April 4, 2007
Lecture 34MUSCLE: 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 myofibrilsand 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-linesand 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 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 complexcauses 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 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 alsocardiac 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 disksby 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.