Muscular System Levels of Organization
The force generation required for skeletal muscle function occurs at the molecular level. You can develop a better understanding of the properties of cells and tissues by studying the molecular mechanisms common to the cells involved:
- Molecular level — actin and myosin
- Microscopic level — sarcomere and myofibrils
- Cell level — myoblasts and myofibers
- Tissue level — neuromuscular junctions and fascicles
- Organ level — major skeletal muscles of the body
Molecular Level—Actin and Myosin
Myosin is a protein that converts the chemical energy stored in the bonds of ATP into the kinetic energy of movement. Myosin is the force-generating protein in all muscle cells, and a coordinated effort among many myosin molecules pulling on actin, generates force for movement. Myosin molecules have two main structural parts. The tail of a myosin molecule consists of two polypeptide subunits wound together, whereas the head is composed of two globular subunits. The tail of a myosin molecule connects with other myosin molecules to form the central region of a thick filament, whereas the heads align on either end of the thick filament where thin filaments overlap with the thick filament. The point at which the head and tail of the molecule meet is flexible and allows the head to move back and forth. This allows myosin to “walk” and pull on actin filaments. Actin filaments are made of individual globular (spherical) protein subunits that assemble linearly into helical (twisted) filaments.
ATP binding to myosin causes it to release actin, allowing actin and myosin to detach from each other. After this occurs, ATP is converted to ADP and Pi. The binding site on myosin that hydrolyzes ATP to ADP is called ATPase. The energy released during ATP hydrolysis changes the angle of the myosin head into a “cocked” position. The myosin head is then in a position for further movement, possessing potential energy; however, ADP and Pi are still attached.
Cross-bridge formation occurs at this point, as actin binds while ADP and Pi are still bound to myosin. Pi is then released, causing myosin to form a stronger attachment to actin, and the myosin head moves toward the M line, pulling actin along with it. As actin is pulled, the filaments move approximately 10 nanometers toward the M line. This movement is called the power stroke, as the thin filament “slides” over the myosin and ADP is released during this step.
When the myosin head is “cocked,” myosin is in a high-energy configuration. This energy is expended as the myosin head moves through the power stroke. At the end of the power stroke, the myosin head is in a low-energy position. Each myosin molecule may form many cross-bridges during muscle contraction. The collection of power strokes and cross-bridges allows collections of individual molecules to generate large forces.
In skeletal muscle, tropomyosin and troponin regulate contraction by controlling the interaction between actin and myosin filaments. Tropomyosin acts to block myosin binding sites on the actin filament, preventing cross-bridge formation and thus preventing contraction in a relaxed muscle. Calcium triggers muscle contraction by binding to troponin and altering its shape so that tropomyosin does not block the myosin binding sites on actin, thus allowing muscle contraction to occur. Calcium is generally an important molecule in muscle function, as we will discuss later.
Titin, as the name implies, is a very large structural protein in muscle cells. Unlike actin and myosin, which bundle together to form a multiprotein complex, titin is a single protein that holds large structures together. Thus, titin is a large, multifunctional protein (hundreds of times bigger than these other proteins) that forms an elastic filament. Titin helps align the myosin proteins and allows the muscle cell to maintain structural integrity by resisting extreme stretching, preventing damage due to overstretching.
Dystrophin is a protein that helps bind actin to the muscle cell membrane. Insufficient dystrophin production results in an inability to transfer the force of the organized actin-myosin contraction to the muscle cell membrane and ultimately to the tendons. Loss or insufficient production of this molecule causes Duchenne muscular dystrophy (DMD).
At the end of the power stroke, the actin-myosin cross-bridge is still in place (until ATP binds to the myosin head to change its shape). When energy is depleted, ATP is no longer available to bind to myosin; without ATP, actin remains bound to myosin, making both relaxation and further contraction impossible. This state, with an intact cross-bridge and depleted ATP, is called rigor.
This situation is exemplified during rigor mortis, which occurs after death. Dead cells can no longer produce ATP. Without ATP, the myosin heads can not detach from actin. Recall that ATP is required for the myosin to come off of the actin. Rigor mortis eventually subsides as proteins in the body, including actin and myosin, degrade.
Microscopic Level—The Sarcomere
The fundamental functional unit of muscle is called a sarcomere. One muscle may contain as many as 100,000 of the repeating sarcomere units. In the sarcomere, the myofilaments (thick filaments and thin filaments) are organized into parallel units. Sarcomeres were first identified by imaging (histology), and the nomenclature described below reflects their microscopic “appearance.”
Molecular Organization of Muscle
Myofilaments are organized structures in muscle cells that contain the actin and myosin. The organized globular proteins of actin in muscle cells form a thin filament, and bundles of over 200 myosin proteins form a thick filament. The thick filament myosin heads “walk” along the actin thin filaments. A single thin filament is composed of 300-400 globular actins with 40-60 troponin and tropomyosin molecules. A single thick filament is composed of more than 200 myosin molecules.
Actin filaments are thin, causing the actin “rope” to appear skinny. The myosin filament contains many myosins bundled up with all of the head groups sticking out, so that it looks “fluffy.” That fluffiness makes it look thick.
Sarcomere Anatomy—H Zone, M Line, Z Disc, I Band and A Band
Histological sections of muscle show the anatomical features of the sarcomeres. Thick filaments, composed of myosin, are visible as the A band of a sarcomere. Thin filaments, composed of actin, attach to a protein in the Z disc (or Z line) called alpha-actinin, and they are present across the entire length of the I band and a portion of the A band. The region where thick and thin filaments overlap has a dense appearance, as there is little space between the filaments. This zone where thin and thick filaments overlap is very important to muscle contraction, as it is the site where filament movement starts. Thin filaments do not extend completely into the A bands, leaving a central region of the A band that only contains thick filaments. This central region of the A band looks slightly lighter than the rest of the A band, and is called the H zone. The middle of the H zone has a vertical line called the M line, where accessory proteins hold together thick filaments.
Microscopic Level—Organelles and Cell Structures
Cellular Organelles and Structures
Muscle cells contain organelles found in all cells, including nuclei, the endoplasmic reticulum, mitochondria and the Golgi apparatus. The amount and organization of organelles and structures is slightly different in muscle cells. Actin is found inside every cell in the body, but actin is specially organized within the sarcomeres of muscle cells. Muscle cells also have extremely high numbers of mitochondria to produce ATP for force generation. Recall that an ATP molecule is required for one myosin to perform one power stroke.
Click here to review cells and organelles in the Levels of Organization unit.
Organelles and Structures Specific to Muscle Cells
Each skeletal muscle fiber is a single cell produced from the fusion of many precursor cells. These fused cells are therefore functionally quite large, with diameters of up to 100 micrometers and lengths of up to 30 centimeters. Compare this with a cell of the skin which is a cube of 20 micrometers in nearly every diameter. In muscle fibers, sarcomeres arrange into parallel structures called myofibrils, so both the Z disc and the M line hold myofilaments in place to maintain the structural arrangement and layering. Myofibrils are connected to each other by intermediate, or desmin, filaments that attach to the Z disc.
There is some special nomenclature associated with these fused cells. Each skeletal muscle fiber cell has more than one nucleus, which is called multinucleate. The plasma membrane of this fused skeletal muscle cell is called the sarcolemma. The muscle interacts with the nerves that stimulate the muscle at the sarcolemma, and we will describe this interaction later. Within the sarcolemma is the sarcoplasm, which is the cytoplasm of the fused muscle fiber. The sarcoplasm has most of the same components as standard cytoplasm in addition to high levels of the protein myoglobin, which stores oxygen.
Also, the sarcolemma contains many structures similar to the plasma membrane of other cells, but it also possesses structures unique to muscle cells. The sarcolemma has transverse tubules, or T tubules, which are indentations of the sarcolemma into the interior of the cell along the length of the muscle cell. The T tubules are filled with extracellular fluid, and they conduct the action potential from the nerve deep into the interior of the muscle cells, which can be very large. With T-tubules, nerves can stimulate entire muscles and muscle groups quickly and effectively. Without T tubules, action potential conduction into the interior of the cell would happen much more slowly, causing delays between neural stimulation and muscle contraction, resulting in slower, weaker contractions.
Inside skeletal muscle fibers is a network of membranous tubules called the sarcoplasmic reticulum (SR), which is similar to the smooth endoplasmic reticulum found in other cells. SR tubules are filled with high-calcium fluid, and they surround each myofibril. Terminal cisternae are dilated regions of the SR that form on either side of each T tubule extending into the cell. A grouping consisting of a T tubule, from the outside of the muscle fiber, and two terminal cisternae, from the inside of the muscle fiber, is called a triad.
T tubules conduct an action potential along the surface of the muscle fiber into triads that trigger the release of Ca2+ ions from the nearby terminal cisternae. This, in turn, triggers muscle contraction when the calcium ions in the sarcoplasm can bind to the troponin of the sarcomeres.
Skeletal Muscle Cells
Skeletal Myocytes—Myoblast Fusion, Myotube Organization in Skeletal Muscle Tissue and Satellite Cells
Each skeletal muscle fiber is a single skeletal muscle cell, also known as a skeletal myocyte (“myo-” refers to “muscle” and “-cyte” refers to “cell”), that is formed from the fusion of precursor cells. As described before, cell fusion leads to multinucleation of each mature muscle fiber. Each myoblast, the embryonic cell type that differentiates into muscle, contributes one nucleus when the muscle fiber is formed during development.
During development, individual myoblasts (“-blast” refers to “building” … like osteoblasts), migrate to different regions in the body and then fuse to form a myotube. A myotube is a type of syncytium, which is the term used for a group of fused cells. Skeletal muscle cells are multinucleate because the syncytium (“syn-” means “same” and “cyt” refers to “cytoplasm”) fusion retains the nucleus of each contributing myoblast. This syncytium leads to the collective sarcoplasm and sarcolemma, described above.
Mature muscle does not grow by this process. Mature cells can change in size, but new cells are not formed when muscles grow. Instead, structural proteins are added to muscle fibers in a process called hypertrophy. The reverse, when structural proteins are lost and muscle mass decreases, is called atrophy. Cellular components of muscles can also undergo changes in response to changes in muscle use.
Although the number of muscle cells is set during development, satellite cells help to repair skeletal muscle fibers. Satellite cells are similar to myoblasts in that they are able to divide, fuse and differentiate. These satellite cells are located outside the muscle fibers and are stimulated to grow and fuse with muscle cells by growth factors that are released by muscle fibers under certain forms of stress. Satellite cells can regenerate muscle fibers to a very limited extent, but they primarily help to repair damage in living cells. Satellite cells facilitate the protein synthesis required for repair and growth. If a cell is damaged to a greater extent than can be repaired by satellite cells, the muscle fibers are replaced by scar tissue in a process called fibrosis. Because scar tissue cannot contract, muscle that has sustained significant damage loses strength and cannot produce the same amount of force or endurance as it could before being damaged.
Cardiac Muscle Cells
Cardiac tissue is only found in the walls of the heart chambers, where it provides the muscle contractions required to pump blood throughout the body. At the tissue level, cardiac muscle is striated (or striped) since, like skeletal muscle, it has organized sarcomeres. However, cardiac muscle fibers are shorter than skeletal muscle fibers and usually contain only one nucleus, which is located in the central region of the cell.
Cardiac muscle fibers are branched, whereas skeletal muscle fibers are unbranched. This branching allows individual cells to contact several adjacent cells at specialized cell junctions called intercalated discs. Intercalated discs are part of the sarcolemma and contain two structures important in cardiac muscle contraction: gap junctions and desmosomes. Gap junctions are tunnels or protein channels in the cell membrane connecting adjacent cardiac muscle cells, allowing ions involved in electric currents to move quickly from one cell to the next. This is called electric coupling, and in cardiac muscles, it allows the quick transmission of action potentials and synchronized contraction of the entire heart. Desmosomes are especially strong cell-to-cell junctions that help maintain structural integrity at the connections between these contractile cardiac muscle cells.
Cardiac Cell Specialization
There are two specialized types of cardiac cells: the contractile cells and the pacemaker cells. The contractile cells that produce the force for the beating of the heart have the capability to beat on their own, but for useful organ level contractions, the cells must beat as a unit. The stimulus for contraction is normally provided by the pacemaker cells and this stimulus is passed through gap junctions to synchronize the signals. These electrically conductive pacemaker cells are important for electrical stimulation since cardiac muscle cells are not under voluntary control. Pacemaker cells are spontaneously depolarizing at set intervals (faster than contractile cells would do on their own), starting a wave of depolarization that then spreads throughout the heart and triggers contraction. Because the pacemaker cells are located in the heart, the heart is said to control its own contraction, which is called autorhythmicity (or automaticity). Pacemaker cells depolarize at set intervals, and the heart beats a steady, predictable 60 to 80 beats per minute at rest. These repetitive contractions ensure a constant blood supply to all body cells.
Smooth Muscle Cells
Smooth muscle tissue is found in many different body systems, including as part of organs in the digestive, respiratory, and reproductive tracts and in the walls of blood vessels. Smooth muscle cells are approximately the same size as cardiac muscle cells and also have only one nucleus. However, smooth muscle cells are not branched and, unlike both cardiac and skeletal muscle, smooth muscle cells don’t have sarcomeres. Smooth muscle cells form layers that are usually arranged so that one runs parallel to an organ and the other wraps around it. These two muscle layers then contract in turn, causing alternating dilation and contraction or lengthening and shortening of the organ, moving substances through internal passages. This is called peristalsis and is displayed in the process of digestion as food moves through the gastrointestinal tract.
Similar to skeletal and cardiac muscle cells, smooth muscle can undergo hypertrophy to increase in size. Unlike the other two muscle types, mature smooth muscle cells can also divide to produce more cells, a process called hyperplasia. This can be observed in the uterus, which responds to increased estrogen levels by producing more uterine muscle cells.
Smooth muscle cells also do not possess T tubules and do not have a very extensive sarcoplasmic reticulum. Smooth muscle has actin and myosin but they are not organized into sarcomeres, so there are no obvious bands or striations. Instead, actin and myosin is organized into dense bodies attached to the sarcolemma, shortening the muscle cell as thin filaments slide past thick filaments. Thin and thick filaments are aligned in a diagonal pattern across the cell so that contraction produces a twisting or corkscrew motion, rotating one way as it contracts and the other way as it relaxes. Cross-bridge formation and filament sliding processes are the same in smooth muscle as they are in skeletal and cardiac muscle. Actin, myosin, and tropomyosin are all present, but smooth muscle cells do not possess troponin as their regulatory protein. Instead, a molecule called calmodulin binds to calcium and activates myosin cross-bridge formation. There is also a greater ratio of actin to myosin in smooth muscle, meaning that there are more thin filaments for every thick filament.
Most smooth muscles must function for long periods without rest, so their power output is relatively low, but contractions can continue without utilizing large amounts of energy. This occurs because the ATPase in myosin works at a relatively slow rate, meaning that high levels of ATP are not available for powerful contractions but a steady supply is produced for sustained contractions. Smooth muscle can also maintain contractions through a latch state, during which actin and myosin remain locked together, or latched, in the absence of Ca2+ ions. This does not require ATP, thereby producing sustained contractions without using energy. This allows smooth muscles to keep your blood vessels partially contracted for your entire life without them fatiguing.
Similar to cardiac muscle, smooth muscle is not under voluntary control. In addition to spontaneous stimulation, smooth muscle can be stimulated by pacesetter cells that are similar to pacemaker cells and trigger waves of action potentials in smooth muscle. Smooth muscle can also be stimulated by the autonomic nervous system or hormones. Neuromuscular junctions are not present in smooth muscle, but varicosities, enlargements along autonomic nerves, release neurotransmitters into synaptic clefts. Smooth muscle can respond to a variety of neurotransmitters to produce different effects at different locations.
Smooth muscle can be divided into two types based on how depolarization and muscle contraction occur. Single-unit smooth muscle cells contain gap junctions, which allow the cells to be electrically coupled. Electric couplings allow action potentials to spread quickly from one cell to the next, permitting coordinated depolarization and contraction. In this manner, groups of muscle cells act as a single unit, contracting in unison. This type of smooth muscle is found in hollow organs, including the gastrointestinal tract, and in the walls of small blood vessels, and it is often stimulated spontaneously or by stretching, to produce an action potential.
Multiunit smooth muscle cells rarely possess gap junctions, so they are not electrically coupled. Stimuli for multiunit smooth muscles come from autonomic nerves or hormones but not from stretching. This type of tissue is found in the walls of large blood vessels, in the respiratory airways, and connected to hair follicles (to make your hair “stand up”), among other places.