Muscle Structure

Skeletal muscle connects the various parts of the skeleton through one or more connective tissue tendons and is the type of muscle used to produce movement or force during physical activity or exercise. During muscle contraction, skeletal muscle generates tension, which may involve shortening of the muscle (concentric contractions), lengthening of the muscle (eccentric contractions), or no change in muscle length (isometric contractions). Movement of the limbs is associated with concentric and eccentric contractions, but not with isometric contractions.

Muscle cells are called muscle fibers. Each skeletal muscle fiber is produced by the fusion of many immature myoblasts to form a multinucleated cylinder-shaped cell. The muscle fiber is contained within the cell’s plasma membrane covered by an outer connective tissue sheath; the muscle fiber’s plasma membrane is called the sarcolemma, and the outer layer of connective tissue is called the endomysium (Figure 20-1, C). The endomysium contains capillaries, nerves, and lymphatics. The sarcoplasm of each muscle fiber contains an array of cylindrical contractile filaments called myofibrils that are stacked lengthwise and run the entire length of the fiber, being connected to the cell surface membrane at each end. The nuclei are pressed against the outer edges of the fiber, adjacent to the sarcolemma. The mitochondria are located between the myofibrils, as are the intramyocellular lipid droplets and glycogen granules (Figure 20-2). At each end of the muscle fiber, the surface layer of the sarcolemma fuses with a tendon fiber, and the tendon fibers in turn collect into bundles to form the muscle tendons that then attach to bones.

Each myofibril is about 1 μm in diameter, extends along the complete length of the muscle fiber, and is composed of contractile units called sarcomeres that are attached end to end (Figure 20-1, D). Each sarcomere contains thick filaments (diameter of ~15 nm) that contain myosin and thin filaments (diameter of ~5 nm) that contain actin, with the thick and thin filaments overlapping in a structured way. In addition to actin and myosin, skeletal muscle sarcomeres also contain other proteins, such as troponin and tropomyosin, which are necessary for muscle contraction, and nebulin and titin, which give structure and stability to the sarcomere. In skeletal muscle, the sarcomeric subunits of one myofibril are in nearly perfect alignment with those of the myofibrils next to it. This alignment forms bands of alternating high and low refractive index that gives skeletal muscle its striated appearance.

Ten to more than 100 muscle fibers are bundled into fascicles, and each fascicle is covered by a sheath of connective tissue called perimysium (see Figure 20-1, B). Fascicles are, in turn, grouped together to form a muscle, which is covered by a layer of connective tissue that ensheathes the entire muscle and is continuous with the tendons (see Figure 20-1, A). The size, number, and arrangement of fascicles within the muscle determine the strength and range of movement of a muscle.

Tunnel-like extensions of the sarcolemma, called tranverse tubules or simply T tubules, pass through the muscle fiber from one side of it to the other, forming rings around every sarcomere. The sarcoplasmic reticulum of the muscle fiber consists of tubules that run parallel to the sarcomeres from T tubule to T tubule. The sarcoplasmic reticulum serves as a repository for calcium ions (Ca²⁺). When a signal comes from the motor nerve activating the fiber, the neurotransmitter acetylcholine is released and travels across the neuromuscular junction. The action potential then travels along the T tubules until it reaches the sarcoplasmic reticulum, where it changes the permeability of the sarcoplasmic reticulum. Once a cell is sufficiently stimulated, the cell’s sarcoplasmic reticulum releases Ca²⁺, which then interacts with the regulatory protein troponin. Calcium binding by troponin results in a conformational change in troponin that leads to the movement of tropomyosin, uncovering the myosin-binding sites on actin. In resting muscle, myosin-binding sites on actin are obscured and myosin exists in a high-energy conformational state poised to carry out a contractile cycle. When myosin binding sites on actin are exposed, myosin and actin form a crossbridge or complex, which is followed by the dissociation of inorganic phosphate (P_i) and a conformational change in myosin that propels the attached actin filament toward the center (M-line) of the sarcomere (see Figure 20-1, D). The actomyosin complex then releases ADP, which is followed by ATP binding to the myosin of the actomyosin complex and breaking of the crossbridges. As soon as detachment occurs, myosin splits the ATP, reversing the conformational change performed while it was attached to actin and returning myosin back to its high-energy state. Repetition of these processes allows for myosin and actin crossbridge cycling, which in turn leads to the generation of tension or fiber contraction.

Muscle Fiber Types

Individual human muscles are a mixture of muscle fiber types that are differentiated by their myosin heavy chain isoform expression (Canepari et al., 2010). A particular motor unit innervates only one type of muscle fiber within the muscle (see Figure 20-1, E). In fact, the muscle fiber type and myosin heavy chain (MHC) isoform expression depends on the motor neuron axon supplying that particular fiber.

Myosin is a motor protein that moves along actin filaments while hydrolyzing ATP. The skeletal muscles of human adults contain three isoforms of MHC: MHC-1, MHC-2A, and MHC-X, which are encoded by MYH7, MYH2, and MYH1, respectively. Rodents, but not adult humans, express MHC-2B. The myosin heavy chain isoforms are important determinants of the contractile characteristics of the muscle fibers, because the heavy chain is the portion of myosin that attaches to actin and hydrolyzes ATP. The myosin isoforms differ in their rate of release of ADP during the attachment to actin and therefore have different attachment times. Characteristics of muscle fibers that express type 1, type 2A, and type 2X MHC are given in Table 20-1. Hybrid fibers that contain type 1/2A or type 2A/2X MHC isoforms also exist in human muscles.

Type 1 fibers have the relatively slow acting myosin isoform and hence contract slowly, but they have a high capacity for oxidative metabolism (many mitochondria and hence high activities of enzymes of the citric acid cycle, of fatty acid oxidation, and of the electron transport chain), a high content of intramyocellular triacylglycerols (IMTGs), high hormone-sensitive lipase activity, and moderate glycolytic capacity. Type 2A fibers possess a more rapidly acting myosin ATPase and thus have faster contraction times than type 1 fibers. Type 2A fibers have a high glycolytic capacity but also have a moderate oxidative capacity. Type 2X fibers have the fastest acting myosin ATPase and a very high glycolytic capacity but a low oxidative capacity. These type 2X fibers contain more glycogen and much less IMTG than do the type 1 fibers.

Although all three types of fibers are found within individual muscles, the proportions of fiber types vary depending on the action of that muscle. Although a mixture of fiber types is present within skeletal muscles, only one type of muscle fiber is contained within a particular motor unit. Therefore if a weak contraction is needed, only the type 1 motor units will be activated, whereas if a stronger contraction is needed, the type 2A fibers will also be activated to assist the type 1 fibers. Type 2X fibers are activated last and are needed for maximal contractions, but these fibers tire easily. In addition to increasing the number of contractile units simultaneously activated, the intensity of the overall muscle contraction can be increased by increasing the frequency at which action potentials are sent to muscle fibers.

It has traditionally been assumed that type 2 fibers are specialized to perform sprinting exercise, whereas type 1 fibers are more suited to perform endurance exercise. In agreement with this, the better sprinters tend to have a high percentage of type 2 fibers, whereas a marathoner may have a much higher percentage of type 1 fibers. Certainly, genetic factors play a role in determining fiber type distribution. In addition, muscle fibers display a degree of plasticity that allows them to reversibly change their biochemical and morphologic properties when exposed to different functional demands. For example, strength or resistance (low repetition, high load) training can lead to an increase in the myofibrillar volume (hypertrophy) of both type 1 and type 2 fibers. High-intensity endurance (high repetition, low load) training can increase the proportion of type 1 fibers (increase in mitochondrial and capillary density), but it does not result in an increase in fiber size. It is thought that both metabolic and mechanical signals are involved in bringing about these changes (Putman et al., 2004; Hoppeler and Flück, 2002).

The Energy Cost of Movement

Muscle shortening and movement are brought about by repeated formation of crossbridges between the thin (actin) and thick (myosin) filaments of the myofibrils. This process costs energy and requires hydrolysis of ATP by the myofibrillar ATPase. The contraction cycles are under nervous control. Whenever a sufficient number of nerve impulses during a limited time period arrive at the muscle fiber, the following sequence is set into action: (1) the plasma membrane is depolarized by a short-term loss of potassium ions (K⁺) and uptake of sodium ions (Na⁺) into the muscle fiber; (2) the formed action potential is propagated along the sarcolemma into the T tubules, where (3) the signal is transmitted to the sarcoplasmic reticulum; this then leads to (4) a rapid release of Ca²⁺ from the sarcoplasmic reticulum and a 1,000-fold increase in the cytosolic Ca²⁺ concentration. This increase in cytosolic Ca²⁺ leads to (5) crossbridge formation between the actin and myosin filaments of the myofibrils and (6) activation of the myofibrillar ATPases, which couple ATP hydrolysis with breaking the formed crossbridges. The cytosolic Ca²⁺ concentration simultaneously is reduced again by the action of the calcium ATPase in the sarcoplasmic reticulum, and the muscle is ready for the next contraction.

The myofibrillar ATPase, the Na⁺, K⁺-ATPase (needed to restore the membrane potential following a depolarization), and the Ca²⁺-ATPase are all much more active during exercise than at rest, resulting in consumption of large amounts of ATP. A muscle can in seconds increase its aerobic ATP turnover rate by more than a hundredfold. The higher the exercise intensity, the more contraction cycles are needed per unit of time, the greater the amount of ATP that needs to be synthesized per unit time, and the higher the amount of fuel that needs to be oxidized. Energy expenditure of skeletal muscle therefore is greatly influenced by the increased contractile activity needed to walk, work, or run.

At rest, whole-body energy expenditure of humans is about 80 watts or 68 kcal/hour (comparable to that of a light bulb), with approximately 25% (20 watts or 17 kcal/hour) being expended in the skeletal muscles. Energy expenditure during a marathon run covering 42 km in a little over 2 hours is about 20 times resting energy expenditure (1,600 watts or 1,377 kcal/hour). Because more than 90% of the increase in energy expenditure originates from fuel oxidation in the active muscle (part is needed for the cardiovascular response), and assuming that maximally about one half of skeletal muscle mass is actively used in running a marathon, the energy expenditure of this active half of skeletal muscle can be estimated to increase by more than 130-fold (from 10 watts to 1,368 watts), as shown in Figure 20-3. Skeletal muscle must therefore have powerful mechanisms to increase the rates of ATP synthesis and fuel oxidation. In an individual running a marathon, most of the required ATP is produced by aerobic oxidation of carbohydrate and fat.

A top-class sprinter during a 100-m sprint can achieve a power output of around 3,600 watts, which is approximately 45 times the resting energy expenditure. Because more than 95% of the increase in energy expenditure originates from increased fuel metabolism in the active muscle during a sprint, the energy expenditure of the active muscle is estimated to increase by more than 300‑fold. Most of the ATP for a 100-meter sprint is produced anaerobically by net breakdown of muscle creatine phosphate and by conversion of muscle glycogen to lactate.

Skeletal Muscle Fuel Utilization During Rest

Resting skeletal muscle needs less energy for maintenance per kilogram than that needed by such tissues as liver, gut, or kidney. The latter tissues not only have to take care of their own maintenance but also serve many essential functions in whole-body metabolism (e.g., digestion, absorption, fluid retention, urea synthesis, and lipoprotein synthesis) and are the sites of synthesis of many export proteins (e.g., albumin, fibrinogen, apolipoproteins, and digestive enzymes). Apart from a few muscles that are active continuously in the maintenance of posture, skeletal muscles in resting conditions have low energy expenditures. At rest, energy in the form of ATP is required for basic functions, including the maintenance of electrolyte and calcium gradients via ATP-dependent ion pumps, the maintenance of amino acid gradients (much higher intracellular than extracellular concentrations), the replacement of fuel stores lost via oxidation (glycogen and intramuscular triacylglycerols), the operation of substrate cycles (e.g., the fructose 6-phosphate/fructose 1,6-bisphosphate cycle and the triacylglycerol/free fatty acid cycle), and the maintenance of protein turnover (the continuous synthesis and breakdown of proteins). Even from the point of view of protein turnover, skeletal muscle needs less energy than abdominal tissues because the mean turnover rate of skeletal muscle protein (0.05% per hour) is lower than that of most other proteins of the human body and much lower than that of the intracellular and export proteins of liver and gut (e.g., apolipoprotein B‑100, which is synthesized in the liver, with a turnover rate of 16% per hour). Therefore the need for ATP synthesis during rest is easily met by aerobic metabolism. For these reasons, skeletal muscle oxygen consumption constitutes only about 20% of whole-body oxygen consumption during resting conditions, despite the fact that the skeletal muscle compartment constitutes about 40% to 50% of body mass in a lean individual.

Skeletal muscle oxidizes a mixture of carbohydrate and fat even at rest. Although the impact of resting skeletal muscle gas exchange on the whole-body respiratory quotient (RQ) is small, measurements of the arteriovenous difference for oxygen and carbon dioxide across skeletal muscle have demonstrated the relative importance of fat and carbohydrate as fuels for the resting muscle. Himwich and Rose (1927), using such techniques in dogs, observed that the RQ of skeletal muscle in fed dogs was about 0.92, whereas the RQ of skeletal muscle in starved dogs was 0.80 and lower. The RQ is defined as moles CO₂ produced/moles O₂ consumed, and it is usually measured as volume of CO₂ produced/volume of O₂ consumed (see Chapter 21). Because an RQ of 1.00 indicates 100% carbohydrate oxidation and a value of 0.70 indicates 100% fat oxidation, it is clear that skeletal muscle at rest always oxidizes a mixture of carbohydrate and fat, even though the proportions vary substantially. This finding has been confirmed in humans on many occasions, using the same technique.

As discussed in Chapter 19, skeletal muscle of insulin-sensitive individuals is able to adapt to changes in fuel availability in response to meal intake or fasting and uses proportionately more glucose during the postprandial period and more fatty acids during the postabsorptive period. Carbohydrate is the main fuel for resting skeletal muscle in the fed situation, whereas fat oxidation accounts for two thirds or more of oxygen consumption in the postabsorptive and fasted situation. The transition from the fed to the fasted state is carefully controlled, as described in Chapters 12, 16, and 19.

Blood-borne fuels are sufficient for resting muscle. Plasma glucose is the major source of carbohydrate for oxidation in skeletal muscle at rest, particularly in the postprandial state. Plasma glucose originates from the diet in the first hours after a meal and originates from the liver in the postabsorptive or fasted state. The breakdown of liver glycogen to glucose is the major source of hepatic glucose output in the first 16 hours of fasting, whereas gluconeogenesis from glycerol and amino acids becomes the primary source of hepatic glucose output after 16 to 24 hours of fasting. The resting muscle uses mainly fatty acids during fasting, which originate from adipose tissue lipolysis and from very-low-density lipoprotein hydrolysis by muscle lipoprotein lipase. Fat oxidation by muscle is increased and carbohydrate disposal is decreased when the availability of fatty acids is increased by feeding high-fat diets or by infusion of lipids. Likewise, glucose infusion or loading can increase the muscle’s utilization of glucose as fuel. Intramuscular fuels are relatively unimportant for resting muscle, so breakdown of muscle glycogen or of IMTG makes a minimal contribution to the energy needs of resting muscle.

Fuel Utilization by Working Muscle

Along with the increased energy expenditure by muscle when muscle is used to perform work, the fuel needs of muscle increase dramatically. At the onset of physical activity, signals from inside and outside the muscle fibers increase the availability of both carbohydrate and fat fuels as well as the ability to upregulate oxidation of both fuels simultaneously.

The fuel requirements of working muscle and the particular fuels that meet those energy requirements depend to a large extent on the intensity of the work being performed. The intensity of muscular work is often defined relative to a person’s maximum aerobic capacity (VO_2max). VO_2max is a measure of the maximum volume of O₂ consumption. The maximal aerobic work rate is defined as 100% VO_2max. To exert a more intense effort, the fast glycolytic muscle fibers must be recruited. These fast glycolytic fibers function anaerobically using creatine phosphate and muscle glycogen as fuels, which is accompanied by lactate production. The extent to which an activity is primarily aerobic or primarily anaerobic depends on its intensity relative to the individual’s capacity for that type of physical activity.

Physiological Changes that Accompany Physical Activity

The onset of exercise results in changes in circulating hormone levels, an increase in blood flow to the working muscle, changes in muscle cytosolic Ca²⁺ concentration, and changes in the AMP/ATP ratio of the myocytes. These changes are responsible for many of the changes in fuel availability and fuel utilization that accompany an increase in physical activity.

Glucagon Increases Hepatic Glucose Production

With the onset of exercise, there is a fall in plasma glucose level (Figure 20-4). In response to the fall in the plasma glucose level, glucagon secretion from the pancreatic alpha cells increases during exercise, whereas insulin secretion from the pancreatic beta cells decreases (Figure 20-5). The increase in glucagon is the primary stimulator of hepatic glucoenogenesis during exercise. Berglund et al. (2009) showed that increasing glucagon in sedentary mice to levels similar to those seen during exercise caused a marked discharge of hepatic energy stores so that the AMP to ATP ratio increased. This increase in the AMP to ATP ratio presumably acts at least partially through activation of AMP-activated protein kinase (AMPK), as well as through allosteric mechanisms, to stimulate breakdown of glycogen in the liver. Glucagon is released from the pancreas into the portal circulation and may be largely removed by the liver before the blood reaches the arterial circulation, so that an increase in glucagon levels in the systemic circulation may not always be detected (Wasserman et al., 2011). Catecholamines do not seem to directly play an important role in increasing hepatic glucose production during exercise, although catecholamines can increase glucagon secretion. Thus during exercise, glucagon is important in stimulating hepatic glycogenolysis to maintain plasma glucose levels.

Catecholamines Stimulate Lipolysis and Use of Intracellular Fuels

The main stimuli to fat mobilization during exercise are the catecholamines, epinephrine and norepinephrine. Circulating catecholamine levels are regulated by the sympathoadrenal system. Current evidence indicates that the adrenergic stimulation of lipolysis during exercise is due mainly to circulating catecholamines rather than to sympathetic innervation of adipose tissue (Stallknecht et al., 2001; de Glisezinski et al., 2009). As shown in Figure 20-5, plasma catecholamine concentrations increase markedly with exercise (Hiscock et al., 2005; Febbraio et al., 2004). The fall in plasma insulin levels during exercise also creates a lipolytic environment and likely reinforces the effects of catecholamines. Growth hormone and glucocorticoids may also play a role, especially in prolonged exercise.

The consequence of this stimulation of adipose lipolysis during exercise is an increase in the rate of free fatty acid appearance in the plasma. The release of fatty acids into the plasma is typically two to three times that observed at rest. Because the release of free fatty acids is greater than the rate of total free fatty acid oxidation by the whole body, the plasma free fatty acid level increases above resting levels (see Figure 20-5). A portion of the free fatty acids released by adipose lipolysis can be reesterified, mainly in the liver where triacylglycerol synthesis is important for secretion of very-low- density lipoprotein (VLDL) triacylglycerol. Thus increased adipose lipolysis during exercise results in increased provision of both plasma free fatty acids (i.e., bound to albumin) and esterified fatty acids in the triacylglycerols of plasma lipoproteins.

The increased level of catecholamines also stimulates the use of the glycogen and triacylglycerol stores within the muscle fibers. Skeletal muscle fibers have β-adrenergic receptors that are activated by epinephrine and norepinephrine, and the intracellular cAMP-signaling pathway stimulates lipolysis of the IMTG and breakdown of glycogen to glucose phosphate for use by the muscle fiber. Therefore working muscle is able to use internal lipid and glycogen fuel stores and the circulating fuels supplied to the working muscle by the liver, adipose tissue, and diet.

Blood Flow to the Muscle Is Increased

Muscle blood flow is markedly increased with exercise. Local arterioles compensate for this by dilating and allowing more blood to reach the tissue, resulting in more delivery of oxygen and blood-borne fuels to working muscle as well as increased surface area for exchange due to increased capillary perfusion.

Stimulation of Muscle Contraction Results in Increases in Muscle Cytosolic Ca²⁺ Concentration and AMP/ATP Ratio

The stimulation of muscle fibers results in large increases in the cytosolic concentration of calcium ions, which in turn promotes muscle contraction. Muscle contraction and maintenance of ion fluxes require large expenditures of ATP. Thus both the cytosolic Ca²⁺ concentration and the AMP/ATP ratio are elevated in working muscle fibers. The levels of free ADP, free AMP, and P_i are particularly likely to be elevated during the first minutes of exercise before blood flow to the muscle is increased and the muscle is able to function aerobically, during prolonged endurance activity, and during work at super maximal intensities. Note that most of the AMP and ADP in muscle is bound to myosin and actin; “free” refers to the portion of these nucleoside phosphates that is not bound to proteins and hence is available for metabolic regulation.

The increase in free AMP level leads to activation of AMPK in skeletal muscle. AMPK acts as a sensor of cellular energy status and is activated by metabolic stresses, such as a decrease in substrate supply (as discussed in Chapter 19) or an increase in energy demand (such as muscle contraction), both of which increase the AMP/ATP ratio. The increases in cytosolic Ca²⁺ that accompany muscle contraction can also activate AMPK independently of adenine nucleotide changes. Once activated, AMPK acts on its downstream target proteins to alter metabolism in the working muscle to promote utilization of both glucose and fatty acids as fuels.

AMPK Overrides the Fatty Acid–Glucose Cycle and Permits Upregulation of Both Glucose and Fat Utilization

One of the targets of AMPK is the inhibitory phosphorylation of acetyl-CoA carboxylase (ACC2) to prevent malonyl-CoA formation which would block transport of fatty acids into the mitochondria. This action of AMPK essentially overrules the biochemical mechanisms involved in the glucose–fatty acid cycle, so that glucose oxidation by muscle no longer inhibits concurrent fatty acid oxidation. AMPK may also mediate enhanced secretion of lipoprotein lipase (LPL) and enhanced translocation of CD36 fatty acid transporter to the plasma membrane, both of which would favor fatty acid uptake by muscle.

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