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REVIEW ARTICLE |
1 Department of Anatomy and Cell Biology, School of Dental Medicine
2 Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia.
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Abstract |
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There are two conceptually different kinds of atrophy. Acute atrophy is associated with disuse, and chronic atrophy is associated with aging, which may be the underlying cause of sarcopenia. With aging, both kinds of atrophy can occur, and aging can impair the recovery process from acute atrophy conditions (3). While there are some similarities between acute and chronic atrophy, including comparable decreases in muscle mass and fiber size, there are also key differences that exist. Specific force (force per cross-sectional area) significantly decreases only with aging, or chronic atrophy (4). Fiber properties tend to shift toward faster fiber types in acute atrophy, whereas chronic atrophy exhibits a decrease in both total fiber number and a selective atrophy of the fastest, most powerful fiber types (5).
For our studies of acute atrophy, we have adopted the hindlimb suspension model in the mouse (6,7). Over the course of 2 weeks of hindlimb suspension, the soleus muscle, a general postural muscle, loses about 35%–40% of its muscle mass over that time. In contrast, the extensor digitorum longus (EDL) muscle, a fast muscle that is not recruited as often as the soleus muscle, does not exhibit the same kind of atrophy. In cross-sections taken from the mid-belly of the mouse soleus in an unsuspended case and after 14 days of suspension, there is a dramatic decrease in the size of that muscle affected by this disuse atrophy (Figure 1).
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Even though IGF-I promotes growth pathways, it cannot prevent loss of muscle mass associated with disuse. Transgenic animals that express high levels of IGF-I exhibit a decrease in muscle mass after hindlimb suspension, which is proportional to that observed in nontransgenic animals (12). In addition, systemic administration of growth hormone and IGF-I to rats does not prevent the disuse atrophy associated with this hindlimb suspension (13). However, the addition of intermittent exercise to IGF-I administration throughout the period of hindlimb suspension can attenuate the atrophic response.
These experiments suggest that activation of the IGF-I receptor does not give rise to any prevention of disuse atrophy. The lack of muscle-loading blocks the activity of the IGF-I receptor in some way. However, the return of both muscle loads, perhaps through the integrin complex and dystrophin complex, enables IGF-I to do its job. Therefore, to block disuse atrophy, we mimicked load on the muscle. Because the activation of membrane complexes does not block the loss of muscle mass, we looked inside the cytosol to find what other factors we could use to block muscle atrophy. Although there are many factors to choose from, including signaling cascade members, most signaling proteins are involved in numerous pathways. Therefore, the effects of modifications to these proteins would not be limited to blocking muscle atrophy, nor could they provide a clear test of what mechanism was underlying the process of muscle atrophy. However, one protein—BCL-2—stood out in that it is a key regulator of apoptosis.
If there is an acute shift in the level of activity, especially in a disuse atrophy model, increased apoptosis is associated with the elimination of myonuclei from these fibers (14,15). Because apoptotic events have been documented to occur with disuse atrophy, blocking those events from happening might block atrophy associated with disuse. BCL-2 works by blocking cytochrome C release from the mitochondria (16). One aspect of the instigation of apoptosis is the uncoupling of the mitochondria; as they uncouple they release cytochrome C, which starts a cascade of events leading to apoptosis. So if we can prevent that initial trigger of apoptosis from happening by having high levels of an agent in the cell, which can block it, perhaps we can also prevent disuse atrophy. Preliminary experiments support that BCL-2 expression can attenuate loss of muscle mass associated with disuse.
Aging muscle, a model of chronic atrophy, incurs a loss of about one-third of the muscle mass and strength between ages 30 and 80 years in humans (5). In a mouse life span, that represents the difference between an approximately 12-month-old mouse and an approximately 2
-year-old mouse. The specific force, that is, the force of the cross-sectional area, also goes down, and there is a loss of these very powerful fiber types (4). To test what causes the aging-related decline in muscle mass and function, we have applied the same tests used in the acute atrophy setting.
IGF-I can increase satellite cell proliferation and regeneration, and can increase protein synthesis (17–20). While IGF-I over-expression does not prevent acute atrophy, can its actions prevent chronic atrophy? Because the loss of fast fiber types is associated with chronic atrophy, we now targeted our experiments to the mouse EDL, which is a well-characterized fast muscle of the ideal size and shape to perform functional analysis. We used the myosin light chain 1–3 promoter enhancer (which limits expression to fast skeletal muscle) in an adeno-associated virus to deliver the IGF-I gene to the EDL. We injected middle-aged mice (i.e., 12–18-month-old mice) and waited until those mice aged to at least 27 months; we then analyzed their functional capabilities, muscle size, and histology. The mice injected with IGF-I maintained both muscle mass and specific force over the course of the aging period, compared with their uninjected control limbs (21). We simply maintained muscle function at the level that it was at the start of the experiment.
How does IGF-I work in aging muscle? As the muscle declines with age, the repair signals calling for muscle regeneration decrease. Increased IGF-I expression amplifies the regeneration pathway when IGF-I receptors are expressed on activated satellite cells, thereby increasing the proliferation of the satellite cell pool and increasing the amount of repair that happens during the repair and regeneration process (Figure 2). Over-expression of IGF-I also prevents the preferential loss of type IIb (fast) fibers, in that the percent of IIb fibers is maintained at about 65% in the mouse EDL (21). Because IGF-I expression can prevent the loss of muscle function associated with aging, it is clear that different processes underlie chronic and acute atrophy. At this point, it is unknown if apoptosis, and the prevention thereof, contributes to chronic atrophy.
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Why is there a loss of IIb fibers in aging? One possibility is that it is a matter of scaling, in that large fibers have a smaller surface area to volume ratio. The amount of contractile protein is proportional to muscle volume, and that contractile protein is generating force that is imposed on a relatively smaller surface area, thereby making those large fibers more susceptible to damage. Preferential damage occurs in these larger fibers, which happen to be those IIb fibers. Again, there is always going to be repair going on, but if the damage is sufficient, those muscle fibers will lose innervation. Reinnervation by the motor neuron pool will occur while the fiber is being repaired. However, there is also a competition between the slow motor neurons and the fast motor neurons enervating that muscle. A study done by Desypris and Parry in 1990 showed that if you denervate a muscle and allow it to reinnervate, the slow motor neurons win that race (23). The type I (slow) motor neuron pool increases after that reenervation. As a result, two different processes possibly lead to a decrease in type IIb fiber population in aged muscle: first, preferential damage to large fibers and second, preferential reinnervation by slow motor neurons. It is unclear where IGF-I enters into the prevention of fast fiber loss. Is it that we have increased or enabled the muscle to repair itself even faster, which we believe is true, or are we also increasing the ability for fast motor neurons to actually innervate more completely?
Why is there a loss of slow fibers in acute atrophy? The contractile proteins and the gene expression profiling that has been done most recently by Cros and colleagues (24) show that these expression profilings shifts toward fast fiber properties. The fiber shifts in acute atrophy are likely activity dependent. We know from Pette and Vrbova's work over several years that tonic stimulation drives slow fiber-type gene expression (25). In a mouse soleus muscle, the presence of tonic activity likely maintains the slow fiber-type profile. However, in disuse atrophy, less nervous activity occurs. Therefore, with the lack of nervous activity or the lack of tonic stimulation, muscles can shift toward their default, that is, they shift towards a fast fiber type. So again, those are two very divergent processes that occur in acute and chronic atrophy: Impaired repair happens with the aging process, and lack of tonic activity contributes to the fiber shifts in acute atrophy.
Potential therapies for acute atrophy might include antiapoptotic agents that might help to prevent the elimination of myonuclei (26). Another possibility that has not been explored is to mimic muscle load. If we somehow trick the muscle into being loaded, perhaps the loss of muscle mass will be prevented. IGF-I does not help at all in the acute atrophy, but it might help in the recovery process.
Is muscle atrophy an active or passive process? The drive-through growth pathway actually ceases, in that there is less activation through the IGF-I pathways, and has shown that IGF-I is ineffective in preventing this disuse atrophy. This suggests that disuse atrophy is a passive process. However, there also seems to be an active process that directs the systematic elimination of myonuclei by apoptosis. Therefore, a combination of therapies might be required to prevent loss of muscle mass associated with inactivity and aging.
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Acknowledgments |
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Received May 8, 2003
Accepted May 23, 2003
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