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Identification of skeletal muscle mass depletion across age and BMI groups in health and disease—there is need for a unified definition

Abstract

Although reduced skeletal muscle mass is a major predictor of impaired physical function and survival, it remains inconsistently diagnosed to a lack of standardized diagnostic approaches that is reflected by the variable combination of body composition indices and cutoffs. In this review, we summarized basic determinants of a normal lean mass (age, gender, fat mass, body region) and demonstrate limitations of different lean mass parameters as indices for skeletal muscle mass. A unique definition of lean mass depletion should be based on an indirect or direct measure of skeletal muscle mass normalized for height (fat-free mass index (FFMI), appendicular or lumbal skeletal muscle index (SMI)) in combination with fat mass. Age-specific reference values for FFMI or SMI are more advantageous because defining lean mass depletion on the basis of total FFMI or appendicular SMI could be misleading in the case of advanced age due to an increased contribution of connective tissue to lean mass. Mathematical modeling of a normal lean mass based on age, gender, fat mass, ethnicity and height can be used in the absence of risk-defined cutoffs to identify skeletal muscle mass depletion. This definition can be applied to identify different clinical phenotypes like sarcopenia, sarcopenic obesity or cachexia.

Introduction

In the strict sense, the term sarcopenia (Greek sarx=flesh, penia=loss, literally: poverty of flesh) is used to define loss of muscle mass and strength that occur with advancing age.1 A decrease in muscle mass can, however, have many causes that are related to lifestyle (inactivity, inadequate diet), metabolic and neuroendocrine changes associated with ageing, diseases and obesity (for example, insulin resistance, inflammation, oxidative stress) or therapy (for example, cortisol, operation, chemotherapy). Although researchers and clinicians from different disciplines all use their individual terminology to describe lean mass depletion (sarcopenia in gerontology, sarcopenic obesity in obesity research and cachexia in oncology), there is an overlap in the underlying multifactorial pathophysiology of these phenotype descriptions (Figure 1). For example an overlap between sarcopenic obesity and cancer cachexia may be observed in obese cancer patients. In these patients lean mass deficiency is referred to as ‘hidden cachexia’ due to the masking effect of expanded adipose tissue that impedes the clinical identification of lean mass deficiency.2 On the other hand, an overlap between age-related sarcopenia and sarcopenic obesity is likely becoming more frequent considering the demographic change with an increasing number of elderly people and the obesity epidemic.3 Irrespective of the etiology, lean mass depletion is associated with impaired prognosis in patients with chronic disease and reduced life expectancy in healthy subjects as well as impaired quality of life and increased personal and health care costs.4, 5, 6

Figure 1
figure1

A low muscle mass can be driven by ageing, disease or obesity with considerable overlap between the pathophysiology of the three.

Besides the heterogeneous terminology used to characterize lean mass depletion, current diagnostic strategy differs among studies and even among consensus definitions.7 This is due to the diversity of body composition parameters used and discrepancies in the method of normal range-definition. These inconsistencies contribute to a great variety in prevalence estimates and prevent comparative evaluation of interventions directed against lean mass depletion. Commonalities in the pathophysiology, overlapping etiology and consequences justify a unique definition and terminology of lean mass depletion in several conditions such as ageing, obesity and disease. The aim of this review is to summarize basic determinants of a normal lean mass (age, gender, fat mass, body region) that need to be considered in a unique definition of lean mass depletion. In addition, we demonstrate limitations of different lean mass parameters as indices for skeletal muscle mass and discuss their appropriate normalization.

Parameters and indices used to determine lean mass depletion

Fat-free mass (FFM) is a widely used parameter that differs from lean mass because it is chemically defined as the sum of all non-lipid components of the body (including non fat components of adipose tissue), whereas the term lean mass is anatomically defined as the sum of all non-adipose tissues of the body (including essential lipids, for example, from cell membranes or central nervous system). Others describe lean mass as fat-free soft tissue mass (total body mass without FM and bone mineral mass) that can be measured using dual X-ray absorptiometry (DXA) and if derived from arms and legs is a more specific measure for skeletal muscle mass than FFM (which can be also derived from DXA by summing total bone mineral content and fat-free soft tissue mass8). Besides by DXA, FFM can be measured by densitometry (underwater weighing or air-displacement plethysmography) or bioelectrical impedance analysis. In order to normalize FFM for body size, it is either expressed as a percentage of body weight (%FFM) or by dividing FFM by height squared (fat-free mass index, FFMI=FFM (kg) per ht (m)2). FFM scales to height with a power of ~2 ranging from 1.86 in non-Hispanic white women to 2.32 in non-Hispanic black men.9 Scaling of FM to height shows a greater variability ranging from 1.51 in non-Hispanic white women to 2.98 in Mexican men. Both body compartments therefore scale to height rounded to a power of 2 as the nearest integer.9 The rationale for using FFMI and FMI instead of normalizing both compartments for body weight is illustrated in Figure 2. During follow-up, the same %FM can result either from a gain in FM or a loss in FFM (Figure 2a). In addition, people with the same %FM who differ in height have a different nutritional status (Figure 2b).

Figure 2
figure2

Rationale for using FFMI and FMI instead of %FM. (a) Theoretically, the same percentage of FM can result from a grain in FM (right image) or a loss in FFM (left image). The change in body composition is not reflected by %FM, whereas the increase in FMI (on the right) or the decrease in FFMI (on the left) clearly reveal discrepant nutritional states like obesity or hidden cachexia. (b) People with the same body weight and percentage of fat mass who differ in height have a different nutritional state (for example, elevated FMI=higher adiposity on the left and decreased FFMI=lower muscle mass on the right).

FFM is a heterogeneous compartment that comprises components with different functional importance like skeletal muscle mass, organ mass and parts of connective tissue. With respect to sarcopenia, the major interest is on skeletal muscle mass. Although muscle mass is the main constituent of total FFM, the use of FFMI as a proxy for skeletal muscle mass is not without limitation. This is evident from Swiss reference data showing an increase in FMI with advancing age, whereas FFMI remained fairly constant across age groups.10 Because the decrease in muscle mass with age is likely compensated by an increase in connective tissue (that is, an increase in the FFM component of adipose tissue) FFMI is insensitive to age-related changes in muscle mass.

Baumgartner et al.11 summed the lean (or fat-free) soft tissue mass of the four limbs from a DXA scan as appendicular skeletal muscle mass and defined a skeletal muscle index (SMI) as appendicular skeletal muscle mass/height2 (kg m−2). This would provide a more accurate measure of muscle mass, especially when considering that bone density differs by age, ethnicity and in response to medications and so on. However, this index also has limitations with increasing age or advancing body fat mass. Comparison of regional lean mass measured by DXA with skeletal muscle mass assessed by magnetic resonance imaging revealed that the contribution of skeletal muscle to appendicular lean soft tissue is lower at a higher degree of adiposity especially in women who store more adipose tissue at the limbs compared with men who proportionally store more adipose tissue at the trunk with increasing FMI.12 Thus with advancing adiposity (and possibly also with advancing age) the increase in connective tissue masks a decrease in skeletal muscle at unchanged total lean soft tissue or FFM. Even in the post obese (weight reduced) state the composition of FFM remains altered. This is supported by a higher extra- to intracellular water ratio in post obese people that is indicative of a higher contribution of connective tissue to total lean mass.13,14

Validity of body composition methods to assess skeletal muscle mass is also affected by disturbancies in the hydration of FFM. Conditions like cancer cachexia, chronic heart or renal failure, morbid obesity and ageing are frequently accompanied by increased or decreased water content of FFM that violate the underlying assumptions of two-compartment methods for body composition analysis. An increase in hydration will thus lead to an overestimation of FFM by bioelectrical impedance analysis (owing to decreased resistance per body length) or deuterium dilution (because calculation of FFM from total body water would require a higher hydration factor) and an underestimation by densitometry or DXA (because of similar densities of fat and water; for a review, see Muller et al.15).

Impact of fat mass on the identification of lean mass deficiency

Lean mass deficiency may occur in the presence of a normal or elevated fat mass. For example, the loss of lean body mass in rheumatoid cachexia is often compensated for by a gain in body fat.16 ‘Hidden cachexia’ may also occur owing to muscle wasting in obese cancer patients.2 On the other hand, metabolic disturbancies related to a high fat mass may also contribute to a loss in muscle mass (for example, insulin resistance, mitochondrial dysfunction, low grade inflammation and so on, Figure 1). Because a normal weight gain consists of fat as well as lean mass, overweight and obese patients are expected to have a higher FFMI or SMI when compared with normal weight individuals.17 Hence, normal values of lean mass as the sole basis for the diagnosis of lean mass deficiency likely lead to an underestimation of sarcopenia in overweight and obese subjects. In addition, a diagnosis of sarcopenic obesity that is often based on a body mass index (BMI) 30 kg m−2 in addition to a low FFMI or SMI is also inaccurate because it does not take into account the relationship between FFM and FM.

Gilbert Forbes18 had developed an empirical non-linear equation that quantifies the fat-free proportion of a weight change as a function of the initial body fat (ΔFFM/ΔBW=10.4/(10.4+FM)) based on cross-sectional data in women. Thus, Forbes’s theory predicted that the contribution of FFM to an infinitesimal weight change depended only on the FM.19 A study in a larger sample of white and African-American men and women found a FM-FFM relationship very close to that originally described by Forbes (constant 9.7 instead of 10.4), absent of significant variability by ethnicity or sex.20 By contrast, in a very large and more diverse multiethnic population from NHANES survey Thomas et al.21 were able to show that the FFM-FM relationship varies with age, height, race and gender. This argues in favor of age-, gender- and ethnicity-specific reference values for FFMI or SMI per FMI. The relationship described by Forbes is also affected by body region in both genders. Figure 3 shows how much skeletal muscle in relation to adipose tissue contributes to each body region (arms, trunk, legs) with increasing quintile of FMI.12 With increasing FMI, the ratio of skeletal muscle to adipose tissue decreases faster at the trunk than corresponding ratios for the extremities in men. This is explained by the preferential accumulation of trunk adipose tissue with higher degrees of obesity in men. By contrast in women, body fat accumulates predominantly at the extremities.

Figure 3
figure3

Regional relationship between skeletal muscle to adipose tissue volume (by MRI) and fat mass index (FMI, kg m−2). (a) In men, with increasing FMI the ratio of muscle/adipose tissue declines faster at the trunk when compared with the extremities. (b) In women, with increasing FMI the ratio of muscle/adipose tissue declines faster at the limbs when compared with the trunk. In summary, the relationship described by Forbes18 differs with respect to body region and gender: In women, with increasing adiposity relatively more fat is stored at the limbs whereas in men, more fat is preferentially stored at the trunk. (cross-sectional data from 117 healthy men and 146 women, Schautz et al.12).

One might ask why we should pay attention to the ratio of muscle and fat when we want to determine whether a muscle mass is normal or low. The answer is that there is a physiological relationship between the two compartments that likely leads to functional impairment when the ratio is out of range. This means that the same muscle mass is worth less at a higher fat mass. To give an example, Figure 4 shows representative magnetic resonance imaging images of two young women with a similar skeletal muscle mass of 21 kg but great differences in the total volume of adipose tissue (24 vs 41 liter). Because there is evidence for impaired muscle quality in obesity,22,23 the women with a higher adipose tissue could have an altered fiber size, -number and fiber type, higher intramyocellular lipids, higher intermuscular adipose tissue (because of a positive association between total adipose tissue and intermuscular adipose tissue24) and an increased collagen content in skeletal muscle. These changes are known to be associated with metabolic disturbances (insulin resistance, mitochondrial dysfunction) and impaired neurological modulation of contraction. Additional impairments of muscle function in obesity involve limitations in physical performance.25,26 Given the same work load, energy expenditure and muscle force required for an obese person are higher27 leading to ‘dynapenic obesity’ characterized by a limitation of strength and increased disability. Finally, obesity also adversely affects the relationship between muscle and bone mass. The interaction of adipose tissue with muscle and bone involves endocrine regulation (fat-muscle-bone axis determined by adipokines, myokines-and osteokines-like osteocalcin) as well as commitment of progenitor mesenchymal stem cells in the bone marrow/adipose/muscle microenvironment into the osteoblastogenic, adipogenic or myogenic linage (for a review, see Ilich et al.28).

Figure 4
figure4

MRI images at the level of the upper arms, the umblilicus and the thigh of two healthy young women with a similar skeletal muscle mass (SM) but a great difference in adipose tissue volume. This example is used to illustrate the argument that the definition of a normal muscle mass should depend on the amount of fat mass. Because a high fat mass is known to impair muscle quality (for example, fatty infiltration and insulin resistance) and muscle function (lower strength, higher disability) the same muscle mass is worth less at a higher adiposity.

The simultaneous evaluation of adipose tissue and skeletal muscle mass can be done by combining appendicular SMIDXA or FFMI with FMI. Appendicular SM adjusted for height and fat mass using regression analysis prevented an underestimation of the prevalence of sarcopenia especially in overweight or obese people.29,30 Alternatively, lumbal SMICT and adipose tissue area can be used in cancer patients where computer tomography images are obtained for staging or diagnostic purposes. These images can be easily segmented into fat and muscle compartments using Hounsfield unit ranges from −29 to 150 for skeletal muscle, −190 to −30 for subcutaneous and intermuscular adipose tissue, and –150 to −50 for visceral adipose tissue.31 Skeletal muscle and adipose tissue areas at the lumbar vertebral landmark (L3) have been shown to correspond to whole-body tissue quantities in nonmalignant populations as well as cancer patients (for a review, see Mourtzakis et al.31).

Impact of age and gender on the lean to fat mass relationship

FFM (primarily skeletal muscle) progressively decreases up to 40% from 20 to 70 years of age,32, 33, 34, 35 whereas FM increases and reaches a maximum at ~60–70 years.32,33 To evaluate the relationship between FFMI and FMI with age in both genders a Hattori chart can be used (Figure 5, Schautz et al.12). The chart reveals that in men at the same adipositiy (quartile of FMI), lean mass increases up to the age group of 20–40 years and decreases thereafter (Figure 5a), whereas in women, at the same adiposity lean mass slightly increases only up to the age group of 16–20 years and sharply decreases thereafter (Figure 5b). The starting point as well as the increase in lean mass with increasing adiposity are gender-specific but the latter is similar between age groups in both genders.

Figure 5
figure5

Hattori chart showing the relationship between fat-free mass index (FFMI, kg m−2) and fat mass index (FMI, kg m−2) measured by air-displacement plethysmography different stratified into age groups and quartiles of FMI (a) for male and (b) for female subjects. (1737 healthy Caucasians, 947 females, 790 males, age: 36±20 years (11–84 years), BMI: 26±6 kg m−2 (13.5–52.5 kg m−2, Schautz et al.12). See text for details.

Aging is not only associated with an increase in FM and a decrease in muscle mass but also with a redistribution of both FFM and FM characterized by a greater relative decrease in appendicular than in trunk FFM (because the rate of decline in skeletal muscle exceeds the decline in organ mass), as well as a greater relative increase in intraabdominal fat compared with subcutaneous or total body fat.36 The latter is also reflected by the increase in visceral adipose tissue volume per cm of waist circumference with increasing age in both genders (Figure 6, Bosy-Westphal et al.37). In addition, intermuscular,38 intramuscular and intrahepatic fat are higher in older persons and associated with insulin resistance.39,40

Figure 6
figure6

Relationship between visceral adipose tissue volume (VAT) measured by MRI and waist circumference measured midway between the lowest rib and the iliac crest in children, adolescents and adults stratified by age groups and gender. (a) females and (b) males (data are taken from Bosy-Westphal et al.37).

Reference values for detection of lean mass depletion

Generation of reference values for lean mass should ideally take into account the aforementioned physiological determinants: gender, age, ethnicity and fat mass. However, many publications disregard the effect of age and fat mass and use a simple stratification of their own male and female study populations based on cutoffs (for example, two s.d.’s below the mean or percentiles).7 Contrary to this stratification approach, a normative approach is based on cutoffs derived from a healthy reference population (s.d., percentiles) and facilitates comparison of results between studies. Sarcopenia can thus be defined as a FFMI, appendicular or lumbal SMI more than two s.d.’s below the mean for a young adult reference population (that would be ideally not only stratified for gender but also for fat mass). Criteria for a low lean mass can also be based on the amount of lean mass lower than expected for a given amount of fat mass using residuals from linear regression models. Thus, the residual distribution derived from the regression of appendicular skeletal muscle mass on height and FM was used to define sarcopenia.41,42 The most advanced reference values for FMI, FFMI and appendicular SMI are gender, age and ethnicity specific and have been published as 3rd, 5th, 25th, 50th, 75th, 95th and 97th percentiles derived from the NHANES population-based sample acquired with modern DXA fan beam scanners in 15 counties across the United States from 1999 through 2004.43 Corresponding high standard reference values are still lacking for the lumbal adipose tissue areaCT and SMICT as well as more simple body composition techniques like FMI and FFMI by bioelectrical impedance analysis. Applying age- and fat mass-specific reference values avoids the methodological limitations of FFMI and appendicular SMI that both show an increase in connective tissue in relation to skeletal muscle mass with advancing age or obesity.12 In this respect, DXA scans of the NHANES survey have been used to develop sex-specific mathematic models to predict FFM from a subject’s age, fat mass, height (instead of normalization of FFM and FM for height) and ethnicity (download calculator at http://pbrc.edu/calculators/fatfreemass).21 These prediction models are most useful to evaluate a lean mass of a patient. A drawback of these reference values is that Asians have not been differentiated but were included in a group of non-African-American people that includes all ethnic groups other than African-American subjects. However, Asians (especially Chinese) are known to have a shorter leg length and Afro Americans have a longer leg length compared with Caucasians.44,45 Because appendicular skeletal muscle accounts for 75% of the total-body skeletal muscle, subjects with shorter legs are expected to have a lower skeletal muscle mass at a given height.

An additional method-inherent limitation of reference values obtained by DXA and bioelectrical impedance analysis is that the output of these techniques is analyzer specific and varies with different manufacturers and software types.46,47

A less statistical definition is the employment of the health risk-related BMI classification from WHO (25 kg m−2 for overweight and 30 kg m−2 for obesity)48 in order to generate FMI cutoffs by assigning FMI values corresponding to each BMI classification threshold (normal, overweight, obese class 1and so on).43 Although this method has also been applied to establish cutoffs for waist circumference49 as well as age-and ethnicity-specific cutoffs for %FM,33 respective information on FFMI or SMI cutoffs has not been published yet.

Figure 7 summarizes three basic concepts how to define skeletal muscle mass depletion. The second concept is more physiological than the first because it takes into account the relationship between muscle and fat mass. The third concept shows a vision for future research that seeks to define cutoffs using functional consequences of skeletal muscle mass depletion.

Figure 7
figure7

Three different strategies for identification of lean mass depletion. The second strategy is better than the first and the third strategy remains to be developed in future studies. (SM stands for a direct or indirect measure of skeletal muscle mass (for example, lumbal skeletal muscle index, appendicular skeletal muscle index or fat-free mass index), FM stands for fat mass index).

Applications for evaluation of a normal composition of weight change and implications for future research

Evaluation of a normal composition of weight gain as FFM and FM is important when studying the effect of different pharmacological treatments on body composition (for example, cortisol, PPARγ-agonists, megestrolacetat, anti-retrovirals, myostatin antagonists, testosterone and growth hormone and so on). Likewise, the evaluation of a healthy weight loss with different energy deficits or dietary macronutrient composition requires knowledge on the expected normal values for changes in fat and lean mass. Individual deviations from predicted changes in FFM (according to the model by Thomas et al.21) can be used to evaluate changes in body composition. Instead of most commonly used absolute changes in FFM and FM, a favorable modulation of energy partitioning during weight gain or weight loss should be a major outcome in interventions targeted for sarcopenic elderly or obese people as well as cachectic patients. A precondition for interpreting changes in energy partitioning is understanding its determinants (for example, energy balance, composition of energy intake, type, amount and duration of physical activity, metabolic and endocrine parameters, for a review, see Heymsfied et al.17). In addition, the impact of weight cycling on body composition is still a matter of debate. A disproportional regain in fat mass has been observed in young people recovering from severe starvation (for a review, see, Dulloo et al.50). whereas unequivocal findings have been obtained in obese patients.51 There might, however, be a sex-specific redistribution of adipose tissue with weight regain in obese patients (for example, an increased propensity of lipid storage in subcutaneous trunk or limb depots in men and women, respectively). When compared with weight regain, the regain in adipose tissue of the extremities was disproportionally higher in women, whereas men showed a preferential regain in abdominal subcutaneous adipose tissue.51 This complies well with the preferential deposition of subcutaneous limb adipose tissue with increasing FMI in women or trunk adipose tissue in men.12 Furthermore, a redistribution of lean mass may occur with weight cycling. In both genders, reconstitution of skeletal muscle at the trunk during weight regain seems to lag behind the extremities.51 These findings are supported by Byrne et al.52 who found a preferential regain of lean soft tissueDXA at the limbs compared with the trunk in weight regaining obese African American and white women.

Conclusion

Lean mass deficiency is a symptom not a diagnosis. Irrespective of the underlying etiology, lean mass depletion can be associated with fatigue, impaired strength, endurance, power and thermoregulation that contribute to the diagnosis and prognosis in different diseases like cancer, metabolic syndrome or frailty. Different conditions associated with a low lean mass have commonalities in the underlying causes of ‘sarcopenia’ and would therefore benefit from a unified definition and reference values. A unique definition of lean mass depletion should be ethnicity specific and based on a measure of skeletal muscle mass normalized for height (FFMI, appendicular SMI, lumbal SMI) in combination with FM. Age-specific reference values for FFMI or SMI are more advantageous because defining lean mass depletion on the basis of total FFMI or appendicular SMI could be misleading in the case of advanced age, severe obesity or weight reduced obese patients due to an increased contribution of connective tissue to lean mass. In the absence of risk-defined cutoffs, mathematical modeling of a normal lean mass based on age, gender, fat mass and height can be used to identify different phenotype characteristics like sarcopenia, sarcopenic obesity or cachexia.

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Acknowledgements

The studies by the authors were funded by a grant of the Germany Ministry of Education and Research (BMBF 0315681), the German Research Foundation (DFG Bo 3296/1-1) and the BMBF Kompetenznetz Adipositas, Core domain ‘Body composition’ (Körperzusammensetzung; FKZ 01GI1125).

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Bosy-Westphal, A., Müller, M. Identification of skeletal muscle mass depletion across age and BMI groups in health and disease—there is need for a unified definition. Int J Obes 39, 379–386 (2015). https://doi.org/10.1038/ijo.2014.161

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