store is consumed. Many glycolytic fibers contain creatine phosphate to store
high energy phosphate for rephosphorylation of ADP→ATP during muscle contraction.
There are also cardiac and smooth muscles. Cardiac muscles are only found in the heart
and are striated like skeletal muscle. There are significant differences in structure
between skeletal and cardiac muscles that contribute to differences in conduction and
contraction. All cardiac muscles are electrically coupled at intercalated disks by gap
junctions. Thus contraction initiated at one part of the heart will spread through the entire
heart and contract as a single unit. Smooth muscles are found lining blood vessels and
many organs in the body. These cells are not striated because their myosin and actin are
not organized into well-defined filament arrays. Further smooth muscle lack troponin,
extensive plasma membrane infoldings of the T-tubules and smooth endoplasmic
reticulum organization of the sarcoplasmic reticulum. Smooth muscle contraction is still
Ca2+-dependent and regulated by phosphorylation of the myosin head. Contractions are
generally weaker, slower and longer lasting. Invertebrates contain other types of
muscles, which are specialized for particular functions.