Sarcopenia: etiology, clinical consequences, intervention, and assessment

The age-related loss of muscle mass results from loss of both slow and fast motor units, with an accelerated loss of fast motor units. In addition to the loss of fast motor units, there appears to be fiber atrophy, or loss of CSA, of type II fast glycolytic fibers [13, 14]. As motor units are lost via denervation, an increased burden of work is transferred to surviving motor units, and as a potential adaptive response, remaining motor units recruit denervated fibers, changing their fiber type to that of the motor unit. Thus, there is a net conversion of type II fibers to type I fibers, as the type II fibers are recruited into slow motor units (Fig. 2). As a result, although there is relatively little change in the average CSA of type I fibers, the percentage of the total muscle cross-sectional area occupied by type I fibers tends to increase with age, whereas not only are type II fibers lost but the CSA and the aggregate power-generating capacity of the remaining fibers also decrease dramatically. Finally, while in young muscle tissue there is a mosaic-like appearance corresponding to presence of both types of fibers, in aged muscle, the recruitment of denervated fibers by surviving motor units causes a clustering of similar fiber types [13, 14].

The loss of both type I and accelerated loss of type II fibers results in sharp age-related changes in muscle function. The loss of fast motor units and the concomitant loss of type II fibers result in loss in muscle power necessary for actions such as rising from a chair, climbing steps, or regaining posture after a perturbation of balance. The extent of skeletal muscle power loss with age has been confirmed by studies of cycle ergometry in which the cycle velocity at maximal power was measured. In a study of human volunteers ranging in age from 20 to 90 years, Kostka et al. found that velocity at maximal power decreased by roughly 18% between ages 20–29 and 50–59 and by a further 20% between 60–69 and 80–89 [15]. In addition to studies examining muscle power and contraction velocities, other studies have cross-sectionally examined age-related changes in strength, showing strength declines as great as 30–35% [16]. These alterations in strength have been linked primarily to declines in muscle mass as well as reductions in power per unit area and force per unit area, as nonmuscle tissue components replace lost muscle fiber [17].

Another morphologic aspect of aging skeletal muscle is the infiltration of muscle tissue components by lipid, which can be contained within adipocytes as well as deposited within muscle fiber. The aging process is thought to result in increased frequency of adipocytes within muscle tissue. As with precursor cells in bone marrow, liver, and kidney, muscle satellite cells can express both adipocytic and a myocytic phenotypes, and recent studies have reported that expression of the adipocytic phenotype is increased with age [18‐21]. This process is still relatively poorly understood in terms of its extent and spatial distribution. Another well-known source of adiposity in muscle tissue is through increased deposition of lipid within muscle fibers [22‐28]. This type of lipid distribution, often referred to as intramyocellular lipid, may result from net buildup of lipid due to reduced oxidative capacity of muscle fibers with aging [22, 29].

The correct functioning of motor neurons is essential to the survival of muscle fibers. Age-related neurodegeneration may contribute importantly to the effects of age on muscle structure, including loss of muscle fibers, atrophy of muscle fibers, and increased clustering of muscle fibers as denervated fibers are recruited into viable motor units. Multiple levels of the nervous system are affected by age, including the motor cortex (beyond the scope of this review), the spinal cord, peripheral neurons, and the neuromuscular junction. Within the spinal cord, there is a substantial decline in the number of alpha motor neurons, and there may be a preferential loss in those motor neurons supplying fast motor units. Other reports have noted age-related losses in peripheral nerve fibers and alterations of their myelin sheaths. Finally, age-related changes have been noted in the neuromuscular junction, with reduced number [30] but increased size of terminal areas and a reduction in the number of synaptic vesicles [31]. Others have noted increases in the amount of neurotransmitters released in nerve impulses and increased sprouting and branching of terminal axons, all of which may serve as an adaptive mechanism underlying the ability of viable motor units to recruit denervated muscle fibers [32].

Skeletal muscle is characterized by a dynamic balance between the synthesis of protein from free amino acids in the cellular milieu and the dissociation of muscle protein into free amino acids. Maintenance of muscle mass requires that the rate of synthesis be in balance with the rate of degradation; over time, deficits can result in severe muscle loss. Aging is associated with decreased expression of hormonal factors that promote protein synthesis and increased expression of both endocrine and inflammatory factors that contribute negatively to protein balance by increasing protein degradation. Figure 3 summarizes the role of endocrine, inflammatory, and other factors in protein synthesis.

Age-related loss of skeletal muscle contractile power, which is essential to human motions such as rising from a chair or climbing a flight of stairs, is one of the clinical consequences most commonly linked with sarcopenia. The decline in muscle power has been established in both genders, under multiple loading conditions, in multiple limbs, and in both cross-sectional and longitudinal studies [17]. The most important anatomic sites for muscle function measurement have primarily been in the lower body, as the muscles in these sites are critical for daily function and allow for closest comparison to biopsy data. Further, power and strength losses in the lower limbs confer the largest risk factors for falls and other sources of injury and disability [66, 67]. Lower-limb power and strength are often measured using knee extension and flexion. Measurements can be isotonic, changing the length of the muscle fibers against constant resistance, isokinetic, in which fibers are shortened or lengthened at fixed velocity, or isometric, in which fiber length remains constant in the presence of a force greater than the muscle is capable of counteracting. Isokinetic and isotonic measurements of knee extension and flexion, in that they involve translating a weight along an arc of motion within a given time interval, are measures of muscle power (although they are mostly reported as joint torques in feet pounds or Newton meters) whereas isometric measurements involve purely the ability to generate force. Because these loading conditions are more relevant to human motion, most studies have reported results of isokinetic and isotonic exercise. Table 1 summarizes results of cross-sectional studies of lower-extremity muscle function [68‐73]. In cross-sectional studies comparing young normal subjects in the 20–40-year age range to healthy elders in the 70–80-year age range, declines in knee extensor torque and power have ranged from 20% to 40%, with greater losses in the 50% range reported for individuals in their 1990s [74‐78]. Over the lifetime, men have inherently greater knee extensor power and torque than women, but on a percentage basis, age-related losses are similar between genders, with losses in men incurring greater absolute losses because they start with higher baseline values. Compared to the abundance of cross-sectional studies, there are fewer longitudinal studies of knee extensor properties with aging. Hughes et al. examined a cohort of 52 elderly men and 68 women who had been examined 10 years earlier, finding similar declines in the knee extensors and flexors ranging from 12% to 18% per decade [79]. Longitudinal studies of smaller cohorts have shown variable results, with one study reporting losses of roughly 3% per year in 23 men aged 73–86 at baseline [80], and another study which reported no changes in strength of either men or women over an 8-year follow-up [81]. Cross-sectional studies of isometric measurements of ankle plantar flexion have shown age-related declines similar to those measured for knee extension torque and power. Studies of age-related muscle strength in the upper extremities show essentially similar results to the lower extremities, with cross-sectional studies reporting declines of 20–40% in measures such as hand-grip strength and elbow extension torque between healthy younger subjects and elderly subjects and longitudinal studies showing yearly declines ranging from 1% to 5% [17].

Loss of skeletal muscle mass with age has been documented by lean body mass measurements with dual X-ray absorptiometry (DXA) and with muscle cross-sectional areas quantified by three-dimensional imaging methods such as X-ray computed tomography (CT) or with magnetic resonance imaging (MRI). Leg lean tissue mass by DXA, a marker for skeletal muscle mass, decreases by roughly 1% per year in longitudinal studies [17], a value roughly threefold smaller than the loss of skeletal muscle strength. Studies which assess muscle mass through CSA measurement have found that CSA decreases by roughly 40% between 20 and 60 years, with the reported amount varying with imaging technique, skeletal site, and gender [9, 16]. Measurements of the CSA of the quadriceps muscle using CT have shown decrements of around 25–35% between older subjects and young normal controls [82]. Large cross-sectional studies including both older men and women have found that men, on average, have larger muscle mass and cross-sectional area values than women but that the largest cross-sectional age-related changes occurred in men. This potential gender difference in age-related loss of muscle mass may reflect differences in the pattern of age-related changes in testosterone, growth hormone, and IGF-1 [17].

Prospective cohort studies have demonstrated the association of age-related loss of muscle strength and mass with adverse clinical outcomes in the older population, including falls, mobility limitations, incident disability, and fractures [66, 67, 83]. Moreland et al. have carried out a meta-analysis summarizing the relation of upper- and lower-body weakness to falls [67]. Measures of lower-body weakness, defined as increased chair stand time and reduced knee extension strength, have been correlated to incidence of any fall with odds ratios ranging from 1.2 to 2.5, to injurious falls with odds ratios around 1.5, and to recurrent falls with much higher odds ratios, ranging from 2.2 to 9.9. Upper-body weakness, which is typically assessed using hand-grip strength or manual muscle testing, is also correlated to fall incidence, with odds ratios for incident falls ranging from 1.2 to 2.3 and for recurrent falls with odds ratios of 1.4–1.7. Clearly, lower-extremity weakness is a better predictor of falls than weakness of the upper body. Other studies have explored the mechanisms by which impaired muscle strength relates to falls by analyzing the effect of muscle strength in single-step recovery from a forward fall [84‐87]. This may be simulated by leaning subjects forward and then releasing them, measuring muscle activation, joint kinetics, and other characteristics as the subjects step forward after release. Multiple studies have found that older individuals have discernible differences in these measurements. Thelen et al. compared muscle activities in young and elderly subjects and found that the latter showed delays in activating the hip flexors and knee extensors during the period in which the stepping leg is swung into position [84, 85]. Wojcik et al. found that elderly adults generate lower hip flexion and extension torques than young adults during single-step recoveries after being placed at a forward lean angle [86, 87]. Thus, there is evidence that reduced strength of the hip and other lower-leg muscles, in addition to impaired neuromuscular activation, may be implicated in poor recovery from falls. In addition to falls, muscle weakness and reduced muscle mass have been associated with incident disability. The Health, Aging, and Body Composition Study investigators carried out studies of body composition, muscle strength, and other risk factors on incident mobility limitation, defined as inability to walk a quarter mile or climb a flight of ten stairs. Visser et al. observed that low-thigh muscle CSA measured at baseline resulted in a 45% and 34% increased risk of mobility limitations 5 years later in men and women, respectively [88]. For low-knee extensor power and torque, the risk of incident mobility limitation was even higher, at 66% and 69% for men and women, respectively [88]. The same study found that men and women in the lowest quartile of thigh muscle cross-sectional area and leg muscle mass had a 30–40% increase of risk for the inability to carry out the activities of daily living. For major disability, which includes inability to carry out activities of daily living, inability to walk a quarter mile, or climb ten steps, low-thigh CSA increased risk by 40% whereas low-knee extensor strength resulted in over a doubling of the risk. These subjects were also followed up for incident hospitalizations, and low-thigh CSA and muscle strength showed a similar predictive power for this outcome. Thigh muscle cross-sectional area and knee extension torque have also been shown to correlate to incident hip fracture in the Health ABC study [89]. Lang et al. observed that knee extension torque and low cross-sectional area individually resulted in increased risk of incident hip fracture by 50–60%, independent of bone mineral density (BMD).

The increased risk of mobility loss and injury resulting from loss of muscle mass and power are part of a vicious cycle which is amplified with age. In addition to reductions in performance, the intermediate consequences of muscle loss include reductions in metabolic rate and aerobic capacity. The loss of power and endurance increase the difficulties associated with procuring adequate nutrition and increase the effort required to undertake exercise. The combination of nutritional loss and reduced physical activity levels results in further loss of muscle mass and power, exacerbating the process of sarcopenia. The resulting decrements in power, endurance, and physical performance, if unchecked, then lead to a loss of independence which may or may not be preceded by injury or illness, for example a fall and/or fracture.

Many studies have documented that exercise provides benefits extending across multiple physiological systems in the aged population. Resistive training, also known as weight or strength training, can be used to counteract age-related muscle loss by increasing the number and cross-sectional areas of skeletal muscle fibers. Increases of 11.4% in midthigh muscle CSA and greater than 100% in knee extensor torque were reported by Frontera et al. in a cohort of elderly men who had undergone 12 weeks of high-intensity resistance exercise training [90], with similar changes observed in a subsequent study in women by Charette and colleagues [91]. Moreover, resistance exercise even has benefits when it is not routinely performed. A recent study by Henwood and Taaffe documented that resistive exercise can produce sustained increases in knee extensor torque even after periods of deconditioning following cessation of exercise [92]. The benefits of resistive exercise have been shown to extend even to frail populations. Increases of 3–9% in muscle CSA, doubling of muscle strength, and improvement in functional performance indices have been reported in nursing home populations after bouts of progressive resistance training [93, 94]. Resistive exercise has been shown to be well tolerated in the elderly and is of value in the prevention of falls and loss of mobility. The time and equipment requirements to undertake a program of resistive exercise are modest, with sessions of 30 min, twice per week, using either exercise machines or body weight and elastic bands. Finally, resistive exercise has been shown to result in improvement in a range of different clinical conditions common in elderly people, including osteoporosis, osteoarthritis, heart disease, diabetes, and depression. A summary of relevant literature on exercise and pharmacologic intervention in the elderly is presented in Table 2.

In elderly men, epidemiologic studies generally support a relationship between declines in testosterone levels with age and loss of muscle strength and functional status [95]. Menopause and age-related reduction of estrogen levels in women may also impact muscle strength because estrogen is converted to testosterone, which has an anabolic effect on muscle protein synthesis. Further, both sex hormones may suppress inflammatory cytokines that exert catabolic effects on muscle. Thus, hormone replacement has always received considerable interest as a therapy for sarcopenia. In women, trials of estrogen and testosterone therapy have failed to yield any meaningful increases of muscle strength [96]. Studies of testosterone replacement therapy in men has had mixed results, depending on age of the subjects. Several studies have shown that administration of testosterone in hypogonadal younger men produced significant increases in lean body mass and muscle strength [97‐99]. Strength increases ranged from 20% to 60% but tended to be smaller than the increases produced by resistive exercise training. Anabolic effects of testosterone therapy on older hypogonadal men tend to be weaker, with most studies reporting minimal changes in body composition and no increases in muscle strength [96]. However, some studies have reported moderate strength improvements ranging from 10% to 25%, but unlike the negative results, all of these trials lacked control groups. However, it should be noted that testosterone is administered to older men in much lower doses than to younger men because of increased risk of prostate cancer and other side effects [96].

Considerable interest has also been devoted to testing the effect of GH on sarcopenia. Growth hormone exerts an indirect anabolic effect on muscle by stimulating production of IGF-1 in the liver. Levels of growth hormone are systematically lower in the elderly, and thus it was hypothesized that GH would be effective in combating muscle loss in elderly subjects. However, most studies have shown that GH treatment is ineffective in the elderly, both from the standpoint of muscle mass and muscle strength. The failure of GH treatment to augment muscle strength in elderly subjects has led to other approaches, such as treatment with growth-hormone-releasing hormone, which was found to increase GH production and produce moderate increases in muscle strength [96‐100]. Additionally, others have tried direct administration of IGF-1. By complexing IGF-1 to its primary circulating binding protein IGFBP-3, it is possible to significantly increase the IGF-1 dose while eliminating the side effect of hypoglycemia that occurs with IGF-1 alone [101]. Boonen et al. reported that administration of IGF-1/IGFBP-3 to elderly women with recent hip fracture was well tolerated and resulted in increased grip strength [102].

Among the newer approaches evolving towards treatment of muscle wasting is inhibition of myostatin, which counteracts the myogenic regulatory factors which promote the differentiation and proliferation of myocytes. In animal studies, myostatin blockade using experimental agents and other approaches appears to produce increases in muscle mass and strength in rodent models [103‐105]. Another approach involves administration of selective androgen receptor modulators (SARMs). These nonsteroidal agents target the androgen receptor, which is found in sexual organs, skeletal muscle, and bone but have less of a stimulative effect on prostate and other sexual organs, making them a candidate for treatment of frailty in older subjects. These agents have been shown to improve lean body mass in rodent models [106] and are currently in early clinical trials.

Maintenance of muscle mass and strength is critical for preservation of physical activity in older age and important for reducing the risks of falls and their most serious consequence, skeletal fractures. However, muscles exert powerful loads on the skeleton, and there is considerable interest in reducing fracture risk by using exercise strategies to increase or at least protect against loss of skeletal mass and strength with age [107]. The use of exercise strategies to strengthen the skeleton is based on the adaptive response of bone to varying mechanical loads as described by Frost, who proposed a homeostatic process governing the balance between bone remodeling, modeling, and repair as a function of varying strains imposed by inputs such as impacts and muscle forces [108]. The relationship between mechanical strains and skeletal tissue responses vary with the skeletal site, but the “set points” that trigger remodeling and modeling responses and thus the overall responsiveness of bone tissue to mechanical loading are modulated by the overall hormonal milieu.

A series of animal experiments have studied the relationships between mechanical strain and bone geometry and strength [109]. These studies have demonstrated the responsiveness of skeletal tissue to dynamic changes in mechanical loading and have shown the importance of the timing as well as the magnitudes of applied loads [110]. Recent studies have also indicated that mechanical loading has an effect on other properties of bone such as fatigue resistance and second moment of inertia that are significantly larger than effects on bone density and mass [111].

However, studies examining the effect of exercise regimes on bone in elderly subjects have indicated relatively modest effects. An excellent review of various exercise strategies on bone health has been published by Suominen [107]. Impact exercise such as walking and aerobic training has a pronounced benefit on overall health, and a small but positive effect on bone mass. However, from an anabolic point of view, resistive exercise seems to exert more favorable effects for potential improvements of bone strength. High-intensity and progressive trials of resistance exercise have shown significant effects on BMD at vertebral and hip sites. Studies in general have shown that the exercise must be continued to maintain the benefit that the additional gain is lost within a few years of the program if the protocol is not continued.

MRI is an imaging technique that is based on using radio waves to excite protons in the presence of an external magnetic field. The resonance frequency at which protons maximally absorb the radioenergy is based on their local chemical environment. Because musculoskeletal tissues are rich in proton-containing molecules such as muscle proteins and lipids, MRI is an inherently powerful tool at depicting the anatomy of muscle tissues, particularly in the delineation of lean and adipose components of muscles. While some investigators have used 3D MRI acquisitions to determine lean tissue and intermuscular fat volumes in a range of applications, the true advantage of MRI is the ability to obtain spectroscopic data that can probe in vivo the ATP-generating functions within skeletal muscle and the storage of important nutrients such as lipid and glycogen.

Proton magnetic resonance spectroscopy (¹H-MRS) is a technique that can differentiate lipids stored within adipocytes (extramyocellular lipid, EMCL) from intramyocellular lipid (IMCL) stored as droplets on the border of the myoplasm [122‐127]. This differentiation is based on the variance in resonance frequency between protons contained in relatively cylindrical deposits of EMCL in adipocytes and protons contained in IMCL deposits which are spherical in shape. These resonances show up as different peaks on the proton spectrum of skeletal muscle (Fig. 5). Probing IMCL is of clinical importance because IMCL stores represent lipid which borders mitochondria and which represent an energy supply of free fatty acids for oxidation. IMCL intensity determined by ¹H-MRS has been found to correlate with insulin resistance and obesity. The risk of insulin resistance is known to increase with age, and aging skeletal muscle is characterized by decreasing oxidative capacity that may lead to increased IMCL.

MRS may also be used to detect resonances of ³¹P and ¹³C nuclei contained in ATP, ADP inorganic phosphate, glycogen, and other chemical forms in skeletal muscle cells, shedding important light on muscle metabolism. ³¹P-MRS can be used to directly analyze relative abundances of ³¹P contained in compounds of interest to energetics of skeletal muscle, including ATP, inorganic phosphate, and phosphocreatine [128‐134]. Based on these primary measurements, it is also possible to use ³¹P-MRS to indirectly estimate the intracellular pH, as well as the free concentrations of ADP and Mg²⁺ ions. These measurements allow the technique to be used to estimate rates of ATP synthesis under ischemic (glycogenolytic) conditions or aerobic (oxidative) conditions. Other applications in skeletal muscle studies include estimates of the oxidative capacity of skeletal muscle, as well as the proton efflux and buffer capacity, which provide insight into the recovery of skeletal muscle from exercise.

The wide chemical shift of the ¹³C resonance allows ¹³C-MRS to assess the relative abundances of a wide range of molecules related to glycogen synthesis and glycogenolysis [129, 135‐143]. Using the natural abundance (1.1%) of ¹³C, it is possible to detect resonances of ¹³C in glycogen and triglyceride. This allows for estimates of glycogen turnover in skeletal muscle and for studies of insulin resistance and type 2 diabetes. By administration of ¹³C glucose, it is possible to enrich ¹³C, allowing for more advanced determinations, such as examining glycogen synthesis rate and quantifying organelle and mitochondrial activity during the TCA cycle.

Positron emission tomography (PET) is an imaging technique which is employed to image the biodistribution of a compound of interest labeled with a positron-emitting atom, for example an ¹⁸F or ¹¹C. The most commonly employed PET imaging agent is ¹⁸F-fluorodeoxyglucose (FDG), a glucose analog which is widely employed to study glucose metabolism across multiple tissue types. ¹⁸F-FDG penetrates the cell membrane and is phosphorylated to FDG-6-phosphate and is no longer metabolized and thus is trapped within the cell. It builds up in the cell in proportion to the rate of glucose transport across the cell membrane and also in relation to the activities of hexokinase and glucose-6-phospotase within the cell. In skeletal muscle, FDG imaging has been employed to study glucose utilization. When used in conjunction with compartmental modeling, this approach has been employed to dissect the rate of glucose utilization in terms of the components of cell membrane transport and phosphorylative activity in insulin resistance associated with both obesity and diabetes [144, 145]. Another application of PET which is relevant to skeletal muscle is the use of ¹¹C-methyl-methionine to estimate the rate of protein synthesis. This agent accumulates in skeletal muscle as ¹¹C-labeled protein, and the use of this methylated agent has advantages over radiolabeled leucine in that the latter accumulates in the blood as ¹¹C-labeled CO₂. Fischmann and others have validated this technique against skeletal muscle biopsy and have used it to outline the rate of skeletal muscle protein synthesis in healthy young volunteers [146‐148].