Chapter 12 Part 1_ Muscle Physiology.docx

Chapter 12: Muscle Physiology Skeletal Muscle Structure Muscles are the effectors of movement, and they act on impulses sent from the nervous system. In this chapter, we will focus on skeletal muscle, which is attached to the skeleton and produces movement of the body and face. The following diagram...

Chapter 12: Muscle Physiology Skeletal Muscle Structure Muscles are the effectors of movement, and they act on impulses sent from the nervous system. In this chapter, we will focus on skeletal muscle, which is attached to the skeleton and produces movement of the body and face. The following diagram shows the gross anatomy of a typical muscle. Note, however, that muscles often have many more fascicles than shown in this highly stylized diagram: Most skeletal muscles are connected to at least two bones by tendons, which are bands of connective tissue responsible for transmitting the force produced by the muscle to the bone. Skeletal muscles are unique in the body; they are long, with multiple nuclei, and they compose roughly 80% of the human body. Because of this, they have individual names associated with their microscopic parts. Skeletal muscles are organs because they consist of multiple tissue types, including skeletal muscle tissue, connective tissue, blood vessels, and nerves. Muscles consist of many fascicles (bundles) of individual muscle cells (which are also referred to as muscle fibers, myofibers, or myocytes). Note that muscles and groups of muscles are surrounded by bundles of connective tissue run the entire length of the muscle fiber and are actually longer than the muscle fiber itself. Individual muscle fibers are wrapped in connective tissue called the endomysium, individual fascicles are wrapped in a layer of connective tissue called the perimysium, and all of the fascicles in a given muscle are wrapped in a layer of connective tissue called the perimysium. An unusual characteristic of skeletal myocytes is that they have multiple nuclei. This is because during the development of skeletal myocytes, stem cells fuse together end- to-end to form one long cell. Multiple nuclei are retained to maintain adequate control over the length of the cell. Muscle fibers run the length of the muscle cell. They are surrounded by a plasma membrane referred to as the sarcolemma. (The prefix sarc- means " flesh," so when you eat the flesh of an animal, you are eating its skeletal muscle.) This plasma membrane is similar to other plasma membranes in the sense that it consists primarily of phospholipids and proteins. Within the plasma membrane are several organelles surrounded by the sarcoplasm, or the skeletal muscle cell's cytoplasm. The sarcoplasm has two components that are not usually found in other cells: Glycogen is a polymer of glucose, which is used for glucose storage. Muscle cells are highly metabolically active and require a constant energy input. Glycogen stored in the muscle cells replenishes glucose when it is needed. Like hemoglobin, myoglobin is a red protein that binds oxygen. However, myoglobin is found exclusively in muscle cells. The red appearance of skeletal muscle tissue is due to myoglobin. Rod-like, contractile organelles called myofibrils are located throughout the sarcoplasm. They fill the sarcoplasm almost completely and push the nuclei of the cell to the outside, just inside the sarcolemma. Even some of the mitochondria within a muscle cell are pushed to the periphery. EXAM TIP: Don't confuse myofibrils (which are organelles) with myofibers (which are entire muscle cells). Myofibrils are made up of three different classes of proteins: Contractile proteins - Contractile proteins are responsible for generating the muscle's pulling force. They include the thick and thin myofilaments, which are made of actin and myosin. o Thin filament (actin) - The thin filament is made of many actin molecules that are strung together in a double helix like a twisted pearl necklace. Each of these actin "beads" has a myosin binding site that interacts with myosin during muscle contraction. Note that actin filaments (sometimes called F actin) are made up of many globular actin (G actin) molecules. In the pearl necklace analogy, the F actin is the entire twisted pearl necklace, and the G actin is each individual pearl. o Thick filament (myosin) - The thick filament is made of about 300 individual myosin molecules. Myosin molecules have long, globular proteins that look like golf clubs with two heads instead of one. These myosin heads stick out from the rod-shaped myosin filaments and interact with actin during muscle contraction. Each head has a site that binds to actin and an ATPase site. (The myosin heads are called crossbridges because they bridge the gap between actin and myosin during contraction.) The thick and thin filaments overlap one another and collectively form a sarcomere, which is the basic repeating unit of a myofibril. We will discuss sarcomeres and how actin and myosin combine to generate a pulling force in greater detail below when we cover the sliding filament model of muscle contraction. Regulatory proteins - Regulatory proteins determine whether or not contraction can occur. The two major regulatory proteins found in the thin filaments of myofibrils of skeletal muscle are tropomyosin and troponin. o Tropomyosin - A long, cordlike protein molecule called tropomyosin covers many of the actin monomers, blocking their myosin-binding sites. When the myosin-binding sites are blocked, actin cannot bind to myosin and muscle contraction is impossible. o Troponin - Troponin is a regulatory protein complex that attaches to tropomyosin. As we will discuss in greater detail below, the binding of calcium to troponin causes a conformational change in the tropomyosin, exposing the myosin binding sites on the actin. This allows muscle contraction to proceed. Structural proteins - Structural proteins hold everything together structurally. Two important structural proteins include titin (which helps anchor the thick myosin filament to the Z-line at the end of the sarcomere) and dystrophin (which attaches the myofibrils to the sarcolemma at the end of the muscle cell). Tit in is highly elastic, and it helps give the muscle the ability to stretch and recoil. Distinguishing Among Terms This chapter contains many terms that sound like one another. It is important that you keep the terms straight. The following is a hierarchy of terms, from the most "macro" (large scale) to most "micro" (small scale): Skeletal muscles consist of many fascicles. Fascicles are bundles of many skeletal muscle fibers. Skeletal muscle fibers (skeletal myocytes) consist of many myofibrils. Myofibrils are organelles that contain myofilaments. Myofibers are entire muscle cells. Myofilaments include the thick and thin filaments, made of myosin and actin. In addition to the structures identified above, two key organelles found in muscle cells are sarcoplasmic reticulum (SR) and T-tubules: The sarcoplasmic reticulum (SR) is a web-like membranous organelle located adjacent to the T-tubules and surrounds each myofibril. It functions primarily in the storage of calcium ions, which are released upon stimulation by electrical signals. Calcium is important because it triggers a muscle contraction by binding to troponin: which causes a conformational change in tropomyosin, uncovering the mysoin binding sites on the actin heads. This allows actin and myosin to bind together, which begins a muscle contraction. Calcium is normally present in very small concentrations in the cytosol; storing calcium in the sarcoplasmic reticulum allows the cell to regulate cytosolic calcium levels to achieve the desired amount of muscle contraction. The sarcoplasmic reticulum encircles the myofibrils like fishnet pantyhose surrounds a leg. This can be seen in the diagram to the right. A transverse tubule, or T-tubule, is a deep invagination of the sarcolemma (the plasma membrane of the skeletal muscle cell) into the cell's interior. The invagination weaves around and between the myofibrils. T-tubules are integral to signal transmission between the sarcolemma and the myofibrils, as we will discuss below. Terminal cisternae ore enlarged areas of the sarcoplasmic reticulum that lie adjacent to the T-tubule. They store calcium and release it in response to an action potential traveling down the T-tubule. A triad is formed by a T-tubule plus the two adjacent terminal cisternae. (Dr. Nguyen described it as a " T-tubule sandwich.") Triads are typically found at the A- I junction-the junction between the A band and the I band. The fact that triads are dispersed throughout the entire length of the muscle fiber ensures that calcium will be distributed evenly in response to an action potential. The Sliding Filament Model of Muscle Contraction In this section, we will briefly discuss the process of skeletal muscle contraction. The Basics of the Sliding Filament Model Scientists once believed that the proteins that make up a muscle squeeze together and get smaller during a muscle contraction. This view has been replaced with the modern view, which states that muscle contraction occurs when the myofilaments slide past each other. Significantly, the myofilaments do not change in length during a muscle contraction. However, the muscle fiber itself becomes shorter because the myofilaments slide past one another towards the medial line of the sarcomere. Recall that each muscle fiber contains a bundle of myofibrils, which are composed of two types of filaments: Thin filaments containing actin. These actin strands are wound around one another in a helical fashion, like a twisted pearl necklace. Actin is formed from globular Gactin proteins (each with a myosin binding site) that b ind together to form a strand known as F-act in. One strand of F-actin forms a double helix with another strand to form the myofilament, actin. Troponin and tropomyosin bind to actin; they are not made of actin. Thick filaments containing myosin. Myosin consists of a long strand with many myosin heads, which look like golf clubs that have two heads instead of one. The sacromere is the smallest fundamental, repeating unit of striated muscle, located between two adjacent Z discs, or Z lines. (The terms Z disc and Z line can be used interchangeably.) You can also think of it as the fundamental unit of muscle contraction. Note that the diagram above only shows a single sarcomere; in actuality, a single myofibril consists of thousands of adjacent sarcomeres in series-end-to-end, in a row. A stylized version of a typical sarcomere is shown to the right. The following are the components of this pattern: The sarcomere is the fundamental, repeating unit of striated muscle, delimited by the Z discs. The Z disc serves as the border of the sarcomere, and it also anchors the thin filaments (actin) at one end. The Z discs are histologically dark because they contain a lot of actin filaments. The A band is the broad region that corresponds to the length of the thick filaments (myosin) of the myofibrils. However, both actin and myosin exist in the A band. The I band is the area near the edge of the sarcomere where there are only thin filaments (actin), hence the lighter color. The H zone is the area in the middle of the sarcomere where there are only thick filaments (myosin). This zone is histologically slightly darker than the I band. The H zone is also referred to as the “bare zone” due to the absence of globular myosin heads. The M line is the axis of the thick filaments (myosin). It is the "midline" of the sarcomere. The diagrams shown previously present a two-dimensional representation of a sarcomere. Remember that muscle fibers have a cylindrical shape, so the myosin and actin filaments are bundled together in a tubular shape. For each myosin filament there are six actin filaments surrounding it. EXAM TIP: The I band and H zone shorten during a muscle contraction, but the A band does not shorten; it remains the same length What happens to this diagram when the muscles contract? According to the sliding- filament model of muscle contraction, the thick and thin filaments do not change length when the sarcomere shortens. Rather, actin is pulled in toward the midline. This causes the region occupied only by the actin (the I bands) and the region occupied only by the myosin (the H zone) to shrink. This is shown as follows: Although overall the sarcomere is contracting, it doesn't rip apart from adjacent sarcomeres because the Z-disc is so heavily fortified with proteins. Note that the A band- the broad region that corresponds to the length of the thick filaments-does not shorten during a muscle contraction because the filaments themselves do not shorten; they just slide over one another. The Crossbridge Cycle in Detail The mechanism that produces the motion by which actin and myosin slide over one another is called the crossbridge cycle, and it occurs in five steps: 1. The myosin binds to actin. Energized myosin has a very high affinity for actin, and so the myosin heads bind to nearby actin. Calcium (Ca2+) is required for this step to proceed. This is actually known as the "energized state." 2. Power stroke. The binding of the myosin to the acting causes the release of the inorganic phosphate (Pi) and ADP from the ATPase site on the myosin. The myosin head pivots toward the middle of the sarcomere, which pulls the actin towards the sarcomere's middle. Myosin then enters into a low-energy state. 3. Rigor. At this point "in the crossbridge cycle, the actin and myosin are tightly bound together, in a condition referred to as rigor. 4. Unbinding of myosin and actin. When another ATP is put into the ATPase site on the myosin head, the myosin and actin unbind. This step requires ATP. This is why dead animals enter a state of constant muscle contraction called rigor mortis soon after death. ATP is not produced, so myosin and actin cannot unbind and the muscles are locked in a state of contraction. (Decomposition of myofilaments occurs 48-60 hours after peak rigor mortis, or about 13 hours after death.) 5. Cocking of the myosin head. The ATP is hydrolyzed into its components (ADP and phosphate) and energy is released. This energy is used by the myosin, which reenters its high-energy state, and the cycle begins again. EXAM TIP: ATP is not directly involved in the power stroke It is involved in the unbinding of myosin and actin. A Closer Look at the Neuromuscular Junction The neuromuscular junction {NMJ) is the location of the interaction between an axon of a motor neuron and a muscle. As it approaches skeletal muscle fibers, a myelinated axon branches off into projections that end in axon terminals, which relase acetylcholin (Ach). The axon terminals may appear to attach directly to the muscle fiber, but they are actually separated from the sarcolemma of the muscle fiber by a tiny space called the synaptic cleft. At the site of the synapse, the sarcolemma of the muscle fiber contains motor end plates that exist within the kinky borders of junctional folds in the sarcolemma. The junctional folds function to increase the surface area of the sarcolemma so that the sarcolemma house more receptors for neurotransmitters. The receptors located along the junctional folds are nicotinic (acetylcholine) receptors. This activates muscle cells for contraction. Excitation-Contraction Coupling Muscle contractions are triggered by excitation- contraction coupling (ECC), a sequence of events that links an action potential to a contraction. The signal to initiate a contraction begins with an upper motor neuron in the cortex of the brain. This motor neuron sends an action potential to a lower motor neuron whose soma is located in the spinal cord. Once activated, the lower motor neuron sends an action potential down an axon that leads to a skeletal muscle. The action potential results in a release of acetylcholine from the motor neuron's axon terminal into the sarcolemma. This causes an extremely large, graded depolarization in the sarcolemma called an end plate potential (EPP). The action potential travels across the entire sarcolemma, and in T-tubules, it triggers a release of calcium from the sarcoplasmic reticulum, which is crucial to the cross bridge cycle. The movement of calcium is integral to the contraction and relaxation of muscle fibers. When a muscle cell is relaxed, there is very little calcium in the cytosol, and so the binding between calcium and troponin is minimal. This is because the sarcoplasmic reticulum (SR) actively pumps calcium from the cytosol into the SR. The SR also contains voltage-gated calcium channels that are normally closed, but when an action potential travels through the T-tubules, they open and allow calcium to flow out and increase the calcium concentration in the cytosol. If the frequency of action potentials is great enough, calcium doesn't have time to be reabsorbed by the sarcoplasmic reticulum, and so it can continue to initiate the crossbridge cycle. Note that there is a bit of a delay between the onset of muscle activation (due to an action potential) and muscle force production because it takes time for an action potential to cause calcium release and crossbridge cycling to occur. This delay between electrical activity and tension or mechanical output is called the electromechanical delay. The links between the action potential reaching the T-tubules and the SR releasing calcium are the dihydropyridine (DHP) and ryanodine receptors. (Dihydropyridine receptors get their name from a class of drugs called dihydropyridines, which inhibit them. Likewise, ryanodine receptors get their name from a class of inhibitory drugs that include ryanodine, an alkaloid.) DHP receptors are found in the T- tubules and they undergo voltage-triggered conformational changes. The ryanodine receptors are found in the SR and are connected to the DHP receptors. When an action potential reaches a DHP receptor, it undergoes a conformational change that sends a signal to the ryanodine receptors, causing their calcium channels to open. For this reason, ryanodine receptors are also called calcium-release channels. Once calcium- release channels open, calcium moves into the cytosol relatively quickly because it follows a strong concentration gradient. In the presence of calcium, the crossbridge cycle (discussed above) can begin. The cytosolic calcium binds to troponin, causing tropomyosin to undergo a conformational change that exposes the myosin-binding sites on the actin monomers. Once the action potential's stimulus is removed, the SR resumes its active transport of calcium out of the cytosol, and the tropomyosin and troponin revert to their original shapes and hide the myosin-binding sites. This causes a muscle contraction to end. The more frequently an action potential reaches the neuromuscular junction, the more frequent action potentials make their way down the T-tubules, and the more calcium is released. The more calcium is released, the more frequent contractions occur. An outline of excitation-contraction coupling is as follows: ACh is released from a motor neuron and binds to the motor end plate, causing an end-plate potential, which will then trigger an action potential in the muscle cell. The action potential then travels along the sarcolemma and through the T-tubules, triggering the release of calcium from the sarcoplasmic reticulum. The calcium binds to troponin, causing a conformational change in tropomyosin, and myosin-binding sites are exposed. The following events follow excitation-contraction coupling: The crossbridge cycle begins, and the muscle contracts. The calcium is actively transported back into the sarcoplasmic reticulum. Tropomyosin blocks myosin-binding sites, and the muscle fiber relaxes.