Keywords

1 Introduction

Muscle strength generally reaches its peak in 20s to 40s of age in human life and then decreases with age. Skeletal muscle mass (SMM) also decreases with age (Figs. 3.1 and 3.2). The study of Allen et al. (1960) was probably the first scientific report about SMM decrease with age [1]. Allen et al. reported that muscle mass is decreasing with age by calculating total body potassium (TBK) via whole body counter, using the fact that a small amount of radioisotope 40K exists naturally. In this method, based on the hypothesis that the potassium volume (concentration) in body cell mass (BCM) is constant, the BCM was estimated from the TBK, and then the BCM was used as an index for skeletal muscle mass [2, 3].

Fig. 3.1
figure 1

Typical example of mid-thigh cross-sectional area (CSA) obtained by X-ray computed tomography (CT) in each age individual. Skeletal muscle CSA (gray area) is decreased with advancing age. In addition, the signal intensity of muscle area became low with advancing age. (The figure is reprinted from Yamada 2015 [2] with permission (see detail in Sect. 6 in this chapter))

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Fig. 3.2
figure 2

Relationship between age and whole-body skeletal muscle mass assessed by magnetic resonance imaging (MRI). (The figure was created based upon Table 1 of Janssen et al. 2000 [3] for the present article by Yamada)

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Since then, various methods such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) have been invented (Figs. 3.1 and 3.2). Using these methods, the SMM change with age in the human body has been examined in many researches. In the systemic review for the SMM change with age by various measurement methods [4], the SMM decreased only 0.37% per year in female and 0.47% per year in male when compared with the young adult (18 to 45 years old) to the elderly (65 years old or over). The decrease rate of muscle mass per 10 years drops more steeply after a certain age (i.e., 50 to 65 years old) than younger age; the longitudinal study that assessed in older adults (65 years old or over) over 5 to 12.2 years showed that the decrease rate was approximately 0.51% [4]. The decrease rate is much lower than muscle strength.

The longitudinal study with the elderly showed the muscle strength decreased 2.5 to 3% in female and 3 to 4% in male in a year. In the cohort that muscle mass and muscle strength were measured at the same time (e.g., Baltimore Longitudinal Study and Health ABC study), the decrease rate of muscle strength was twice to four times as large as that of the SMM [5, 6] (Fig. 3.3). Furthermore, it is clear that low muscle strength rather than low SMM is a risk factor for mobility disability and mortality [7,8,9]. In consideration of the above, the meaning of muscle mass or strength measurement has become a controversial topic; it has been discussed that “dynapenia,” which focuses on age-related loss of muscle function, is probably more useful than “sarcopenia” which is mainly considered on age-related loss of SMM [10, 11].

Fig. 3.3
figure 3

Changes of knee extension strength (KES) and leg muscle mass (LMM) in Baltimore Longitudinal Study of Aging. KES was measured by isokinetic dynamometry, and LMM was assessed by dual-energy X-ray absorptiometry (DXA). The rate of decline for both parameters is steeper with older age (in particular, 45+ and 75+); the decrease rate of muscle strength was twice to four times as large as that of the muscle mass. (The figure is reprinted from Ferrucci et al. 2012 [5] with permission)

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The term “sarcopenia” was originally created by Rosenberg at a meeting summary (1989) [12] of “Epidemiologic and methodologic problems in determining nutritional status of older persons (Albuquerque, New Mexico, USA, October 19–21)” in 1988. In its proceedings, Rosenberg mentioned that “the prevention and/or attenuation of decreasing lean mass with age” is one of the most important public health issues for exercise and nutrition for older adults and coined sarcopenia from Greek words σάρξ sarx, “flesh,” and πενία penia, “poverty.” Rosenberg summarized the meeting to introduce what the meeting was like and what the sentence meant [12].

One out of 25 persons was the elderly population (65 years old or over) in 1900, 1 out of 9 in 1989, and then 1 out of 5 in the twenty-first century. Drs. Samet, Rhyne, Harris, Hegsted, and Goodwin et al. [13,14,15,16,17] emphasized the diversity of elderly in the meeting; there is not only non-negligible differences between a 65-year-old and an 80-year-old person (chronological age) but also inter-individual variation of aging (biological age) which is different from chronological age. There are also difference in races, ethnicity, and sex. Furthermore, the activity level of elderly varies: some are independent and active, some cannot leave home, and others stay in the nursing home. Some uses multiple medications, which affects to the body and mental functions. We must conduct research for all those elderly since we cannot evaluate the populations of “normal aging” or “normal nutritional status” if we use the cohort of only elderly who visit a hospital, excluding active healthy elderly, or the cohort of elderly excluding persons who are charged in the nursing home or cannot leave home. Therefore, the method we should use is to evaluate various old population including a marathon runner and a person who needs nursing care, to clarify the effect of decreased function of each organ with age to food and nutritional conditions, and to have better understanding for the influence of food and nutrition to the maintenance or decreased function of each organ. From the NHANES, National Health and Nutrition Examination Survey, III (from 1988 to 1994), Harris and Kuczmarski et al. [15, 18] revealed these problems applying oversampling technique for 5000 elderly including 1300 who were older than 80.

Drs. Kuczmarski, Chumlea, Heymsfield, and Schoeller [18,19,20,21] lectured about body composition assessment method in the meeting, which is essential for nutritional status assessment. Each method has both advantages and disadvantages. Because of recent drastic progress of body composition assessment method, it is possible to evaluate various compositions instead of using a traditional two-composition model (fat and lean mass). Thus, using these methods, it is necessary to have a wide variety of data including the abovementioned race and ethnic differences. Rosenberg asseverated that there is no important dramatic functional change with age other than lean mass change. Decreased lean body mass influences on various aspects such as mobility ability, physical functions, energy (calorie) intake and expenditure, nutrient consumption, nutritional condition, independence (nursing care requirement), cardiovascular function and/or respiratory function. To pay more attention to lean mass decrease, Rosenberg proposed the term sarcomalacia/sarcopenia and suggested that more research should be conducted for the relationship lean mass decrease and exercise. Muscle mass would be increased even in the elderly, and the elderly with frailty would drastically improve physical function.

In summary, Rosenberg [12] picked up Dr. Hegsted’s topic related to recommended dietary allowance (RDA) [16]. What is the role of RDA for elderly with wide variety of characteristics? When it comes to the recommended food to maximize one’s healthy living and to maintain activities in one’s life cycle, it is necessary to understand the diversity and variability in young and old women and men.

Sarcopenia was originally the proposed term to proceed the research about loss of lean mass during age considering appropriate nutrition and exercise for each old person with understanding of variety of old people in the meeting summary comment. However, as it is mentioned above, from the results that many researches had proceeded focusing on muscle mass and strength since 1990, the risk for mortality and/or loss of physical function and independence cannot be fully explained by only muscle mass.

Therefore, the European Working Group on Sarcopenia in Older People (EWGSOP) in 2010 [22], the International Working Group on Sarcopenia (IWGS) in 2011 [23], the Asian Working Group for Sarcopenia (AWGS) [24], and the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Sarcopenia Project [25] in 2014 defined sarcopenia as low muscle strength and/or low physical function in addition to SMM.

In those consensus, muscle strength and physical function are important components of sarcopenia, but the assessment of muscle strength and/or physical function is not sufficient to apply a medical diagnosis under the precedent of the medical diagnosis of osteoporosis or metabolic syndrome. The SMM is still used as a primary marker, which is a more objective parameter than voluntary force production or conducting physical function test [26,27,28,29,30,31].

It is, however, not easy to assess human’s SMM in vivo accurately, and its definition is needed to be reconsidered. Especially, I would like to explain the concept of in vivo SMM is different from that of “muscle cell mass” (MCM). The ratio of MCM against SMM (MCM/SMM) changes with advancing age.

All methods of assessing SMM are indirect methodology since human body composition cannot be measured directly except for cadaver. As they are indirect methods, there are always hypotheses. The results of any indirect methods have systematic and/or random bias from those of direct measurement [32]. Therefore, when body composition is mentioned, the term “estimate, assess, or calculate” is used; avoid using the term “measure” in this article.

2 Estimate of Skeletal Muscle Mass (SMM) in Human Body

It has been tried to estimate SMM as one of the body compositions along with the fat and bone mass [1, 33]. In relation with obesity, the amount of body fat or percent body fat against body mass has been focused along with visceral fat, ectopic fat, hyperglycemia, hypertension, and hyperlipidemia. Bone mass and bone mineral content has been given attention with bone density, bone metabolism markers, and spine morphology because of its relationship with osteoporosis and risk of fracture. The SMM has been given importance in complex metabolic disorder syndrome (cachexia) that is characterized by the loss of muscle mass observed with drastic weight decrease in patients with chronic disease and myopathy such as muscular dystrophy and amyotrophic lateral sclerosis (ALS); however, the establishment of its clinical meaning in non-disease adult is delayed in comparison with body fat amount (obesity) and bone mass (osteoporosis).

On the other hand, in sports science area or exercise physiology, skeletal muscle mass assessment has been conducted relatively early because skeletal muscle mass has strong correlation with muscle strength or power which is one of the essential sport performance factors [34]. After various imaging methods and other estimation methods are invented, the research using assessment of muscle mass or muscle mass distribution has been performed strenuously [3, 34,35,36,37,38,39,40,41,42,43,44]. Especially, CT and MRI are currently considered as standard methods to estimate whole-body skeletal muscle volume or mass (e.g., skeletal muscle tissue density, 1.041 g/cm3 [45]) since they can estimate the total volume of whole-body skeletal muscle tissue by filming the whole body and extracting signal from skeletal muscle tissue. Dual-energy X-ray absorptiometry (DXA) is considered an alternative method to separate bone mass, adipose mass, and other soft lean tissues. It does not estimate whole-body SMM itself that is different from MRI and CT; however, appendicular lean soft tissue (ALST) estimated by DXA can be converted to SMM measured by MRI (at least in American) using the equation by Kim et al. [46].

3 The Difference of Age-Related Decreases Between Muscle Mass and Strength

In consideration with the above, muscle strength decreases 2.5 to 4% in a year, but SMM decreases only 0.5 to 1% [4]. To scrutinize Janssen et al. [3] research which measured skeletal muscle mass by MRI in 468 females and males with age from 18 to 88, the SMM difference of 20s to 70s in the upper body is approximately 8%. The SMM difference of 20s to 70s in the lower body is ~26% in male and ~23% in female; the decrease rate of lower body is about three times as high as that of the upper body, but it is still only about 0.5% decrease in a year. It is worth noting that there is a significant difference in decrease rate between muscle groups even in the lower body muscles. Assessing for muscle thickness change of each body part with age, ultrasound imaging device has been especially used for many previous researches [34, 44, 47,48,49,50,51,52,53]. For example, when it is measured by ultrasound imaging, the decrease rate of the front thigh is greater than that of the back thigh [42, 43, 54, 55]; the decrease ratio of 20s to 70s in the front thigh muscle thickness is ~30%. These values are very similar to the direct measurement of cross-sectional area (CSA) of the vastus lateralis muscle in the cadavers by Lexell et al. [56]; the decrease ratio of 20s to 70s was ~26% (Fig. 3.4).

Fig. 3.4
figure 4

Relationship between age and skeletal muscle mass (SMM) in the lower body and upper body in 268 men (a) and 200 women (b) aged 1888 years old. The SMM was assessed by MRI, and its difference of 20s to 70s in the upper body is approximately 8%. The SMM difference of 20s to 70s in the lower body is ~26% in male and ~23% in female; the decrease rate of the lower body is about three times as high as that of the upper body, but it is still only about 0.5% decrease in a year. (The figure was created based upon Table 1 of Janssen et al. 2000 [3])

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With all the above considered, the measurement sensitivity of muscle mass change is higher in using MRI or CT than in using traditional two-component method of lean mass estimation. Furthermore, the measurement of muscle groups, which atrophy rate is large, such as muscle mass in the lower body, is seemingly more useful than that of the whole-body muscle mass for the relationship with physical function. However, this explains only 20 to 50% of muscle force or its decrease rate, and the rest of 50 to 80% can be explained by, what we call, “factors other than SMM decrease” [4]. For these “factors other than SMM decrease,” “neural factors” that include from central nerve to neuromuscular junction have been considered as major factors. Various researches have been proceeded, however, and other potential factors of neural factors are also discussed recently as described in the following sessions.

4 Concept About Skeletal Muscle Cell Mass (MCM)

In the abovementioned cadaver research by Lexell et al. [56], in addition to measurement of vastus lateralis CSA, myofiber number, myofiber size, and the ratio of fast muscle fiber to slow-twitch fiber were also measured under the microscope (Fig. 3.5a and b). Scrutinizing this research data brings about significant meanings. The CSA decrease rate of 20s to 70s was ~26%, but the myofiber number decrease ratio was up to 41%. The decrease rate of mean CSA of one myofiber was ~11% (Type I myofiber, ~0% decrease; Type II myofiber, ~25% decrease). Thus, from the values in literature, when I calculate “total myofiber CSA” using the equation of myofiber number multiplied by mean one myofiber CSA, the decrease rate of 20s to 70s is ~48% [57, 58]. This shows that the proportion of myofiber (cell) area to whole-muscle CSA is decreased with advancing age. SMM decrease rate with age is different from MCM decrease rate (Fig. 3.5c). As implied by Fig. 3.1a, this is because intercellular gap becomes large. Intercellular gap includes connective tissue, adipose outside of muscle cell, and extracellular water (ECW) (Fig. 3.5).

Fig. 3.5
figure 5

(a) Micrographic picture of cross section of m. vastus lateralis from a young (left) and an old (right) individual. (Originally from Lexell et al. 1988. The scale of the picture from old individual was modified to match into the scale of the younger one by Yamada.) (b) The picture of prepared cross section of m. vastus lateralis for measurement of cross-sectional area (CSA). (c) The rate of loss of whole-muscle CSA and total muscle fiber (cell) CSA. Total muscle fiber CSA was calculated as muscle fiber number multiplied by mean fiber size by Yamada 2015. (Figures A and B are reprinted from Lexell et al. 1988 [56] and Fig. C is reprinted from Yamada 2015 [32] with permission)

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Normal imaging methods, like MRI, CT, or DXA, cannot evaluate this intercellular gap, and this results in overestimating muscle cell mass. Skeletal muscle is not a homogeneous tissue and composed of MCM, extracellular space (ECS), and adipose tissue mass (ATM) in its cell level (Fig. 3.2) [59]. Since the MCM gives tension, the assessment of MCM and/or the ratio of MCM/SMM is essential. It is well known that the proportion of ATM to SMM increases with advancing age; except for this, the MCM/SMM changes if ECS and MCM ratio changes. The ratio of solid to liquid in the MCM (intracellular water, ICW), the ratio of solid to liquid in the ECS (extracellular water, ECW), and the ratio of water in the ATM (adipose tissue water, ATW) are not always constant but can be considered to be relatively stable as 0.72, 0.97, and 0.14 in normal hydration status of homeostasis, respectively. Therefore, in this case, the ratio of intracellular water to total water (TW) in the skeletal muscle tissue (ICW/TW) can be considered an index for the MCM/SMM (Fig. 3.6).

Fig. 3.6
figure 6

Model of muscle composition (Mingrone et al. 2001). Skeletal muscle contains not only “contractile” tissue but also “non-contractile” tissue. Inter-muscular adipose tissue and intramuscular fat and extracellular water are “non-contractile” components in muscle tissue. (The figure is reprinted from Yamada 2015 [32] with permission)

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5 Estimation Method of MCM/SMM

Segmental bioelectrical impedance spectroscopy (BIS) or multifrequency bioelectrical impedance analysis (MF-BIA) is useful to assess the ratio of ICW/TW that is related to the MCM/SMM. The detailed explanation for BIS and MF-BIA was described in our previous articles [60, 61] (Fig. 3.8), which is briefly summarized below. Muscle cell membrane is composed of phospholipid bilayer and works as a capacitor on the alternating current circuit. The alternating current with low frequency (e.g., 5 kHz) cannot pass through inside of cells and mainly pass through extracellular space. On the other hand, the alternating current with high frequency (e.g., 250 kHz or 500 kHz) can pass through inside of cells [62] (Fig. 3.4a). Since the ICW/TW is relatively stable in normal young adults and there is strong correlation among TBW, ICW, and ECW [63, 64], single-frequency bioelectrical impedance analysis (SF-BIA) using 50 kHz is sufficient to evaluate skeletal muscle mass [65, 66]. For example, Miyatani et al. research [65] in young adults showed that, with impedance value at 50 kHz (Z50), the impedance index (L2/Z50; L, segment length), which is an index related to muscle mass in the upper leg, lower leg, upper arm, and forearm, was highly correlated to SMM obtained by MRI and maximal voluntary joint torques of corresponding muscle groups (Fig. 3.7).

Fig. 3.7
figure 7

(a) Upper panel: electrode placements of segmental bioelectrical impedance spectroscopy (S-BIS) measurement for a single leg. Lower panel: schematic representation showing muscle mass detection by dual-energy X-ray absorptiometry (DXA) and S-BIS. DXA measures appendicular lean mass and cannot inform about lean mass composition. (b) S-BIS takes advantage of the partitioning of contents in appendicular skeletal muscle between intracellular and extracellular pools. (c) Representative Cole-Cole plot of resistance versus reactance measures obtained by leg S-BIS from one individual from the study cohort. The intracellular resistance (RI) was calculated using 1/[(1/R∞) − (1/R0)]. (d) Representative frequency versus reactance measures obtained by leg S-BIS from 29-, 56-, and 76-year-old female adults (solid line, dashed line, and chain line, respectively). Older adults tended to have lower reactance. (The figure is reprinted from Yamada et al. 2017 [61] with permission)

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On the other hand, in our research with 405 old female and male participants aged 65 to 90 years old [60], the impedance index of 50 kHz in the upper leg segments (L2/Z50) was just moderately correlated to maximal voluntary knee extension strength. This means the muscle mass must be evaluated in consideration with the ICW/TW change with age in the elderly [67]. Actually, the relative expansion of ECW and decrease of ICW/TW were observed in older adults compared with younger adults (Fig. 3.8). We, therefore, proposed to use the segmental MF-BIA for skeletal muscle mass evaluation and validated it against CT [68]. While the traditional method overestimates muscle mass in the people who have larger ECW/ICW ratio, the newly developed segmental MF-BIA can evaluate muscle mass properly in the elderly since the impedance value combination of 250 kHz and 5 kHz can discriminate ICW from ECW. In addition, this method shows more significant correlation in muscle strength in the elderly in comparison with the traditional method [60]. This index is also correlated to walking speed in the elderly [69] (Fig. 3.9).

Fig. 3.8
figure 8

Water distribution in the lower leg estimated by S-BIS (mean ± SD). (a) ***significantly lower intracellular water (ICW) than young adult (p < 0.001); †significantly lower ICW than elderly adults. No significant main effect was observed in extracellular water (ECW). The total bar shows the sum of ICW and ECW (total water [TW]). (b) The ECW/TW ratio increased significantly with aging. ***significantly higher than young adult (p < 0.001); †significantly higher than elderly adults. (The figure is reprinted from Yamada et al. 2010 [67] with permission)

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Fig. 3.9
figure 9

The relationships between the ratio of extra- and intracellular water (ECW/ICW) in the upper legs as assessed by segmental bioelectrical impedance spectroscopy (S-BIS) and isometric knee extension strength (a) and maximal gait speed (b). ○ women and ● men. (The figure is reprinted from Yamada et al. 2017 [69] with permission)

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While this method used fixed frequencies of 250 kHz (or 500 kHz) and 5 kHz [63, 70], various frequency currents ranging from 1 to 1000 kHz (BIS; Fig. 3.4b) were used in the other method [71, 72]. Resistance values (R0 and R∞) at 0 kHz (direct current) and infinite frequency (∞ kHz) obtaining from Cole-Cole plot of resistance (R) vs. reactance (Xc) resulting in a semicircular arc, BIS characterizes the measurement segment for ECW and ICW. There is another model that is the combination of this model with the emulsion electrochemical model [64, 72] by Dr. Tetsuya Hanai (Hanai mixing theory) [73]; this is beyond scope of this article. The BIS method is theoretically reflected to ECW and ICW more precisely [64]. But when there is correlation coefficients with the muscle strength or power were compared between MF-BIA and BIS, there is no significant difference between MF-BIA and BIS. Although BIS is more strictly stick to the theory but reactance measurement is difficult especially at lower or higher frequency, R0 and R∞ that are calculated by extrapolation method of curve regression may have a large margin of error. It is, therefore, meaningful to directly use impedance at 250 kHz or 5 kHz that has less error cause [60]. Note that there is an alternative way for SF-BIA to use Xc and phase angle information to obtain body compositions [74, 75] and electrical characteristics of BIS are related to muscle function [61]. Additionally, most recent study shows that appendicular ICW estimating BIS have interesting information for sarcopenia [76].

Impedance is influenced not only by the amount of water but ion concentration in the fluid; thus, it is required to use assumption for the specific resistance of ICW and ECW. In relationship K+ ion and BCM or ICW in the elderly [77], TBK/FFM or TBK/TBW decreases with age in the whole-body measurement, but TBK/BCM and TBK/ICW are constant [78]; this is supported by the data in rat exenterate skeletal muscle [79]. Therefore, ICW can be considered the index to reflect MCM. As another issue, the change of ICW/TW in the limbs with age obtained by BIS or MF-BIA is seemingly greater than that of ICW/TBW in the whole body in physiology field. This may be partly because few research has been conducted in elderly with age over 80; it is necessary to perform the investigation of skeletal muscle compositions in various ages. It is also necessary to evaluate edema, inflammation, body fluid shift after exercise or posture change, or the influence on various diseases [80,81,82].

6 Relationship Between Muscle Composition and Muscle Function

Whenever BIS or MF-BIA is used, ICW in the limbs, which is reflected to MCM, decreases with age [67], especially the elderly who require nursing care shows low ICW in the limbs [77]. In comparison with a traditional muscle mass index, ICW shows stronger correlation to muscle strength, muscle power, and ability to stand up from the chair; it is possible to discriminate the requirement of nursing care with good sensitivity and specificity. In addition, ICW/TW, which is a biomarker of MCM/SMM, also decreases with age and especially shows low value in the elderly who require nursing care. Interestingly, ICW/TW, being independent of skeletal muscle index of ICW, is also statistically significantly correlated to muscle strength, muscle power, and ability to stand up from the chair. ICW/TW decrease reflects the decrease of the ratio of muscle cells per unit volume; it is also the index for relative expansion of ECW or dilatation of extracellular matrix, connective tissue, or adipose tissue between muscle cells. The relationship between this index and the increase of adipose tissue mass and connective tissue must be scrutinized; if the density of muscle fiber is low (low muscle density), the decrease of lateral transmission of force can happen [83].

It is possible to evaluate muscle composition or muscle quality by not only relative increase of ECW by BIS but CT, MRI, diffusion tensor MRI (DT-MRI), Dixon MRI, or ultrasonic image echo intensity [84]. For example, Hounsfield unit (HU), signal strength of CT, is the degree of X-ray attenuation with the following conditions: distilled water at standard pressure (1000 hPa) (STP defined by IUPAC) and standard temperature (0 °C) is defined as 0 HU; the radiodensity of air is defined as −1000 HU. The HU value of the fat tissue is negative (approximately -100 to -50HU) while that of the muscle tissue is positive (approximately 0 to 100HU). Mean HU value of muscle tissue area decreases with age; the proportion of normal-density muscle area (30 to 100HU) decreases, and that of low-density muscle area (0 to 30HU) increases. This fact especially reflects to adipose tissue mass [85, 86]. However, since HU value of water is 0 HU and that of solid mass in the skeletal muscle shows high, mean HU value decreases even if the MCM/SMM decreases. Thus, the low HU value in the elderly possibly also reflects relative ECW increase in addition to adipose tissue mass increase. It is known that adipose tissue mass measured by MRI or a non-contraction factor is high in the elderly [87], the λ value of diffusion tensor MRI changes with age [88], and T2 value of the skeletal muscle at rest is high in the elderly [89]. In addition, in recent years, it is clear that ultrasonic image shows brighter in the elderly than in the young, and its echo intensity is negatively correlated to muscle force [52, 90,91,92]. Most recent study suggests that ultrasonic image echo intensity is correlated to muscle strength independent of the ratio of intracellular fluid to extracellular by BIS in the elderly [93] (Fig. 3.10).

Fig. 3.10
figure 10

(a) Ultrasound sites for each muscle. a.. Biceps brachii, two-thirds of the way between the acromion and the antecubital crease. b. Quadriceps femoris, midway between the anterior superior iliac spine and the proximal end of the patella. c. Rectus abdominis, 3 cm lateral to the umbilicus. d. External oblique, internal oblique, and transversus abdominis, 2.5 cm anterior to the midaxillary line, at the midpoint between the inferior rib and the iliac crest. (b) Representative ultrasound images. Echo intensity (EI) can be assessed by computer-assisted 8-bit gray-scale analysis using the standard histogram function in Adobe Photoshop Elements (Adobe Systems, San Jose, CA, USA) or other image software as an index of muscle quality. (The figure is reprinted from Fukumoto et al. 2015 [52] with permission)

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As it is mentioned above, while muscle force decreases 2.5 to 4% in a year, the SMM decreases only 0.5 to 1% in a year [4]. In contrast, the actual decrease rate of MCM is thought to be as twice as that of SMM since the composition of muscle changes drastically. However, MCM decrease rate does not explain fully about the muscle force decrease. For this part, as it is mentioned above, ICW/TW (or MCM/SMM) is the factor to explain muscle force independent of ICW; the decrease of myofiber density is probably related to the decrease of lateral transmission of force [83]. But, in addition to this, various changes happen to the muscle tissue and the neuromuscular system [4]. Muscle tissue factors are as follows: the decrease of pennation angle and muscle fascicle length with age [94], selective atrophy of fast muscle fiber with change of its cross-sectional shape (e.g., a crushed shape) [56], qualitative and quantitative changes of extracellular matrix (ECM) [83, 95], decrease in the number of satellite cells relative to the total number of nuclei of muscle fibers [96], increased occurrence of coexistence of myosin heavy chain isoforms in single fibers [97], increased myonuclear domain (MND) size variability [98], and the decrease of Ca2+ sensitivity and the reduction of Ca2+ release [99]. Age-related change in the tendon tissue also occurred [100]. Neuromuscular system factors are as follows: decrease in the number of motoneurons and the remaining intact motoneurons sprouting to innervate the denervated fibers [101], decrease in α-motoneuron excitability [102, 103], excitability of the motor cortex to the spine [104, 105], decrease of nerve conduction velocity [106], co-contraction of the antagonistic muscle [107], and elaborated muscle synergy adjustment [108]. However, exhaustive research is required to determine how much degree these factors influence to the decrease of muscle force with aging since there is a literature stating antagonist torques cannot explain the observed torque declines at the knee joint, for example [109].

At any rate, skeletal muscle cell mass in the body may change more drastically than it used to be considered. Ikenaga et al. reported that ICW at the thigh increased when slightly weighted (+200 g) shoe interventions were given to the elderly and the lower and long-term low degree burden (average 10,000 step walking for 100 min a day) was given to the lower limbs [110]. Also, ICW increase in the thigh was observed when weekly 90- to 180-min/wk moderate intermittent slow jogging interventions for 12 weeks were given, although the total muscle CSA obtained by CT was not changed [111].

7 Frailty, Sarcopenia, Skeletal Muscle Cell Mass, and Muscle Composition

World turns into the aging, aged or super-aged society, and life expectancy is increasing worldwide. The population of elderly over 75 is drastically increasing. The elderly gradually decreases physical function, daily activity level, and independence with advancing age [112]. This process is called frailty [113, 114]. According to Fried et al. criteria, if one has the presence of three or more of the following five components, one is frail: “shrinking: weight loss, unintentional,” “grip strength weakness,” “poor endurance and energy,” “slowness,” and “low physical activity level.” “Poor endurance and energy” is included because it is a good indicator of VO2max and is a predictive indicator of cardiovascular disease. Depending on cohort design, it is possible to determine frailty by just asking all questions, but basic concept of Fried criteria is to use actual measurement values since it consists of “weight (muscle mass) decrease,” “grip strength,” “aerobic capacity,” “walking speed,” and “daily physical activity.” The concept of this type of frailty seems to be based on factors measured in exercise physiology area [113, 114]. Other several types of frailty indices were also proposed [115,116,117]. The frailty with or without muscle atrophy is a research topic for healthy life span from rodents [118,119,120,121,122], nonhuman primates [123], and human [114, 115, 124, 125].

The concept of frailty and sarcopenia is overlapped currently, and central component of frailty is considered to be sarcopenia. Since EWGSOP proposed the definition of sarcopenia with advancing age and its diagnosis criteria in 2010 [22, 26], active discussion is ongoing like IWGS [23, 27], FNIH sarcopenia project [28,29,30,31, 126], and AWGS [24]. In addition, the concept between sarcopenia, cachexia, and muscle wasting disorders is complex and sometimes confused in research or clinical settings [127,128,129,130]. One of the current important issues is that it is difficult to reach international consensus because the prevalence of sarcopenia is different depending on what guidelines and which SMM assessment techniques are used [131,132,133]. One of the biggest problems is that there is no consensus about how to assess “skeletal muscle mass (SMM)” quickly and easily in clinical settings [134]. For example, since it is not feasible to measure skeletal muscle mass in the whole body by CT or MRI in clinical environments and the measurement by DXA or BIA is device-dependent, there is no absolute method [135, 136]. Furthermore, SMM or CSA by CT that is estimated by ALST via DXA is moderately or poorly correlated to physical function decrease or total death risk [7,8,9]. To solve this, it is necessary to reconstruct the definition of “skeletal muscle mass.” Most recent 4-year longitudinal study found that association of physical activity with age-related changes in quadriceps femoris muscle thickness and echo intensity in older adults [137]. As it is mentioned above, it is necessary to reconsider skeletal MCM and muscle compositions by paying attention to SMM compositions and their quality. In addition, the researches about effects of exercise, physical activity, nutritional status on MCM or SMM and complex frailty cycle are needed for future direction (Fig. 3.11) [138].

Fig. 3.11
figure 11

Schematic diagram of the cycle of frailty by the Kihon Checklist (KCL) and its relationship to protein intake. IADL Instrumental activities of daily living, KCL Q question number of KCL. (This figure is reprinted from Nanri et al. [137] with permission)

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