Decrease in the size of muscle fibers and reduction of muscle mass are the hallmark of muscle atrophy. In a lower motor neuron lesion, the atrophy is regional and related to the particular nerve or root. Atrophy associated with muscle disease is more pronounced in the proximal muscles. The atrophy of disuse is generalized or localized to the immobilized limb(s) and more prominent in the antigravity muscles. It is a consequence of the limited physical activity and musculoskeletal loading that occurs during immobilization, immobility, bed rest, or exposure to microgravity during space flight. As a general rule, increased muscular activity leads to hypertrophy, whereas limited physical activity leads to disuse atrophy and weakness. The changes in muscle fiber size either in atrophy or in hypertrophy and phenotype changes of muscle fibers are the results of remarkable muscle plasticity and adaptability to external physical demands to generate adequate or peak contraction and endurance.

Disuse atrophy is defined as an alteration of metabolism and muscle cell homeostasis in response to muscle inactivity. Recent studies indicate that muscle protein synthesis as well as whole body protein production is significantly reduced during immobility and is considered the main contributor to muscle atrophy. The rate of muscle wasting during bed rest is slow during the first 2 days but becomes rapid thereafter. By 10 days, it reaches 50% of eventual muscle weight loss. Similarly, muscle protein synthesis is reduced to 50% of the baseline level at 14 days of immobilization and then gradually tapers off to reach a new steady state (6). Reeves et al. (7) studied skeletal muscle changes in healthy men exposed to microgravity condition and found a decrease in calf muscle volume by 29%, resting fascicle length of medial head of gastrocnemius and their pennation angulation by 10% and 13%, respectively, and physiological cross-sectional area (PCSA) by 22%. In disuse atrophy, especially if muscle is immobilized in a shortened position, that is flexion, the number of sarcomeres in series is reduced as a result of diminished chronic stretch and adaptation of the muscle to a new resting length. By contrast, immobilization in an elongated muscle resting position or during musculoskeletal growth increases the number of sarcomeres in series (8). In addition, the number of sarcomeres in parallel is reduced contributing to the reduction of muscle fiber PCSA (muscle volume/fascicle length) (9). From data obtained on the
PCSA, the reduction in the number of sarcomeres in parallel is twofold greater than reduction of sarcomeres in series. This indicates that reduction of isometric strength is in proportion to the loss of total number of sarcomeres in parallel and that they are more affected by disuse (9).

Disuse atrophy of type I and type IIa muscle fibers is more prominent than type IIb fiber atrophy during immobility. The mean size of type I fibers in human soleus muscle is decreased by 12% and 39% at 2 and 4 months of bed rest, respectively. This reduction could be prevented by simulating gravity loading for 10 hours a day in supine position (10). Individual muscle thickness can be clinically measured in vivo for some muscle by ultrasound scanning. Using this technique, the reduction of muscle thickness after 20-day bed rest is on average -2.1% to -4.4% and varies significantly for different muscles of the lower limbs (11). Magnetic resonance imaging (MRI) studies have, however, revealed much greater percentages of atrophy of the muscles in the lower limbs with the same duration of bed rest (12). Furthermore, consecutive MRI studies of thigh and calf muscles revealed that cross-sectional area and muscle volume of the gastrocnemius and soleus muscles were reduced to a greater extent than knee extensors and flexors (-9.4% to -10.3% vs. -5.1% to -8.0%) after 20 days of bed rest (12). However, using specific tests, the mean cross-sectional area reduction for the dark adenosine triphosphatase (ATPase) and light ATPase fibers is 46% and 69%, respectively, after 20 days of immobility (13).

Along with muscle fiber atrophy, the synthesis of collagen fibers is also reduced, although this reduction is much less than the reduction in synthesis of muscle proteins. This leads to a relative increase of muscle collagen content and changes in its mechanical elastic properties. The increase in muscle stiffness and alteration in viscoelastic properties of plantar flexors during space flight correlated with the duration of the flight, but the changes were less prominent than during bed rest (14). In both situations, weight bearing is limited, but joint motion is free and abundant during space flights. In healthy subjects with normal mobility, the main resistance to excessive elongation of muscle fiber is due to resistance of the myofibrils and in a lesser part to the sarcolemma itself. Titin, a myofibrillar protein, appears to have a major role in providing resistance to passive elongation, and it is increased in immobility. When titin is chemically removed, this resistance to passive stretch is significantly diminished (14).

Prominent histochemical changes also occur in muscle during bed rest and immobility. Serum creatine kinase (CK) isomer and fibroblast growth factor release (after myofiber injury) are both reduced during bed rest, and this is proportional to the reduction in muscle fiber size. Resistance exercises during bed rest significantly increase the level of these factors and prevent muscle fiber atrophy, indicating that myofiber wound-mediated fibroblast growth factor may play an important role in disuse atrophy (15). Myostatin is a growth factor-beta protein that inhibits muscle synthesis and is increased during bed rest. After 25 days of bed rest, the total lean body mass declines by an average of 2.2 kg, and plasma myostatin-immunoreactive protein level increases by 12%. It is speculated that suppression of myostatin may prevent muscle atrophy during space flight (16).

The muscle mass loss associated with aging is called sarcopenia. It is a major cause of disability and frailty in the elderly population. Inactivity is one of the many factors responsible for development of sarcopenia, along with decline in number of alpha-motor neurons, reduction in growth hormone, inadequate protein intake, and chronic overproduction of catabolic cytokines. High-intensity resistance exercise can reverse sarcopenia, indicating that physical inactivity is a major risk factor for weakness in elders (17). Many articles have been written about functional decline in hospitalized and nursing-home patients. General deconditioning in elderly persons is a frequent cause of functional decline, falls, and increased dependency. Reconditioning takes much longer in the elderly than in younger persons.

Although the primary reason for atrophy is reduction of muscle protein synthesis, an increased protein breakdown with nitrogen loss is also found during immobility despite the fact that the major energy sources during bed rest are primarily derived from carbohydrates and fat. It is believed that decline of mitochondrial function and the reduction of protein synthesis are the main reasons for the onset and progression of disuse atrophy. However, in the later stages of disuse muscle atrophy, the process of protein degradation may become more prominent than decrease in protein synthesis. This may be aggravated by gastrointestinal mechanisms, such as loss of appetite and reduced intestinal absorption of protein. Although daily loss of nitrogen for an immobilized healthy person may reach 2 g/day, a nutritionally depleted person may lose as much as 12 g/day. Urinary excretion of creatine is minimal under normal conditions, except in pregnancy and infancy. The excretion of creatine is much greater in starvation, diabetes, muscular dystrophy, hyperthyroidism, and fever, as well as during immobility. Prolonged bed rest and weightlessness causes a significant increase in the excretion of both creatine and creatinine, the mechanism which is not well understood (18).

Muscle weakness, reduced endurance, and tolerance to work are the functional consequences of muscle atrophy. The maximal strength of a muscle can fall to 25% to 40% of baseline level when a person is exposed to minimal exertions over a 2- or 3-week period (19). During strict bed rest, muscles may lose 10% to 15% of their original strength per week and, over 4 weeks, 35% to 50%. The loss of strength is rapid after the first day of immobilization and reaches its maximum 10 to 14 days later (20). Resistance leg exercises performed above 50% of maximum every second day, for 20 minutes by healthy subjects on bed rest, can maintain the muscle protein synthesis at the same level as healthy subjects engaged in normal physical activity (21). A study on dynamic leg press training during bed rest demonstrated preservation of baseline cross-sectional area and strength for the knee extensors and flexors but not for ankle plantar flexors and ankle dorsiflexors. This can adversely affect functional locomotion, as ankle plantar flexion contributes to forward propulsion (22).

The loss of strength associated with disuse atrophy is more prominent in the lower limbs than in the upper limbs. Loss of muscle power during immobilization reaches -20% to -44% in knee flexors and extensors, comparing to an insignificant loss in the upper limbs of -5%. The decrease in peak muscle tension of knee flexors and extensor ranges from -19% to -26%, far more than the reduction in cross-sectional area of these muscles (-7%), indicating that loss of strength and power is proportionally greater than reduction in size of the respective muscles (23). The major contributors to the loss of strength and endurance in persons with disuse atrophy are the reduced number of myofibrils per fiber volume, reduction in size and number of mitochondria, muscle fiber nuclei, and reduction of sarcomeres in parallel (10).

Another aspect of disuse weakness is reduction of maximal instantaneous muscular power. It can be reduced to a greater extent than the peak muscle strength of one repetition maximum in bed rest subjects. The loss of strength has been well documented in immobility; however, the loss of explosive muscle power as measured by the maximal jump with both feet on force plate was only recently studied. After 45 days of bed rest, instantaneous muscular power was reduced 24%, and recovery required one and half months of remobilization (24). These findings indicate that specific training for instantaneous power should be considered during space flight or prolonged bed rest to preserve functions such as standing up, climbing, and performing transfer functions.

Decline in muscle twitch and tetanic tension parallels the decline in muscle strength. In rats, maximal tension obtained by electrical stimulation in the soleus muscle declined significantly after 6 weeks of immobilization (25). Changes in contractile forces of immobilized muscle are the result of diminished levels of myofibrillar proteins and also due to a reduction of sarcoplasmic reticulum calcium ion uptake, but not the rate of its release (26).

Multiple studies have demonstrated that prolonged inactivity causes a significant and progressive reduction in muscle endurance. Unexercised muscle demonstrates a reduction of adenosine triphosphate (ATP) and glycogen storage sites and rapid depletion of them after resumption of activity. Reduction of muscle protein synthesis and oxidative enzyme function, and premature anaerobic energy production with rapid accumulation of lactic acid, are important factors leading to fatigability and reduced endurance (27).

Metabolic and enzymatic alterations in unexercised muscle result from reduced demand for oxygen and reduction in the blood supply. Initially after bed rest, succinate dehydrogenase enzyme activity per muscle fiber increases, but later, the overall amount is reduced (28). Oxidative enzyme activity and content as well as the number and size of mitochondria are all reduced during immobility (29). Unexercised muscle also shows a decreased ability to utilize fatty acids when compared with trained subjects.

Ferretti et al. studied peripheral and central factors that contribute to the decline of VO_2max after 42 days of bed rest. VO_2max was found reduced by 16%, cardiac output by 30%, and oxygen delivery by 40%, which parallels the reduction in muscle cross-sectional area of 17%, volume density of mitochondria by 16%, and total mitochondria volume in the magnitude of 28%. Oxidative enzyme activity falls by 11%. These decrements indicate a significant contribution of both peripheral and central factors in causing the decline in VO_2max after immobility, confirming a close interrelationship between the muscular and the cardiovascular system (27).

The following sequence of events transpires in the deconditioning process. Prolonged reduction of muscle repetitive contractions below 50% of maximum alters muscle protein synthesis and decreases glycogen and ATP storage, causing a reduction of oxidative enzymes, mitochondrial function, and microvascular circulation, impacting muscle metabolic activity. As a result, the oxygen supply is attenuated, and the extraction of oxygen from blood is diminished, further negatively affecting VO_2max and cardiovascular reserve. The loss of muscle mass leads to reduction of muscle strength and endurance, reducing muscle blood flow, red blood cell delivery, oxidative enzyme activity, and oxygen utilization in the muscle precipitating a further loss of musculoskeletal and cardiovascular functional reserve to low or dangerous levels. In this cascade of events, specific muscle gene activation and expression are altered as well. Physical inactivity causes change in muscle fiber type composition and decreases formation of oxidative muscle fiber types I and IIa, the main factors in reduction of endurance and fitness (30).

The progressive weakness and reduced stamina resulting from inactivity negatively impact the ability to perform basic mobility and ADLs. In the lower limbs, type I muscle fibers, which are active during standing and slow ambulation, are especially affected with a rapid reduction in endurance. If the quadriceps muscle is immobilized in an extended position, the deep layer of vastus intermedius, which has predominantly type I and type IIa fibers, shows the greatest histochemical changes in contrast to the rest of the muscle (31). Such accelerated rate of atrophy and weakness was also noted in hip and back extensors, hip abductors, and ankle plantar flexors and dorsiflexors, impacting the ability to walk (5). Disuse weakness and loss of endurance will result in impaired ability to perform ADLs and ambulate safely, reducing personal independence (Fig. 48-2).

Patients frequently complain of back pain during bed rest. The cause of this pain is still not fully understood. Recent studies in which spine length and degree of movement were measured by miniature ultrasound transmitters have demonstrated that back pain is more prominent when trunk movements are limited in a supine position. It is speculated that localized, prolonged, low-intensity isometric muscle contractions may cause this pain. Back pain can be averted by stretching exercises and walking (32).

Limb muscle pain and stiffness occur after generalized immobility or focal limb immobilization, especially in the presence of limb swelling. However, gentle static or intermittent stretching can alleviate this problem and prevent the reduction in number of sarcomeres in series (33). It has been shown that the position in which a joint is immobilized has a significant
influence on the number of sarcomeres present in a single muscle fiber (33). When immobilized in a shortened position (extensors in a fully extended position or flexors in a fully flexed position), a muscle can lose 40% of its original number of sarcomeres, contributing significantly to weakness and muscle stiffness (34).

Stretching to maintain optimal muscle resting length as well as viscoelastic properties is important for maintaining normal muscle function. Several animal studies indicate that passive stretching of striated muscle is associated with muscle hypertrophy, increase in muscle fiber area, increase in number of sarcomeres, and muscle fiber proliferation. In doing so, undifferentiated, quiescent myoblasts residing on the sarcolemma of muscle fibers (satellite cells) are activated and believed to be responsible for this stretch-induced muscle hypertrophy. Passive stretch is also a potent mechanical stimulus to influence gene expression and muscle proliferation. For example, both myogenin mRNA per microgram RNA and muscle cross-sectional area were significantly increased after 3, 6, 14, and 21 days of stretch (overload) in avian latissimus dorsi (43).

Muscle stiffness due to lack of stretch occurs through the reduction of the elongation properties of elastic and collagen fibers and myofibrils. It is also a result of structural changes in the muscle, such as muscle fiber angulations, reduction of sarcomeres in 18 series, and rearrangement of collagen fibers and their cross-links. Even a relative increase in muscle connective tissue may lead to muscle stiffness and reduction of joint motion. Muscles that cross two joints such as the hamstrings, gastrocnemius, and long back extensors are particularly prone to stiffness, even in healthy subjects with limited physical activity. In immobilized and inactive persons, however, this process is accelerated in the absence of activity-induced stretch. Stiffness and subsequent muscle belly shortening of two-jointed muscles can interfere with functional walking. Hip-flexion contracture at 35 degrees as a result of iliopsoas muscle tightness causes a 60% increase in energy consumption per unit distance during ambulation (5). Thus, daily stretching of a muscle for a half hour can prevent the loss of sarcomeres in series of the immobilized muscle and maintain elongational properties of muscle fibers and surrounding connective tissue, maintaining full ROM of joints.

To prevent disuse weakness and deconditioning, daily physical activity should be encouraged, and progressive resistance exercise (PRE) using isokinetic or isotonic exercises done on a regular basis. A minimum of once a day muscle contraction at 30% to 50% of maximal strength for 3 to 5 minutes, three times a week for a single muscle group, may suffice to prevent muscle loss and weakness in otherwise mobile, active individuals. Strengthening exercise prevents muscle atrophy and improves strength and endurance by mediating the activation of muscle genes, enhancing mitochondrial function, and improving protein synthesis, causing muscle fiber phenotypic changes and muscle angiogenesis (Table 48-2).

Muscle strength can be increased by concentric or eccentric contractions performed isokinetically or isotonically. To improve or maintain strength, there should be 8 to 15 repetitions for each muscle group done twice with brief pauses between sets. There are many studies that indicate that strenuous eccentric exercises may produce muscle damage since CK may increase 50-fold and cytokine and interleukin-6 (IL-6) fivefold. Furthermore, high-intensity eccentric exercises in untrained individuals frequently produce elevation of myofibrillar enzymes in plasma, ultrastructural damage of muscle fibers, infiltration of mononuclear blood cells, and acute inflammation (44). Therefore, it is important that eccentric exercises are started with lower intensity, fewer repetitions, and slower progression of applied resistance or loads.

Muscle weakness can also be prevented by the use of electrical stimulation. For example, applying local stimulation to the quadriceps while in a long leg cast may help preserve muscle bulk and strength and also may shorten rehabilitation time, a factor that may be particularly important in an athlete (45). For astronauts exposed to prolonged periods of microgravity with resulting muscle atrophy, functional electrical stimulation (FES) has prevented atrophy when applied 6 hours/day, with 1 second on and 2 seconds off stimulation at 20% to 30% of maximum tetanic force applied to the two pair of agonist-antagonist muscles in the legs (46).

For chronic disuse atrophy with weakness and stiffness, strengthening and stretching exercises may be required for several months, and, even then, return to normal strength and ROM may not be complete. For example, returning to normal functional capacity and fatigue resistance after 8 weeks of immobilization in persons with ankle fractures required 10 weeks of supervised physical therapy, demonstrating that more time is needed to restore muscle capacity than to develop muscle weakness (47).

Aerobic exercise should be prescribed for physically inactive individuals with history of prolonged bed rest, immobility, or limited physical activity regardless of age and sex and for those with high risk for CAD and metabolic syndrome. Covertino (48) and others have reported that decline in VO_2max is progressive and parallels the duration of bed rest and it occurs independently of age, sex, and the presence of any other disease and it is considered a major factor for the loss of cardiovascular fitness. Daily endurance exercises at 60% to 80% of VO_2max or at the target heart rate are required to maintain or improve aerobic capacity (VO_2max) in persons with deconditioning
or for those who desire to improve their fitness. If resistance exercises are performed on a regular basis for 8 weeks or more, improvements in endurance, VO_2max, and cardiovascular fitness can also be expected (35). Daily or three to four times per week resistance or aerobic exercise to the muscles of the lower and upper limbs should be prescribed for 2 to 3 months to restore and increase endurance and fitness (49).

Short-time exercises can also prevent, attenuate, or reverse the process of deconditioning and functional decline during the period of bed rest. For example, high-intensity and short-duration isotonic ergometer exercises can maintain work capacity, plasma and red-cell volume, reverse negative water and electrolyte balance, and decrease the quality of sleep and concentration when compared with a no-exercise group during bed rest. However, isokinetic exercises, high-intensity short-duration, can only slightly attenuate the decrease in peak VO_2max and the loss of red-cell volume but not loss of plasma volume, cannot reverse negative water balance, and have no effect on quality of sleep and concentration (50). These studies have pointed out that different training protocols are required to reverse or prevent the adverse effects of inactivity.

Regular physical activity and exercises do provide anti-inflammatory effect in conditions with low-grade chronic inflammation such as CAD or type II diabetes resulting in the reduction of inflammatory cytokines and increased production of anti-inflammatory cytokines (51). Regular endurance exercise also activates a number of genes, enhancing their expression and leading to the production of oxidative muscle fibers (type I and type IIa) and phenotypic changes of muscle fibers.

Changes in motor unit recruitment and force of contraction further contribute to the loss of endurance and easy fatigability of immobilized subjects (52). Current international guidelines suggest that 30 minutes/day or 3 to 4 hours/week of aerobic exercise should be enough to improve fitness and prevent cardiovascular deconditioning. One to two hours per week of this activity needs to be of higher intensity (40).

There are two types of intercellular substances in connective tissues: collagen fibers and proteoglycans. Fibers in tendons, ligaments, joint capsules, and muscle endomysium and perimysium are predominantly of the collagen type, although there is a significant population of elastic fibers in tendons. This is consistent with function in that tendons have great tensile strength and some elasticity that allows a joint complex to move through all stages of muscle contraction and relaxation. Ligaments, on the other hand, are relatively inelastic and are composed primarily of collagen fibers. Collagen is the most abundant protein in the body and accounts for more than 20% of total body mass. At least 12 different collagen types have been well-characterized. More than 30 different genes produce different aggregations of specific polypeptides, resulting in the different collagen types.

The terminology used in describing the organization and aggregation of collagen molecules is inconsistent and confusing. All collagen molecules have a unique protein conformation known as the triple helix, a result of three constituent polypeptide chains of the collagen molecule coiled together. The synthesis of these chains from amino acids, known as pro-chains, occurs in the rough endoplasmic reticulum of the fibroblast. The precise amino acid sequence differs between the different types of collagens and accounts for the tissuespecific properties. When the collagen molecules (monomers) are subsequently secreted from the cell, enzymatic cleavage of the end-part of the molecule occurs, and the molecules aggregate in a systematic manner to form fibrils in the extracellular space (56). Collagen fibrils, visible with the electron microscope, are grouped into fibers that are visible with the light microscope. Cross-linking between collagen fibrils is another important structural feature that varies with location and function. The type and location of collagen cross-linking are the key to tensile strength and can be altered, depending on the direction and magnitude of applied mechanical loads. The fibers aggregate into fiber bundles that are grouped together into fascicles. A large number of fascicles form the whole tendon or ligament (57). In striated muscle, collagen fibers form endomysium around the muscle bundles and perimysium around the muscle fascicles. These are covered with thin films of loose or dense connective tissues surrounding collagen fiber bundles of tendon or ligament (endotendon or endoligament), fascicles (peritendon or periligament), and the whole tendon or ligament (epitendon or epiligament). The epitendon and epiligament, as well as endomysium, are thought to be critically important in responding to mechanical loads and injury, and all play a part in the onset of myogenic, arthrogenic, or soft-tissue contractures (58).

In tendons and ligaments, type I collagen predominates, although types III, IV, and VI are also present. Important variations in collagen diameter have been found in association with site, age, activity level, and repair. Investigations in several animal and human models alike have demonstrated that changes in collagen diameter, density, and orientation follow Wolff’s law; that is, connective tissues orient themselves in form and mass to best resist extrinsic forces. This has been established in response to physiologic conditions (e.g., immobilization or exercise) as well as in response to injury. Changes in collagen are mediated by fibroblasts that are sensitive to mechanical stimuli, enzymes (collagenase and tissue inhibitor of metalloproteinases), and growth factors. These factors shift the dynamic equilibrium toward synthesis or degradation, depending on environmental factors (59). If extrinsic factors, such as stretch or weight bearing, are limited, or if a joint is immobilized in a foreshortened position, then collagen fiber density and mass will be readjusted to the new positions or to new loads, reducing ROM of a joint and breaking point of ligaments and tendons (60).

Although proteoglycans make up only about 1% of the dry weight of ligaments and tendons, their functions of lubrication, spacing, and gliding are essential (61). Proteoglycans also impact the viscoelastic properties of dense connective tissues. There are several different types of proteoglycans (e.g., hyaluronic acid, chondroitin sulfate, decorin, aggrecan, biglycan) that are specific to site and function. An examination of different regions of a tendon as it traverses around a bony pulley is an excellent example of adaptation of proteoglycans by dense connective tissues. The proximal region of the tendon (at a distance from the bony pulley) is only exposed to tensional forces and contains a scant amount of decorin providing some lubrication to the surrounding collagen fibers. By contrast, the region of tendon that is in contact with bone (and subjected to compression, gliding, and tension) contains approximately 10-fold more proteoglycans, most of which is chondroitin sulfate. In other words, the tissue is more like fibrocartilage in the area of compression to withstand the mechanical forces in that region. Work in animal models has demonstrated that these proteoglycan levels may adjust to environmental factors and be reduced by immobility (61).