Measuring skeletal muscle and terminology

A number of methods are available for measuring total body composition in vivo, ranging from bioelectrical impedance to dual-energy X-ray absorptiometry. Measures of SMM are typically calculated from these methods. In ‘reference man’ (a traditional term, arising from early research in this area, that describes the typical body composition of adult males of an average body weight) total body mass consists of about 19 % fat mass and 81 % fat free mass (FFM), 91 % of which is lean soft tissue mass, with the remainder consisting of bone^{(Reference Buckinx, Landi and Cesari26–Reference Lam, Redman and Smith32)}. However, in women the proportion of fat mass in the body is, in the main, greater than in men and so is associated with a correspondingly lower proportion of FFM; see also section ‘Loss of skeletal muscle mass’ for further details. Development of three- and four-compartment methods for measuring SMM in populations is relatively recent, and much of the literature relating to sarcopenia and skeletal muscle refers to FFM, which has been considered a suitable measure of SMM, given that contributions from bone are small^{(Reference Mitchell, Williams and Atherton3,Reference Buckinx, Landi and Cesari26–Reference Heymsfield, Adamek and Gonzalez30,Reference Prado and Heymsfield33)} . Appendicular lean mass or appendicular skeletal muscle mass is the sum of lean tissue in the arms and legs^{(Reference Buckinx, Landi and Cesari26–Reference Heymsfield, Adamek and Gonzalez30)}.

Scaling for body size

Since FFM increases with greater body weight and height, studies in human subjects are scaled for body size^{(Reference Heymsfield, Hwaung and Ferreyro-Bravo29,Reference Heymsfield, Arteaga and McManus34–Reference Schuna, Peterson and Thomas36)} . Scaling can be by height, height², as a percentage of total body weight or by BMI.

Loss of skeletal muscle mass

Skeletal muscle, measured as FFM, accounts for about 70–80 % of body weight in men and 65–75 % in women of middle and early older age^{(Reference Welch, Skinner and Hickson37)}. Losses of SMM are gradual and progressive, ranging from 0·5 to 1 % per year, starting around middle age, with rates increasing over the age of 60 years^{(Reference Welch1–Reference Mitchell, Williams and Atherton3)}. Men experience greater rates of loss during older age, although their FFM, as a proportion of body size, is greater than in women at all life stages.

Muscle morphology changes during ageing and links to fat, carbohydrate and energy metabolism

Skeletal muscle is composed of three distinct types of muscle fibre, categorised by their energy metabolism and their myosin structures: slow-twitch, oxidative, type-I fibres; fast-twitch, oxidative-glycolytic, type-IIa fibres and fast-twitch, glycolytic, type-IIb fibres. Each category of fibre also shows different capacities for fatty acid utilisation, with type-I fibres contributing more to fatty acid oxidation and being more insulin-sensitive than type-IIb fibres^{(Reference Pearen, Eriksson and Fitzsimmons38)}. Human muscle shows multiple fibre types within a single muscle group, with different proportions of fibre types in each muscle; for example, the soleus muscle in the calf has mostly type-I fibres, while the vastus lateralis muscle in the thigh is largely type II^{(Reference Edgerton, Smith and Simpson39)}. These proportions are flexible, however, and muscle fibres can remodel their phenotypes to adapt to different circumstances, including ageing^{(Reference Pette and Staron40)}.

Ageing is associated with a conversion of muscle fibres to slow-twitch, oxidative, type-I fibres, and type-II fibres are seen to atrophy and shrink in diameter, while type-I fibres are relatively unaffected^{(Reference Evans and Lexell41)}. This may relate to damage, and ultimately breakage, experienced by muscle fibres during the ageing process^{(Reference Bua, McKiernan and Wanagat42)}. Further, the total number of muscle fibres in skeletal muscle decreases with age^{(Reference Lexell, Henriksson-Larsén and Winblad43)}, along with the cross-sectional area of the muscle, which has been shown to decrease by 25–35 % in older men and women^{(Reference Young, Stokes and Crowe44,Reference Young, Stokes and Crowe45)} . See Wilkinson, Piasecki and Atherton for a review of muscle fibre loss and atrophy with ageing^{(Reference Wilkinson, Piasecki and Atherton46)}. Measures of cross-sectional area underestimate losses in muscle contractile tissue, as muscle ageing is also accompanied by infiltration of fatty and fibrotic tissue^{(Reference Overend, Cunningham and Paterson47)}, which contributes to the disparity between mass and strength losses in sarcopenia. Fatty infiltration (myosteatosis) is related to the higher content of saturated ceramide and diacylglycerol fatty acids in older age^{(Reference Søgaard, Baranowski and Larsen48)}.

Mitochondrial effects during ageing and interaction with macronutrient metabolism

Mitochondria are also important in the context of ageing. In the cell, mitochondria are essential to metabolism as they use oxidative phosphorylation to produce a ready supply of ATP, a fundamental energy unit for cellular processes. Mitochondria in skeletal muscle form complex, anisotropic networks^{(Reference Kayar, Hoppeler and Mermod49)} that supply energy to fuel muscle contraction. There are two distinct subpopulations of mitochondria; one directly beneath the sarcolemma, and the other between myofibrils^{(Reference Takahashi and Hood50)}. Slow-twitch oxidative muscle fibres contain many more mitochondria than fast-twitch glycolytic fibres, and are more resistant to fatigue due to the large amount of ATP generated by their mitochondria. The oxidative phosphorylation efficiency of mitochondria, their capacity to produce ATP, has been shown to decline with age^{(Reference Conley, Jubrias and Esselman51)}, and is also influenced by insulin resistance, as discussed later in this review. Mitochondria also contribute to the ageing process: dysfunctional mitochondria accumulate with age, particularly in skeletal muscle^{(Reference Herbst, Pak and McKenzie52)}, and they ultimately become senescent^{(Reference Wiley Christopher, Velarde Michael and Lecot53)}, losing the ability to proliferate. Dysfunctional mitochondria generate reactive oxygen species (ROS), and the damage associated with these is central to some pathologies, as well as ageing^{(Reference Jensen54–Reference Murphy56)}; these dysfunctional mitochondria produce a vicious cycle of damage and deterioration in ageing muscle.

The ligand binding nuclear receptors found in skeletal muscle are transcription factors involved in metabolic control within skeletal muscle; see Baskin for an elegant review^{(Reference Baskin, Winders and Olson57)}. PPAR are critical regulators of the metabolic genes in striated muscle^{(Reference Fan, Atkins and Yu58)}, with PPARα being involved in transcription of the genes required for fatty acid uptake or oxidation. PPARα activation induces fatty acid utilisation in skeletal muscle^{(Reference Muoio, Way and Tanner59)}. Also PPARγ coactivator 1 α, along with PPARα, coordinates metabolic regulation within skeletal muscle, further regulating the GLUT4, cAMP response element binding protein and nuclear respiratory factors to mediate transcription of genes involved in fatty acid and glucose metabolism^{(Reference Baskin, Winders and Olson57)}.

In summary, the total number and diameter of skeletal muscle fibres decreases with age, fibre type shifts to slow-twitch type-I fibres that are more insulin-resistant and do not utilise glucose. Mitochondria become dysfunctional, or senescent, and generate ROS that further damage muscle. Further age-related changes in skeletal muscle morphology include infiltration of non-contractile material in muscle tissue, denervation, a reduction in the number of satellite cells, and a weakening of the connections between muscle and tendons. All of these have consequences for the functional capacity of skeletal muscle, as well as its ability to regenerate when damaged. The loss of SMM and morphological changes associated with ageing have the potential to impact directly on oxidation and utilisation of fatty acids as well as glucose utilisation and energy metabolism, see Table 1.

Table 1.

Age-related changes to morphology and quantity of skeletal muscle and interactions with macronutrient metabolism

Components of energy expenditure and balance between energy intake and energy expenditure

Total daily energy expenditure (TEE) comprises three main components: (1) REE, also referred to as RMR or BMR; (2) the thermic effect of food and (3) the energy expenditure associated with physical activity. See Fig. 2 for an illustration of these. In adults, REE accounts for 60–70 % of total energy requirements in healthy adults^{(Reference Lam, Redman and Smith32,Reference Bogardus, Taskinen and Zawadzki66–Reference Muller, Bosy-Westphal and Kutzner69)} . The proportion of REE attributable to organ mass ranges from about 5 to 10 %^{(Reference Lam, Redman and Smith32,Reference Muller, Bosy-Westphal and Kutzner68,Reference Muller, Bosy-Westphal and Kutzner69)} . FFM is the main predictor of REE, which is determined by the metabolism of macronutrients protein, carbohydrate, fat and alcohol. The contribution of the thermic effect of food to TEE is estimated at about 10 % of TEE. The contribution of habitual and discretionary physical activity to TEE is variable, ranging from about 15 % in very sedentary people to about 50 % in those who are very physically active. TEE reduces during ageing, partly due to reductions in habitual and discretionary physical activity but also due to the loss of metabolically active FFM, which consists of both skeletal tissue and that found in the internal organs.

Fig. 2.

Components of energy expenditure, energy intake and the concept of energy balance in older adults. Energy is released from metabolism of the macronutrients protein, carbohydrate and fat as well as alcohol. Energy expenditure comprises: resting energy expenditure (REE) or BMR, daily activities and discretionary physical activity and the thermic effect of digestion of food. Greater intake of total energy than total energy expenditure results in gain in body weight.

A balance must be maintained between energy expenditure and energy intake, derived from macronutrients and alcohol, in order to maintain a steady body weight, as described in Fig. 2. Body weight increases when excess energy intake is consumed compared with total energy expended.

Metabolic rate decreases with age in relation to loss of skeletal muscle mass and in clinical conditions of ageing

In the early 20th century, age-related reductions in BMR were observed, with Lewis finding that ‘0·664 calories per hour per square meter per hour’ were lost per decade of age in men^{(Reference Lewis70)}. That this was attributable to loss of SMM with age has been elaborated with further findings during this century in both men and women. Ravussin's study in 1986 identified the key determinants of 24-h energy expenditure in man, finding that FFM explained 81 % of the variance in energy expenditure in an obese population^{(Reference Ravussin, Lillioja and Anderson71)}. Furthermore, even after accounting for physical and spontaneous activity and the thermic effect of food, FFM remained the most important determinant of energy expenditure^{(Reference Ravussin, Lillioja and Anderson71)}. Subsequent studies found that RMR was lower in older than in younger men, and this was attributable to the lower proportion of FFM in older men^{(Reference Fukagawa, Bandini and Young72)}. Zurio and colleagues also found that differences in resting muscle metabolism partly accounted for the variance in metabolic rate amongst individuals of normal body weight^{(Reference Zurio, Larson and Bogardus73)}. Overall, findings were summarised by Weinsier and colleagues in 1992^{(Reference Weinsier, Schutz and Bracco74)}.

Recent research also indicates that FFM is a key predictor of TEE even in highly active younger people^{(Reference Barringer, Pasiakos and McClung75)}. This study measured energy expenditure using the doubly labelled water technique in military personnel engaged in intensive operations. Whilst physical activity was a key predictor of energy expenditure in this group (r 0·9, P < 0·05) the association of energy expenditure with FFM was greater than that with total body mass (r 0·32, P < 0·05; and r 0·28, P < 0·05, respectively) even in this population with a high physical activity.

Sex-specific differences in the relationship between total FFM and REE have been explored further^{(Reference Geisler, Braun and Pourhassan67)}. In men and women aged 18–79 years, women experienced an earlier decline in SMM than men, starting at age 29 years v. 39 years in men. However, SMM, adjusted for fat mass, remained the main determinant of REE in both men and women, with R ² 0·67 in women and R ² 0·66 in men^{(Reference Geisler, Braun and Pourhassan67)}. More recent work also suggests that the proportion of FFM impacts on, and partially determines, energy intake and expenditure, via its mediating effect on RMR^{(Reference Hopkins, Finlayson and Duarte76)}.

During ageing, the contribution of FFM to REE declines in parallel with the age-related decline in FFM, explaining 59·7 % of the decrease in REE. This indicates that the importance of FFM to REE increases with age^{(Reference Geisler, Braun and Pourhassan67)}. This is particularly important in underweight older people with low FFM^{(Reference Weinsier, Schutz and Bracco74,Reference Sergi, Coin and Bussolotto77)} , and the situation is exacerbated in nonagenarians^{(Reference Kim, Welsh and Ravussin78)}. Indeed, two recent studies found that decreased BMR is an objective marker for sarcopenia and frailty in older adults^{(Reference Kim, Welsh and Ravussin78,Reference Soysal, Ates Bulut and Yavuz79)} . Thus, in elderly people who are underweight and have low physical activity, REE represents the greatest part of TEE^{(Reference Weinsier, Schutz and Bracco74,Reference Sergi, Coin and Bussolotto77)} .

Overall, the contribution of FFM to TEE increases with age as the contribution of physical activity declines.

The effects of age-related skeletal muscle loss on metabolic rate and the onset of obesity

In middle and early-older-age the age-related decline in FFM and SMM may have implications for the onset of obesity. Obesity arises from the imbalance of energy intake and expenditure, and so the gradual loss of muscle mass with age has potential consequences for habitual energy expenditure and the energy imbalance that leads to the onset of obesity^{(Reference Wolfe2)}. Discretionary and habitual physical activity also declines during ageing, contributing to overall reductions in energy expenditure. Two studies found that skeletal muscle fibre-type proportion is related to obesity. The first found that obese men had a higher proportion of fast-twitch, type-II fibres in the vastus lateralis muscle^{(Reference Wade, Marbut and Round80)}. The second confirmed these findings in obese women and found that the effectiveness of a weight-loss intervention was positively related to the percentage of slow-twitch, type-I fibres, which contain a greater proportion of mitochondria than do fast -twitch fibres^{(Reference Tanner, Barakat and Dohm81)}, as discussed in the section ‘The effects of ageing on skeletal muscle mass and morphology’.

Robert Wolfe, in his important paper, calculated that every 10 kg of lean mass that is lost with age translates to a decrease in energy expenditure of about 418 kJ/d, assuming a constant rate of turnover^{(Reference Wolfe2)}. This is equivalent to an accumulation of about 4·7 kg fat mass per year, assuming 1 kg fat store represents 32 217 kJ. Clearly, this difference in energy expenditure would disproportionately affect older individuals, who tend to have lower levels of physical activity and thus greater potential to develop obesity, as well as sarcopenic obesity.

In summary, evidence is now clear that skeletal muscle contributes a lower proportion of REE to TEE during ageing, potentially contributing to onset of obesity from middle-age onwards.

Low skeletal muscle mass, sarcopenia and dynapenia are associated with or predict incidence of type-2 diabetes

A number of cross-sectional studies have demonstrated that low SMM is associated with insulin resistance or type-2 diabetes^{(Reference Scott, de Courten and Ebeling20,Reference Park, Goodpaster and Strotmeyer90–Reference Lee, Boyko and Strotmeyer96)} . Existing sarcopenia or dynapenia is also a risk factor for onset of diabetes, as is low SMM^{(Reference Wang, Feng and Zhou97–Reference Cuthbertson, Bell and Ng99)}. An increased hazard risk of 2·05 (95% CI 1·73, 2·43) was associated with onset of type-2 diabetes over 9 years in those with the lowest muscle mass index (appendicular lean mass adjusted for weight), compared with the highest tertile of muscle mass index, who had double the risk^{(Reference Son, Lee and Kim100)}. Moreover, this increased risk of type-2 diabetes was due to relatively small differences in muscle mass index at baseline of only 5·4 % between those at the greatest and least risk. Subsequently, maintenance of appendicular skeletal muscle mass was also found to be protective against the development of type-2 diabetes in men but not women, independent of obesity^{(Reference Kim, Lee and Kim101)}. However, a further study contradicted this finding, as women with a higher SMM were at greater risk of incident type-2 diabetes^{(Reference Larsen, Wassel and Kritchevsky102)}.

Impact of type-2 diabetes on skeletal muscle

Evidence is building that the presence of type-2 diabetes in older people leads to significant loss of SMM over time^{(Reference Son, Lee and Kim100,Reference Park, Goodpaster and Strotmeyer103)} . One study found that accelerated loss of SMM occurred in middle-aged and older women with diabetes^{(Reference Lee and Choi104)}; this is due to a number of disease processes, including the poor glycaemic control that is often associated with the existence of mild metabolic acidosis^{(Reference Sugimoto, Tabara and Ikegami95,Reference Welch, Macgregor and Skinner105,Reference Hayhoe, Abdelhamid and Luben106)} . That this is the case was confirmed in a study where treatment of diabetes with insulin attenuated the decline in muscle mass^{(Reference Bouchi, Fukuda and Takeuchi107)}.

In summary, age-related changes to skeletal muscle lead to glucose dysregulation, with consequent reduction in glycaemic control, increased insulin resistance and ultimately onset of type-2 diabetes, as shown in Fig. 3^{(Reference Scott, de Courten and Ebeling20,Reference Phielix and Mensink82–Reference van de Weijer, Sparks and Phielix84,Reference Barsalani, Brochu and Dionne89)} . These age-related changes in skeletal muscle also have implications for the progression of type-2 diabetes, with the onset of poor glycaemic control also accelerating skeletal muscle loss and the morphological changes that occur with age, leading to a vicious cycle of damage to muscle, as in Fig. 3.