Sport Sci Health (2005) 1:69–74 DOI 10.1007/s11332-2005-004-0013-4 REVIEW

G. Di Tano • S. Fulle • T. Pietrangelo • R. Bellomo • G. Fanò

Sarcopenia: characteristics, genesis, remedies

Received: 30 October 2004 / Accepted: 9 March 2005

Abstract The term sarcopenia is defined as the loss of mass and muscular function with age. It is characterized by a metabolic status in which the muscles present a reduced ability to produce and use energy. Thus, in humans between 20 and 80 years of age, muscle mass decreases about 40%, with negative effects on mobility, strength production, metabolic rate and respiratory function. A continuous reparative process is also present in skeletal muscle due to the presence of quiescent adult stem cells, called satellite cells, which are able to change their phenotype when appropriate conditions are present. Sarcopenia is considered an event with a multifactorial etiology: (1) mitochondrial deletion, i.e., replication errors in mitochondrial DNA that lead to an energetic deficit and fiber atrophy; (2) protein synthesis alterations, with an

imbalance between protein degradation and the ability of the fibers to synthesize protein; (3) loss of repair ability of the satellite cells, caused by an alteration in the proteic growth factors (mainly IGF-1, mIGF-1, HGF) and hormones (growth hormone, testosterone and estrogens), or by an imbalance of the antioxidant system. We are still far from a complete understanding of the causes and characteristics of the sarcopenic process, and from a solution to the problem. However, a suitable lifestyle (programmed physical training) and a suitable diet (caloric restriction) seem to be the most effective therapeutic approaches in order to control at least the more alarming symptoms of sarcopenia. Key words Sarcopenia • Physical activity • Satellite cells

Introduction

G. Di Tano • S. Fulle • T. Pietrangelo • R. Bellomo • G. Fanò () Aging Study Center (CeSI) Interuniversity Myology Institute Faculty of Medicine and Pharmacy G. D’Annunzio University Via dei Vestini 29, I-66013 Chieti, Italy E-mail: [email protected]

Sarcopenia is a term coined by Irwin Rosenberg (Tufts University, Boston, USA) in 1988 to define the loss of mass and muscular function with age [1]. It can be identified with the metabolic condition when the muscle, one of the most important energy consumers of the body (because it represents approximately 40% of body mass and has high unitary metabolic capacity), gradually loses, from about 45 years of age, its ability to produce and consume energy at the same rate as before. Moreover, taking into account that the decreased physical ability leads unavoidably to a parallel decrease in activity, then, in the absence of a suitable dietary adaptation, the ratio of fat to lean mass inevitably grows exponentially. What are the consequences of this situation, which cannot be considered pathological since each of us is bound to lose approximately 40% of our muscular mass (the decrease is more evident in men than in women), when passing from 20 to 80 years of age? The consequences are

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G. Di Tano et al.: Sarcopenia: characteristics, genesis, remedies

Women

Disability arbitrary units

Men

Normal

Moderate sarcopenia

Severe sarcopenia

Fig.1 Relationship between degree of sarcopenia and level of disability in older women and men. The data represent the average±SEM. (Modified from [3])

a negative effect on mobility, production of strength, metabolic rate and respiratory functions; in short, the ability of the elderly subject to lead an independent life is compromised [2] (Fig 1). Although it is true that sarcopenia appears around the age of 40–50 years, it accelerates around the age of 75. The most obvious sign is atrophy of fast-twitch (FT) fibers, those that are activated during high intensity anaerobic work; for this reason not all the muscles present the same degree of tissue loss. Obviously, this functional state debuts and develops faster in inactive subjects, since early physical activity is an element of protection, albeit relative, capable of slowing down both its insurgence and its development. Weight loss and lower effectiveness of muscular enzymes lead to a decrease of the isokinetic strength peak, the maximum speed of extension and the maximum isometric stress, which are still intact until 45 years of age, but decrease by 25% at 65 years and by 35% at 70 years, while in the subsequent decades the loss of strength is even more marked and accelerated. As a consequence, 40% of women aged 55–64 years, 45% aged 65–74 years and 65% aged 75–84 years are no longer able to raise a weight of 4.5 kg [4].

ferent neurodegenerative developments, as a consequence of the lack of trophic stimulus connected to the synaptic activity, a process is started that leads to the atrophy of muscular fibers (anterograde effect). On the other hand, in sarcopenia, it is the muscle which, without evident causes, sends the «remodelling» information to the motor terminal (retrograde effect). With age, indeed, the number of working motor units decreases in an irreversible way, and even if their numbers do not decrease drastically from an anatomic point of view, the number of active terminals is much lower because of functional alterations that reduce the numbers of synapses in the motor terminal and make nervous stimuli ineffective. Nonetheless, as a consequence, retrograde effects and neurodegenerative processes with nerve loss lead to secondary denervation and a consequent atrophic muscular state [5]. One fact is however remarkable, sarcopenia represents a unique event of functional preservation inside an almost completely degenerative state: the myofilaments and the cycle of the cross-sectional bridges, do not seem to undergo appreciable alterations in connection with age. The meaning of this phenomenon and its possible agreement with the data inferred from the oxidative damage of the components, especially the lipids of the cellular membranes, are still in need of explanation [6]. In opposition to notions that seemed consolidated until not many years ago, the muscle tissue is certainly not a postmitotic tissue, i.e. unable of self-remodelling in the presence of different stimuli. There is a group of cells inside the muscle tissue itself that may be considered as adult stem cells: quiescent cells able to assume the muscular phenotype, known as satellite cells [7]. If they are present, suitable stimuli, such as autocrine and paracrine muscular increasing factors (mIGF), are able to proliferate and differentiate, first as myoblasts and after the fusion, in myotubes [8]. Their ability to remodel, however, does not remain constant in time. On the contrary, their intervention seem to be led not only by the functional state of the muscle from which they derive, but also by its age. This seems slightly paradoxical for cells capable of being in a “quiescent” state which, according to the current meaning of the term, should not feel the effect of possible functional dynamics connected with muscular activity. On the other hand, it seems that accumulation of damage by free radicals, a quick but effective way to represent “the wrinkles” both of age and of activity of the muscle, may produce deep changes also in the ability of satellite cells to repair the damage to the fibers [9].

Atrophy and sarcopenia Multifactorial etiology Is sarcopenia only a special mechanism of a general atrophic state of the muscle, or does it have a specific genesis and development of its own? An observation that answers this apparently rhetorical question can be found in the mechanisms of communication inside motor units, between axonal terminals and innervation of muscular fibers. Because of the dif-

In recent years, many hypotheses have been proposed concerning the causes of sarcopenia. These can be roughly summed up as follows: 1. Mitochondrial deletion. An error of replication of mitochondrial DNA (mtDNA) could be the cause of a sub-

G. Di Tano et al.: Sarcopenia: characteristics, genesis, remedies

stantial deletion of the mitochondrial genome. The shorter genome reproduces faster, inducing the formation of malfunctional mitochondria, and this leads, for the reasons mentioned previously, to the accumulation of short genomic inactive mitochondria. To this state of things, the nucleus responds by up-regulating the formation of short-genome inactive mitochondria. This produces energetic deficit and hence atrophy of the fiber. The atrophic fiber becomes necrotic and is replaced by infiltrating connective and adipose tissues [10–12]. 2. Alteration in protein synthesis. Any event leading to a decrease in muscular mass with consequent decrease of the ability to generate strength represents a negative conditioning of the skeletal muscle fiber’s functional ability, which is named atrophy: this is an extreme situation whose insurgence is always negative and sometimes represents, for the muscle but not only for it, a point of no return. In general, the atrophic state, although being connected with a multitude of factors, is always the consequence, provided sufficient nutrients are available, of an imbalance between the ability of tissue fibers to correctly carry out protein synthesis and the degradation component of these proteins [13] (Fig. 2). The rate of protein synthesis in the vastus lateralis muscle of healthy older subjects (over 60 years) is slower than that of young adults. Slower protein synthesis in old age has been observed for total muscle proteins [14], total myofibrillar proteins [15], myosin heavy chains [16, 17] and mitochondrial proteins [18]. The stimulation of myofibrillar synthesis by meals is not affected by age, so protein synthesis is slower in older muscle both before and after meals [19]. The slowing of protein synthesis associated with aging in some animal models has been attributed to reduced expression of elongation factor-1α (which catalyzes the binding of aminoacyl-tRNAs to ribosomes), but in human muscle the expression of this enzyme does not decline with age [20]. The slowing of protein synthesis with aging has been demonstrated only in the vastus lateralis in hu-

Fig. 2 Scheme for the protein synthesis and the degradation component of these proteins in the skeletal muscle

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mans, and it cannot be certain that protein synthesis slows with aging in all muscle group. Furthermore, there is no significant change in muscle proteolysis associated with senescence [21, 22]. However, under some conditions, increased protein breakdown could exacerbate sarcopenia. Disease processes associated with increased production of cortisol and catabolic cytokines could increase protein breakdown and accelerate muscle atrophy. 3. Excitation-contraction coupling. Motor nerve impulses induce contractions by releasing Ca2+ from the sarcoplasmic reticulum. Studies of human muscle fibers indicate that the release of Ca2+ from the sarcoplasmic reticulum is impaired in old age because too few dihydropyridine-sensitive Ca2+ channels (which activate ryanodine-sensitive Ca2+ channels) are available to stimulate efflux of Ca2+ from the sarcoplasmic reticulum through the ryanodine-sensitive Ca2+ channels [23–26]. The rate of relaxation after a contraction is reduced in old muscle [27]. One of the factors that determine post-contraction relaxation rate is uptake of Ca2+ from the sarcoplasm into the sarcoplasmic reticulum by Ca2+-ATPase. In old human muscle, there is a reduced amount and reduced activity of Ca2+-ATPase, and a slower uptake of Ca2+ into sarcoplasmic reticulum [27, 28]. 4. Loss of the repairing ability of satellite cells. The proliferation and fusion of satellite cells (SC) are regulated by specific protein growth factors (mainly IGF-1, mIGF-1, HGF) but are also influenced by hormones such as growth hormone, testosterone and estrogen. The secretion of GH by the anterior hypophysis acts on the liver by stimulating the synthesis and release of insulinlike growth factor 1 (IGF-1), which acts through surface receptors situated on the membrane of SC, making them proliferate as myocytes and hence differentiate into myotubes [29] (Fig. 3). It seems quite obvious, however, that sarcopenia cannot be considered a simple process having a cause-effect relation and a specific etiology; rather, it is necessary to consider it a multifactorial event. With this point of view, it will be possible to follow a more correct line of investigation, running the risk of confusing the effects (e.g. alteration of the electron transport system, hormonal or growth factor alterations, loss of the repair ability of the satellite cells) and the causes (e.g. biological clock, accumulation of free radicals, antioxidant system imbalance, anterograde remodelling) (Fig. 4). The problem is that we are far from defining the causes and specificity of the process, and it is a fair guess that several more years must pass before we can start to solve this question [6]. Obviously, taking into account both the human cost and the serious situation that connects substantial levels of sarcopenia with states of partial or total social inability (cost for the health system), every effort must be undertaken so that at least the most alarming symptomatology (e.g. lowering of the pain threshold, preinflammatory states, depression) may be controlled in some way.

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Fig. 3 Myosin heavy chain (MHC) expression in myotubes derived from human muscle biopsies of a young (28 years old, left) and an old (71 years old, right) subjects. These images show the different percentages of myotubes present in the cultures at 7 days of differentiation

Protein, nmol/min/mg

Catalase

Newborn

Young

Old

Protein, nmol/min/mg

Glutathione transferase

Newborn

Young

Old

Fig. 4 Antioxidant enzyme activities. This figure shows the activity of two scavenger enzymes, catalase and glutathione transferase, indicating a decrease of activity during aging. The data reported are means±SEM

What can be done? Ageing is associated with several modifications of hormonal levels [30], including the drastic modification of plasma GH levels (above all in relation with the variations induced by physical exercise) and the less evident modification of testosterone, IGF-1, dehydroepiandrosterone (DHEA), estradiol, and progesterone [31, 32]. GH, IGF-1 and testosterone levels are likely to be most important endocrine changes contributing to sarcopenia. A decrease in the levels of these hormones can be connected to the development of sarcopenia in view of their action on the regulation of protein synthesis: GH and testoterone are required for the maintenance of protein balance (GH also for the hepatic synthesis of IGF-1) and IGF-1 directly controls the synthesis of proteins with a specific action on filaments (asthenia and myosin heavy chain). In men, the concentration of testosterone that is not bound to sex hormone binding globulin declines by about 40% between the ages of 25 and 75 years [33, 34], and correlates with strength [35]. Testosterone levels also decline with age in women, but the levels are about 10- to 20-fold lower than in men. Most of the decline occurs before menopause, with only a modest change thereafter. Even though women express the androgen receptor and have incresed muscle mass in response to pharmacologic doses of an anabolic androgen, the importance of testosterone in maintaining the muscle mass of women is unclear. The fact that muscle mass and strength correlate with the total and free testosterone levels among 43- to 73-yearold women suggests that women produce enough testosterone to have anabolic effects [36]. It is not clear whether or not the large decline in estrogen and progesterone production at menopause has any significant effect on muscle bulk or performance. DHEA and DHEA-sulfate levels decline markedly during senescence. DHEA is a

G. Di Tano et al.: Sarcopenia: characteristics, genesis, remedies

weak androgen itself, but can be converted to the potent androgen testosterone [37]. Theoretically, DHEA should be more important in women because it contributes much more to testosterone production in women than it does in men. Although the role played by these hormones in protein synthesis is certain, the results obtained by administering them as an anti-sarcopenic therapy are doubtful. One example for all: the prescribing, also in heavy doses, of GH has failed to produce appreciable results, in particular concerning the restoration of muscular mass lost with age [38]. Another attempt of therapeutic-educational type is the result of a 70-year-old discovery: in rats subjected to caloric restriction, through an essential, but well balanced diet, an increase of approximately 50% the average life span was observed, together with a remarkable reduction in the occurrence of sarcopenia and other typical geriatric diseases such as cancer, cardiovascular diseases and osteoporosis [39]. These effects are found in several biological models, but unfortunately this regimen of caloric restriction is unsustainable, since it leads to hunger. Indeed, colleagues at Harvard Medical School (Boston, USA) have isolated molecules stimulating caloric restriction, and the most powerful of these is resveratrol, contained in red wine. Unfortunately, natural resveratrol is not stable: it easily degrades in the presence of oxygen and therefore loses its effectiveness. Hence its use cannot be proposed as a therapeutic agent to fight sarcopenia, even if its presence in the diet in suitable doses (1–2 glasses of red wine per day) could reduce in a substantial way the negative effects of the accumulation of free radicals in the body. A hypocaloric diet is, however, advisable, and not only in elderly subjects with a tendency to increase fat mass and decrease lean mass. On the other hand, in very old subjects with poor eating habits, lack of appetite or chronic pathologies, therefore presenting an insufficient intake of nutrients, the opportunity to introduce dietetic supplements, including vitamins B6, B12, D, calcium and aminoacids, must be taken into consideration [40]. Better results, substantial to produce a relevant improvement both of local conditions (muscular recovery) and of general conditions (reduced inability), can be obtained through programs of physical activity. There is clear evidence that sarcopenia worsens with muscle disuse, and that physical inactivity leads to faster and greater muscle loss than seen in physically active elders. However, even master athletes develop sarcopenia, so it is not completely prevented by execise, and remains a result of aging and not purely of disuse. Nevertheless, the overwhelming trend in industrial and post-industrial societies is toward a decline in physical activity with advancing age, and there is no doubt that this sedentary lifestyle promotes loss of muscle and fat gain, with their attendant morbidity and mortality. The first therapeutic action to be considered is the introduction of a correct training program. Not all the forms of training have the same effectiveness in promoting an in-

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crease of muscular force [41]. The exercises of sub-maximal aerobic type, consisting in several muscular contractions over a longer time period, against relatively low resistance, can help increase mass and muscular strength in the weakened subjects or in patients after long periods of immobilization. On the other hand, in healthy subjects who practice normal physical activity, exercises has an effect mainly on cardiovascular ability and energy metabolism [42]. In order to obtain a substantial improvement in strength, mass and muscular performance, it is necessary to introduce suitable protocols that include anaerobic power exercises, i.e. a limited series of muscular contractions against high resistance [43].

Conclusions There exists a functional state of skeletal muscle that we all, sooner or later, will have to face. This state is characterized by a loss of muscular mass and hence of strength, with obvious psychological and physical consequences. Sarcopenia is an inevitable passage, and the best countermeasure is to adopt both a positive lifestyle (physical activity) and better eating habits (caloric restriction) adapted to the new truth: nothing else will help [44].

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