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In Vivo Alterations in Skeletal Muscle Form and Function after Disuse Atrophy

CLARK, BRIAN C.

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Medicine & Science in Sports & Exercise: October 2009 - Volume 41 - Issue 10 - p 1869-1875
doi: 10.1249/MSS.0b013e3181a645a6
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Abstract

Prolonged reductions in muscle activity and mechanical loading, such as those encountered during bed rest, limb suspension, immobilization, and spaceflight (generically called disuse), result in a myriad of physiological adaptations in skeletal muscle form and function that clinically manifest themselves with losses in muscle performance that require time-consuming physical rehabilitation (34). This review will summarize the most dramatic effects of disuse on muscle morphology (e.g., muscle volume) and performance (e.g., strength, fatigue resistance), with primary reference to systems level changes in humans. Specifically, how the atrophic process varies between muscle groups and disuse paradigms will be addressed, along with the effect of disuse on muscular strength and the respective control mechanisms regulating the induced weakness. In addition, the effects of disuse on fatigue resistance and motor control will be discussed. This article will limit its discussion to disuse-induced changes in healthy conditions only because pathological disease states generally compound the physiological and functional adaptations. As stated before, the effects of disuse are severe and systemic. As such, for discussion on other physiologic and functional responses to disuse, readers are referred to excellent reviews on the following topics: molecular mechanisms (22,26,30,59), neural adaptations (14), comparative physiology (24), and interventions to minimize disuse-induced muscle dysfunction (37,45).

DISUSE-INDUCED CHANGES IN MUSCLE MORPHOLOGY

Disuse atrophy has been of scientific interest for more than 150 yr (43). With the advent of sophisticated imaging technologies during the past quarter of a century, scientists have developed a detailed understanding of the basic quantitative changes in whole muscle volume in healthy, able-bodied individuals associated with a variety of disuse models, namely, those of bed rest, cast immobilization, and unilateral lower limb suspension (2,4,10,15,31,35,38-40,55,56). Although it is tempting to ascribe a generic value to the rate of muscle atrophy over time, it is apparent that the degree of atrophy is not constant across muscle groups or disuse protocols (Figs. 1 and 2A) (2,15,35,38,55).

F1-6
FIGURE 1:
Disuse-induced changes in muscle morphology. The reduction in magnetic resonance imaging-derived skeletal muscle CSA of the legs and lumbar musculature after 17 wk of bed rest. The leg muscles and intrinsic lumbar muscles (e.g., multifidus) displayed significant atrophy (*), whereas the psoas was not significantly (NS) changed after bed rest. SD were not reported in the original article and are thus not included (35). [Adapted from LeBlanc AD, Schneider VS, Evans HJ, Pientok C, Rowe R, Spector E. Regional changes in muscle mass following 17 weeks of bed rest. J Appl Physiol. 1992;73(5):2172-2178. Copyright © 1992 American Physiological Society. Used with permission.]
F2-6
FIGURE 2:
Disuse-induced changes in muscle mass, strength, and central activation. A, Loss of quadriceps femoris muscle mass and strength after 4 wk of experimental disuse. Note that: 1) the losses vary with the disuse model with immobilization resulting in greater atrophy and weakness than bed rest and lower limb suspension; and 2) the loss of strength exceeds the loss of muscle mass suggesting that the induced weakness is not solely due to the loss of muscle mass and contractile protein content. *Different than pre value. [Adapted from Convertino VA, Doerr DF, Mathes KL, Stein SL, Buchanan P. Changes in volume, muscle compartment, and compliance of the lower extremities in man following 30 days of exposure to simulated microgravity. Aviat Space Environ Med. 1989;60(7):653-658. Copyright © 1989 Aerospace Medical Association. Used with permission; Dudley GA, Duvoisin MR, Convertino VA, Buchanan P. Alterations of the in vivo torque-velocity relationship of human skeletal muscle following 30 days exposure to simulated microgravity. Aviat Space Environ Med. 1989;60(7):659-663. Copyright © 1989 Aerospace Medical Association. Used with permission; Manini TM, Clark BC, Nalls MA, Goodpaster BH, Ploutz-Snyder LL, Harris TB. Reduced physical activity increases intermuscular adipose tissue in healthy young adults. Am J Clin Nutr. 2007;85(2):377-384. Copyright © 2007 American Society of Clinical Nutrition. Used with permission; Veldhuizen JW, Verstappen FT, Vroemen JP, Kuipers H, Greep JM. Functional and morphological adaptations following four weeks of knee immobilization. Int J Sports Med. 1993;14(5):283-287. Copyright © 1993 Thieme. Used with permission.] B, Changes in wrist flexor central activation with 3 wk of forearm cast immobilization (filled symbols) and control subjects (open symbols). *Immobilization subjects different than pre value. [Adapted from Clark B, Issac LC, Lane JL, Damron LA, Hoffman RL. Neuromuscular plasticity during and following 3-weeks of human forearm cast immobilization. J Appl Physiol. 2008;105:868-878. Copyright © 2008 American Physiological Society. Used with permission.]

Muscle group-specific adaptations are illustrated by data from LeBlanc et al. (35) describing the changes in skeletal muscle cross-sectional area (CSA) of the leg and lumbar musculature after 17 wk of bed rest (Fig. 1). Here, it was observed that, for the leg musculature, the plantarflexors (soleus and gastrocnemius muscle complex) were most susceptible to atrophy after 17 wk of bed rest (30% decrease), whereas the dorsiflexors, hamstrings, and quadriceps experienced significant, but lesser atrophy (16%-21% decrease). The intrinsic lumbar muscles (rotators, multifidus, semispinalis, spinalis, longissimus, and iliocostalis) atrophied 9%, but the psoas did not demonstrate any significant change in muscle mass. There is considerably fewer data on disuse-induced atrophy of the upper limb muscles, and the existing literature is somewhat discrepant with reports of no atrophy after 21 d of wrist immobilization (32) and significant atrophy (∼4% decrease in CSA) after as little as 9 d of wrist immobilization (39). Recently, Urso et al. (54) determined the effect of 2 wk of adductor pollicis immobilization on muscle CSA in both young (21 ± 2 yr) and old (67 ± 4 yr) men and observed that the young men experienced a nonsignificant 4% reduction in CSA, whereas the old men lost almost 10% of their muscle CSA.

In addition to atrophic differences between muscle groups, the degree of atrophy also varies between disuse models (Fig. 2A). This is illustrated in Figure 2A, where quadriceps muscle atrophy after 4 wk of leg immobilization is considerably more pronounced than that induced via lower limb suspension or bed rest. It is likely that differences in disuse models depend on the degree of restriction imposed, as immobilization has been shown to drastically reduce the afferent input arising from muscle spindles to the nervous system (20) and to decrease the efferent EMG activity by >95% of normal daily values (19).

It should also be noted that disuse-induced alterations in skeletal muscle morphology extend beyond the scope of muscle atrophy alone. For example, when magnetic resonance images obtained before and after 4 wk of lower limb suspension are segmented on the basis of signal intensity into adipose tissue and skeletal muscle, it is observed that, in addition to the characteristic reduction in muscle CSA, there was a concomitant 15% increase in intermuscular adipose tissue (38).

Collectively, these findings indicate that the degree of muscle atrophy varies between muscle groups, with the leg and postural muscles being highly susceptible to atrophy, and that disuse also functions to influence the composition of skeletal muscle (e.g., increased intermuscular adipose tissue [38], transition of myosin isoforms from slow to fast; for review, see [18]). These data also suggest that the degree of muscle atrophy differs depending on the disuse model and that certain factors (e.g., age) have interactive modulating effects.

DISUSE-INDUCED MUSCULAR WEAKNESS

In addition to the reduction in muscle mass, disuse also results in a dramatic loss of maximal voluntary force production (strength). Immobilization results in a more substantial reduction in strength than bed rest and limb suspension (Fig. 2A). In addition, the loss of strength far exceeds the loss of muscle mass (Fig. 2A), suggesting that other alterations in the neuromuscular system, beyond the simple reduction in contractile proteins, function to regulate the excessive loss of strength.

The mechanisms accounting for the immobilization-induced loss of strength can be attributed to two factors, namely, 1) neurological and 2) skeletal muscle properties, because it is well known that the output from these sources controls voluntary force production (6,16). About the nervous system, it has been observed that 3 wk of wrist and hand immobilization results in a deficit in wrist flexor central (neural) activation, with the degree of central activation decreasing from ∼86% of maximum before immobilization to ∼67% of maximum after immobilization (Fig. 2B) (3). It has also been reported that disuse-induced deficits in central activation account for ∼50% of the between-person variability in the loss of plantarflexor strength after 4 wk of lower limb suspension (4,7) and the loss of knee extensor strength after 3 wk of bed rest (31). Accordingly, it seems likely that much of the disuse-induced loss of strength is a result of neural adaptations, which is consistent with the report of a rapid decrease in strength after 2 wk of lower leg immobilization without a concomitant change in the size or fiber-type distribution of muscle biopsy samples (13). Recent evidence for this postulate is provided by data from Seki et al. (47), who reported that the mean discharge rate of the first dorsal interosseous motor neurons during a maximal voluntary contraction decreased 15% after 1 wk of hand immobilization. However, it is likely that the relative contribution of neural and muscular factors dynamically changes over time, with the muscular component contributing more as the duration of disuse is prolonged (12).

In addition to the alterations in the behavioral properties of motor neurons, other neurophysiologic adaptations occur as a result of disuse. This neuroplasticity likely occurs at both supraspinal and spinal levels. For example, Clark et al. (3) recently reported that 3 wk of wrist immobilization resulted in a prolongation of the flexor carpi radialis' corticospinal silent period (Fig. 3A). The silent period is a time of electrical quiescence in the voluntary EMG signal after the delivery of a magnetic pulse to the motor cortex during a muscle contraction that is indicative of corticospinal inhibition (for reviews, see 33,44). On the basis of the duration of the evoked silent periods being 80+ ms, it is probable that the immobilization-induced adaptation was regulated by changes in cortical inhibitory circuits (33). In addition, Clark et al. (9) also observed that 4 wk of limb suspension increased the soleus H-reflex (a global measure of spinal excitability) and that this hyperexcitability was associated with a mal-adaptation in motor performance. Subsequent work by Lundbye-Jensen and Nielsen (36) also reported that 2 wk of ankle immobilization increased the soleus' H-reflex, which was likely due to the decreased presynaptic inhibition of the soleus Ia afferents (Fig. 3B) (51). These aforementioned findings suggest that disuse induces neural adaptations, most likely at both cortical and spinal levels, and that this reorganization may have functional implications on maximal force generation and motor control.

F3-6
FIGURE 3:
Neural adaptations to cast immobilization. A, Temporal changes in the corticospinal silent period of the flexor carpi radialis muscle evoked via transcranial magnetic stimulation during a background muscle contraction equal to 15% of maximal strength before (black bar), during (hatched bars), and after (gray bar) 3 wk of wrist-hand immobilization. A prolongation in the silent period observed with immobilization is typically interpreted as an increase in corticospinal inhibition. *P < 0.05 compared with baseline, †P = 0.10 compared with baseline. [Adapted from Clark B, Issac LC, Lane JL, Damron LA, Hoffman RL. Neuromuscular plasticity during and following 3-weeks of human forearm cast immobilization. J Appl Physiol. 2008;105:868-878. Copyright © 2008 American Physiological Society. Used with permission.] B, Presynaptic inhibition of the soleus group Ia afferents on two different preimmobilization test days (pre1 and pre2), after 2 wk of ankle immobilization (cast removal), and 2 wk after cast removal (re-test). The observation of increased presynaptic inhibition suggests that immobilization causes plastic changes in spinal interneuronal circuitries responsible for presynaptic control of sensory input to the spinal cord. [Adapted from Lundbye-Jensen J, Nielsen JB. Immobilization induces changes in presynaptic control of group Ia afferents in healthy humans. J Physiol. 2008;586(Pt 17):4121-4135. Copyright © 2008 Cambridge University Press. Used with permission.]

Another influential factor on disuse-induced muscular weakness involves intrinsic changes in skeletal muscle fibers. Trappe et al. (53) reported that 84 d of bed rest affected Type I muscle fiber contractile function more than faster fiber-type profiles did (Fig. 4A). Specifically, they observed that bed rest reduced the peak force per CSA of single Type I muscle fibers by 26% and reduced peak power per CSA by 41% (53), which is likely due to a loss of myosin content (11). Disuse has also been shown to reduce the packing density of thin filament proteins (Fig. 4B). Riley et al. (46) observed that 17 d of unweighting because of spaceflight resulted in a 26% decrease in the thin filament density within the overlap A-band region of the soleus muscle. Functionally, this adaptation may result in a structurally weaker sarcomere.

F4-6
FIGURE 4:
Skeletal muscle adaptations to disuse. A, Responses to 84 d of bed rest for Type I and Type IIa single muscle fibers. Bed rest resulted in more pronounced atrophy in the Type I fibers. In addition, it resulted in a greater loss of in vitro force and power in the Type I fibers, with the loss of force and power normalized to fiber CSA (specific force) being reduced 26% and 41%, respectively. [Adapted from Trappe S, Trappe T, Gallagher P, Harber M, Alkner B, Tesch P. Human single muscle fibre function with 84 day bed-rest and resistance exercise. J Physiol. 2004;557(Pt 2):501-513. Copyright © 2004 Cambridge University Press. Used with permission.] B, Schematic representation of the in vivo status of thin filament packing density and spacing of muscle before (normal) and after 17 d of spaceflight (atrophic). Spaceflight resulted in a 26% decrease of thin filament density within the overlap A-band region. [Adapted from Riley DA, Bain JL, Thompson JL, et al. Decreased thin filament density and length in human atrophic soleus muscle fibers after spaceflight. J Appl Physiol. 2000;88(2):567-572. Copyright © 2000 American Physiological Society. Used with permission.]

Mechanical properties of tendons have also been shown to adapt to disuse (12,42). Specifically, 90 d of bed rest has been shown to decrease gastrocnemius tendon stiffness by 58% (42). Recent evidence suggests that 2 wk of lower limb suspension patellar tendon stiffness ∼10%, with an even more rapid deterioration occurring during the third week (29% decrease in stiffness after 23 d) (12). These tendinous adaptations in the third week occurred at a faster rate than observed for muscle atrophy, leading the authors to suggest that the impact of tendon mechanical behavior on muscle strength increases beyond that observed during the first 2 wk of limb suspension.

Collectively, these findings indicate that the rate of strength loss exceeds the rate of atrophy and that immobilization has a more pronounced impact on strength than unweighting models that do not immobilize the joint. They also suggest that disuse results in plastic changes that occur spatially throughout the neuromuscular system, with adaptations occurring in supraspinal and spinal centers, in the mechanical properties of tendons, as well as in the protein structural organization at the level of single myofibers.

DISUSE-INDUCED ALTERATIONS IN MUSCLE FATIGUE RESISTANCE AND MOTOR CONTROL

It is commonly assumed that disuse decreases muscle fatigue resistance. This assumption seems reasonable on the basis of reports of disused-induced changes in muscle energetics and blood flow. For example, animal studies suggest disuse results in a greater utilization of glycogen (21) and a reduced ability to oxidize long-chain fatty acids (1), which is consistent with the human observation of a decrease in 3-hydroxyacyl CoA dehydrogenase activity, a key enzyme in muscle fatty acid metabolism after bed rest (23). In addition, rat hindlimb suspension has been shown to attenuate endothelium-dependent vasodilation in the soleus (27). However, human studies investigating disuse-induced changes in muscle fatigue resistance yield equivocal findings, with approximately equal numbers of studies reporting reduced fatigue resistance (2,40,41,55), no change in fatigue resistance (19,28,29,39,48), and increased fatigue resistance (5,13,50,58).

The mechanisms of muscle fatigue are well known to vary with the specifics of the task being performed (17,25). Accordingly, it seems feasible that the aforementioned between-study variability on the effect of disuse on muscle fatigue resistance may be related to task specificity. Few studies have directly evaluated different fatigue tasks before and after periods of disuse. Yue et al. (58) evaluated the effect of 4 wk of elbow flexor immobilization on changes in muscle fatigability using two fatigue tasks. Here, fatigue resistance was evaluated during sustained submaximal contraction at different force levels: 20% and 65% of maximal voluntary strength. They observed that immobilization had a task-dependent effect on muscle fatigue with a substantially increased endurance time (improved fatigue resistance) at the 20% force level and no change at the 65% force level. Accordingly, it seems probable that disuse preferentially alters mechanisms of fatigue that are more or less prevalent during varying specifics of a given fatigue task.

Collectively, these findings suggest that the disuse-induced adaptations in muscle fatigability vary with the specifics of the task being performed. The mechanistic explanations of these task-specific adaptations are yet to be fully elucidated. In addition, differential responses between muscle groups or disuse protocols have not been fully explored, and further research is needed to more fully determine the explanatory mechanisms and describe the effect of disuse on muscle fatigability.

Another functional outcome of disuse relates to its effect on neuromotor performance and control (9,52,57). A 4-wk period of lower limb suspension was recently shown to reduce the isometric force control of both the knee extensors and plantarflexors (12% and 22%, respectively) (9). In addition, during an isotonic contraction, the knee extensors exhibited a decrease in the force control during a lengthening muscle action; however, no changes were observed during the shortening action (9). Bed rest has also been shown to reduce motor performance (52,57), with the increases in plantarflexor force fluctuations during an isometric contraction being related to the neural strategy associated with the agonist synergistic muscles (57). Thus, although the exact mechanisms responsible for the disuse-induced loss of motor control are far from understood, it does seem that disuse results in reductions in motor performance that are likely related to adaptations in neurophysiologic parameters.

PERSPECTIVES

There are many questions remaining to be answered concerning neuromuscular adaptations to disuse. These surround a wide number of critical issues including developing a better understanding of the molecular underpinnings of atrophy, the mechanisms explaining the functional and structural adaptations, and cost-effective interventions to minimize these changes. In addition, there is emerging evidence that sex differences may exist in the response to disuse. For example, women have been observed to exhibit a greater loss of strength after 2 wk of leg immobilization than men (56), experience less atrophy after 21 d of arm immobilization than men (40), display a marked increase in the endurance time during a low-force fatiguing contraction compared with men (49), and not restore their strength as fast as men during the recovery from disuse (8). As such, investigation into the influence of biological sex on disuse-induced adaptations deserves further attention.

CONCLUSIONS

Disuse results in profound alterations in skeletal muscle form and function. Recent evidence suggests that there are dramatic effects of disuse on skeletal muscle morphology and muscle performance. In summary, these data indicate that: 1) the antigravity muscles are most susceptible to atrophy, although upper limb muscles also demonstrate reductions in muscle performance and size in response to cast immobilization; 2) disuse alters muscle tissue composition by increasing intermuscular adipose tissue content; 3) different disuse models result in varying degrees of muscle mass and strength loss, with immobilization causing greater reductions than bed rest and limb suspension do; 4) disuse decreases strength to a greater extent than muscle mass and adaptations in the nervous system and contractile properties both function to regulate this excessive loss of strength; 5) the effects of disuse on muscle fatigue resistance are ambiguous, which may be a result of task-specific adaptations; 6) disuse reduces neuromotor control, although the mechanisms of this functional loss are poorly understood; and 7) sex-specific adaptations to disuse may exist and further investigation into the differences between men and women is needed to determine the role of biological sex on the alterations in skeletal muscle form and function after disuse.

A portion of the work conducted by the author and discussed in this article was supported by NASA NGT5-50446.

The results of the present work do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

IMMOBILIZATION; BED REST; LIMB SUSPENSION; STRENGTH

©2009The American College of Sports Medicine