Sci. Aging Knowl. Environ., 19 November 2003
Vol. 2003, Issue 46, p. pe31
[DOI: 10.1126/sageke.2003.46.pe31]


Sarcopenia--A Critical Perspective

Russell T. Hepple

The author is a member of the Faculty of Kinesiology and Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. E-mail: hepple{at};2003/46/pe31

Key Words: sarcopenia • skeletal muscle • type II muscle fiber • regeneration • atrophy

The progressive decline in skeletal muscle mass and function that occurs with aging, a process known as sarcopenia, contributes significantly to impaired mobility in the aged (1). The prevalence of sarcopenia is nearly 25% in humans aged 65 years and older and increases to 30 to 50% in those aged 80 years and older (2). With mean life span projected to continue to increase as improved treatments for major diseases are developed, an increase in the impact of sarcopenia in our elderly population seems inevitable. The purpose of this Perspective is to be provocative in regard to the manifestation and fundamental causes of sarcopenia. This article will question (i) the long-held notion that type II skeletal muscle fibers are preferentially lost with aging; (ii) the role played by physical inactivity, hormonal changes, and nutritional changes in affecting the mechanistic causes of sarcopenia; and (iii) the capacity for muscle regeneration or de novo generation in adult skeletal muscle. The objective is to distinguish between modulating influences and fundamental mechanisms that underlie the atrophy and loss of muscle fibers with aging.

Is There a Preferential Loss of Type II Skeletal Muscle Fibers with Aging?

Each of the 660 skeletal muscles in humans contains thousands of individual contractile cells (myocytes) that are commonly referred to as muscle fibers. In general terms, these individual fibers can be classified into two types on the basis of which isoform of the myosin heavy chain (one of the contractile proteins) is expressed. Type I fibers, which are also known as slow twitch fibers, exhibit relatively slow development of force in response to activation and are characterized by an ability to sustain tension development over prolonged periods of time. Type II fibers, which are also known as fast twitch fibers, exhibit faster development of force in response to activation. In human muscles, these fibers can be further subgrouped into type IIa (fast oxidative glycolytic fibers) and type IIx (fast glycolytic fibers) (Fig. 1). The type IIa fibers are usually considered to exhibit an intermediate ability to sustain tension development over time, whereas the type IIx fibers fatigue the most rapidly. Many other animals also express a third subclass of type II fibers: type IIb fibers, which, like type IIx fibers, are also termed fast glycolytic fibers. Of all the fiber types mentioned here, these fibers usually exhibit the fastest development of force in response to activation and exhibit the least resistance to fatigue during repetitive activation.

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Fig. 1. Schematic illustration of a cross section through human skeletal muscle depicting the fiber types, which can be distinguished on the basis of differences in myosin heavy chain isoform expression. Muscle fiber types I, IIa, and IIx are shown (see text for descriptions).

With regard to aging, it has long been known that there is a progressive reduction in the number of muscle fibers, beginning in approximately the fifth decade of life. The notion that type II muscle fibers are preferentially lost with aging was first based on studies of muscle biopsies from humans. These analyses revealed that the proportion of type I fibers within a given muscle increases, whereas the proportion of type II fibers decreases (3). These findings suggest that, with aging, type II muscle fibers are lost in greater numbers than are type I fibers. However, a muscle biopsy samples, at most, several hundred muscle fibers out of the thousands that form a muscle, and the sample-to-sample variability of fiber type with this method of analysis is well established (4). Putting these concerns aside for the moment, several ideas have been proposed to explain the apparent reduction in the proportion of type II muscle fibers with aging. Central to these ideas is the hypothesis that some characteristics of type II fibers render them more susceptible to aging-induced processes, resulting in their preferential loss. For example, recent studies of muscles from rats (5) and rhesus monkeys (6) showed that mitochondrial dysfunction, which arises from the accumulation, over time, of mitochondrial DNA damage as a result of oxidative stress, leads to fiber atrophy at discrete locations along its length and to fiber breakage in aging skeletal muscles. In a subsequent investigation, because this process was found to be more common in rat muscles with a high proportion of type II fibers than in muscles with a high proportion of type I fibers, it was suggested that the lower mitochondrial volume of type II fibers--particularly type IIb fibers--renders such cells more susceptible to death via the mitochondrial dysfunction mechanism. Specifically, their lower mitochondrial volume provides a smaller "buffer zone" through which mitochondrial dysfunction erodes before basal cellular energy needs become compromised (7). Although these ideas are compelling and indeed might help explain the preferential loss of type IIb fibers seen in rats, there is good reason to believe that this situation does not apply in the aging human.

First and foremost, although humans retain the gene for the type IIb myosin heavy chain, it is not expressed (8). We now know that what previously were labeled as type IIb fibers in human muscles are in fact type IIx (9). Thus, a preferential reduction in type IIb fibers in humans with aging is a moot point. Second, the distributions of fibers characterized by size and type were determined by exhaustive analyses of cross sections of whole vastus lateralis (part of the outer thigh) muscles taken from human cadavers between the ages of 15 and 83 years, and no change in the proportion of type II fibers with aging was observed (10). Therefore, perhaps it is time that the idea of preferential type II fiber loss in aging humans be abandoned. We should now focus on identifying mechanisms that might affect all skeletal myocytes, regardless of their metabolic and contractile properties. The mitochondrial dysfunction hypothesis (5, 6) still may be valid for human skeletal muscles, but further studies are required to determine whether it alone, or with other mechanisms, can account for the similar loss of both type I and type II fibers from human skeletal muscle with aging.

Sarcopenia and Age-Related Changes in Physical Activity, Hormones, and Nutrition

A reduction in physical activity has long been thought to play an important role in the decline in muscle mass and function with aging. In young adults, it is clear that a reduction in physical activity leads to muscle atrophy (11) and, conversely, that increasing physical activity (particularly if it is "resistive," such as strength training) can induce muscle growth (12). These adaptations to changes in muscle activation involve modifications in the cross-sectional area of individual muscle fibers (muscle fiber hypertrophy) rather than in fiber number (muscle fiber hyperplasia). Whether fiber hyperplasia occurs in young adult humans in response to exercise training remains controversial (13, 14), although at most this would be a minor contributor to whole-muscle hypertrophy. In contrast, beginning in approximately the fifth decade of life, aging is associated with a reduction in fiber number (muscle fiber hypoplasia), which is the primary cause of whole-muscle atrophy, and changes in fiber size are far more variable (10). Also, aging increases the heterogeneity of fiber cross-sectional area, particularly in muscles that exhibit a continued high level of use, as seen in the soleus muscle (located in the calf) (15) and the heart (16) of aged rats. Indeed, selective fiber atrophy and hypertrophy can be seen within the same muscles, and the distribution of severely atrophied fibers appears to be stochastic: A single atrophied fiber is often seen among fibers that look completely normal (Fig. 2). Thus, although a reduction in the amount of physical activity with aging undoubtedly contributes to atrophy, it alone cannot account for the severe atrophy observed in some fibers.

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Fig. 2. Light micrographs of a lead-adenosine triphosphatase-stained soleus muscle cross section from a 28-month-old (late middle age) Fischer 344 X Brown Norway F1-hybrid rat. Note the presence of atrophied fibers among fibers of normal size (left panel) and hypertrophied fibers (right panel) in this postural muscle. Scale bars, 50 µm.

It remains unclear whether the increase in whole-muscle size in aged people after resistance training (17-19) results from the hypertrophy of only "healthy" fibers or whether it also benefits the aforementioned severely atrophied fibers. The answer to this question will be critical in helping us understand whether exercise training actually affects the fundamental aging processes in skeletal muscle or merely slows the consequences of fiber loss and selective fiber atrophy by promoting compensation by healthy fibers. Because there appears to be little, if any, hyperplasia in response to exercise training in young adults, exercise training in the elderly probably does not restore the number of muscle fibers lost to aging, although this has not been tested directly. The aim of this critique is not to raise doubts about the efficacy of exercise as a therapy in the elderly, because it is clearly beneficial in restoring strength and function, but rather to get researchers to think more specifically about whether exercise affects aging-related processes per se.

It is unclear how systemic alterations, such as reduced blood concentrations of anabolic hormones and growth factors [such as testosterone, growth hormone, and insulin-like growth factor 1 (IGF-1)], increased levels of inflammatory cytokines [such as tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin 6], and nutritional deficits (such as inadequate protein intake) could explain the selective pattern of atrophy that results in the heterogeneous distribution of fiber size with aging. Indeed, the severe atrophy of some fibers accompanied by compensatory hypertrophy of other fibers within the same muscle is at odds with the idea that impaired protein synthesis, resulting from nutritional deficiencies, reduced anabolic hormone concentrations in the blood, or both, plays a major role in the muscle atrophy seen with aging. Clearly, the causes of aging in skeletal muscle must involve processes intrinsic to individual myocytes--or the motor neurons that innervate them--in such a way that only some cells are affected whereas others are not. Systemic alterations could exacerbate the problem without being the cause. For example, increased amounts of circulating TNF-{alpha} may promote apoptosis in susceptible cells (20), aggravating sarcopenia without being its cause. This view does not dismiss the utility of nutritional or hormonal interventions in treating the consequences of sarcopenia or slowing its progress, nor does it exclude the influence of changes in the amounts of growth factor released from the muscle itself (for example, muscle-derived IGF-1). Rather, it focuses on the question of whether systemic changes affect the processes of aging in skeletal muscles. Clearly, answering these questions will bring us closer to an understanding of the nature of sarcopenia and, ultimately, to identifying the most effective treatments.

One of the mechanisms most popularly thought to cause aging in skeletal muscle and other highly metabolically active cells, such as neurons and cardiac myocytes, is oxidative stress (see "The Two Faces of Oxygen"). This theory posits that reactive oxygen species (ROS), normally produced by mitochondria in the process of aerobic adenosine triphosphate production, cause oxidative damage to organelles, lipids, proteins, and DNA (particularly mitochondrial DNA). Over the course of a lifetime, the accumulated impact of ROS-induced damage becomes sufficient to compromise cellular function and may result in permanent removal of the cell by apoptosis. The appeal of this mechanism in explaining skeletal muscle aging is that it is consistent with the stochastic distribution of aging effects. Also, this mechanism can account for impairments at the molecular level that are secondary to oxidative DNA damage. For example, ROS damage to DNA (a process to which mitochondrial DNA is more susceptible than nuclear DNA) (21) can impair cell function as a result of the synthesis of improperly functioning proteins, including those involved in transcription, splicing, or translation (22). Oxidative stress can also lead to the activation of apoptosis via its effects on mitochondria (23). Finally, the ROS theory is also attractive because it could explain the death of motor neurons (as these are highly metabolically active cells) that underlies the well-known denervation of muscle fibers with aging (24). Whether oxidative stress alone accounts for the selective cellular affliction typical of sarcopenia remains to be determined.

Fiber Regeneration and De Novo Generation in Adult and Aging Skeletal Muscles

The number of muscle fibers an adult will have is largely determined during prenatal development by the process of myogenesis. Mesodermal germ cells differentiate into myoblasts, and, during this time, these cells proliferate via hyperplasia. The proliferation of myoblasts is under the control of several growth factors, but one of the key factors is myostatin [previously known as growth and differentiation factor 8 (GDF-8)], which acts to inhibit myoblast hyperplasia (25). The myoblasts go on to fuse and form myotubes, which then differentiate into mature muscle fibers. This process is largely complete before birth--muscle growth between early childhood and adulthood occurs exclusively by increased size (hypertrophy) of the individual muscle fibers. Therefore, by limiting the number of myoblasts that are formed during prenatal development, myostatin concentrations in the fetus play a critical role in determining the total number of muscle fibers a person will have from early childhood to young adulthood.

On this basis, traditional thinking might lead us to conclude that because skeletal muscle fibers are postmitotic, loss of a muscle fiber, for example via aging, would result in a permanent reduction in the number of muscle fibers: Once lost, a muscle cell is not replaced. However, it is now well established that skeletal muscle contains mitotically competent cells that contribute not only to muscle fiber hypertrophy in response to physiological overload but also to the regeneration of muscle fibers after other types of damage. These mitotically competent cells are known as satellite cells (26). Recent research has identified another population of mitotically competent cells in skeletal muscle--"muscle-derived stem cells"--which also appears to be important for muscle regeneration (27). Whereas fiber number is known to decrease with aging (10), the extent to which fibers are regenerated after aging-related loss is unclear, although obviously if regeneration occurs, it is not enough to keep up with the loss.

In avian models, de novo fiber generation in adult animals occurs under particular conditions, such as during chronic stretch induced by hanging a weight from the wing of the animal, and this de novo fiber generation is impaired in aged animals (28). In adult humans and other mammals, injection of bupivacaine, a local anesthetic, into a skeletal muscle causes myocyte necrosis in the affected region within 48 hours, and regeneration of the skeletal muscle fibers follows over a 3- to 4-week period (26). Interestingly, the regeneration process restores the same (or a very similar) number of muscle fibers as were present before necrosis (29), suggesting that myocyte number is tightly regulated even after development. If this is the case, and a certain amount of fiber death and regeneration is normal in adult muscle, it may be that either the regulation of myocyte numbers itself fails with aging (for example, because of changes in the expression of genes that control myogenesis) or that the capacity for regeneration becomes compromised with aging (for example, because of impaired replicative capacity of satellite cells). Regarding the latter, replicative senescence secondary to telomere shortening does not appear to be involved in reducing satellite cell viability with aging (30), although oxidative stress can reduce replicative capacity (31). Booth and colleagues showed that the impaired ability of aged rat muscles and satellite cells to regenerate after hindlimb unloading (induced by placing the hindlimb in a cast) can be at least partially restored by local infusion of IGF-1 (32). This interesting finding suggests that if diminished replicative capacity of the satellite cells is involved in impaired regeneration of lost muscle fibers with aging, it may be possible to partially restore satellite cell replicative potential to better preserve muscle mass across the life span.

On this basis, it would seem reasonable to readdress the question of the capacity for and extent of de novo muscle fiber generation in adult skeletal muscles in an effort to understand how defects at this level could contribute to sarcopenia. If it turns out that de novo fiber generation is a viable process in adult skeletal muscle, it may be prudent to focus on identifying mechanisms that regulate this process with aging in order to develop interventions that counter the normal age-related myocyte loss, rather than focusing only on identifying mechanisms by which myocyte death could be averted.

November 19, 2003
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Citation: R. T. Hepple, Sarcopenia--A Critical Perspective. Sci. Aging Knowl. Environ. 2003 (46), pe31 (2003).

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