other than increased mortality (with odds ratio much higher than those for community‐living older people), depleted muscle mass is also associated with infection, increased duration of mechanical ventilation, longer hospitalization, readmission rates, and rehabilitation needs [9]. Worse outcomes are observed among patients with liver failure.
MOBILITY LIMITATIONS
Functional decline, or mobility limitations, initially classified as one of the adverse consequences, has been incorporated into the definition and diagnosis of sarcopenia. For example, a prospective study of Hong Kong Chinese older people proposed that sarcopenia may be defined in terms of risk of physical limitations [10] and other adverse outcomes [11], and anthropometric cut points based on incident mobility and physical limitation have been proposed [12]. Similarly, the Foundation of National Institute of Health (FNIH) also proposed a data‐driven approach in deriving cut points that is associated with slow walking speed (<0.8 m/s) [13]. Other consensus panel definitions used a combination of muscle mass, muscle strength, and physical performance measures in the diagnosis of sarcopenia [14, 15]. Systematic reviews show that sarcopenia is associated with increased odds ratio of functional decline between 2.5 and 3.0 [1, 3].
FALLS AND FRACTURES
Sarcopenia has been reported to increase the rate of falls in two community‐living populations, with an hazard ratio (HR) between 2.38 and 3.23 [16, 17]. Reduced strength and poor balance would contribute directly to occurrence of falls. As expected, there is also an association between sarcopenia and fractures, not only mediated by occurrence of falls, but also through the hormonal interaction between muscle and bone, with a common factor giving rise to both muscle weakness and low bone mineral density, giving rise to the term osteosarcopenia [18]. The use of sarcopenia screening tool SARC‐F [19] combined with the fracture risk prediction tool FRAX improves fracture risk prediction in older Chinese men aged 65 years and over at 10 years [20] and in both men and women at 14 years [21].
QUALITY OF LIFE
Quality of life represents an important patient‐related outcome measure in the management of sarcopenia. Generic quality‐of‐life instruments such as the Medical Outcomes Study 36‐item Short Form Health Survey (SF‐36) have been widely used, and association examined in relationship to individual components included in the diagnosis of sarcopenia. A decline in these components is associated with poorer physical component of health‐related quality of life. Physical, psychological, and social factors may all contribute to poorer quality of life [22]. Specific tools for musculoskeletal health have also been proposed, including one for sarcopenia [23] (SarQol).
METABOLIC CONSEQUENCES
Skeletal muscle mass accounts for 40–50% of lean body mass in adults, and therefore the majority of whole‐body postprandial glucose disposal. Muscle mass is lost with age, leading to insulin resistance at the tissue level, with an adverse effect on glucose and energy homeostasis. The term “anabolic resistance” has been used to describe the reduced muscle protein synthesis in response to nutrients and the reduced insulin‐mediated suppression of proteolysis that occurs with sarcopenia [24]. It is known that people with type 2 diabetes mellitus (T2D) have a higher prevalence of sarcopenia, resulting in mobility limitations [25]. Increase in body fat in T2D may be one of the factors contributing to muscle dysfunction, by direct muscle fat infiltration or indirectly through upregulation of inflammatory cytokines. The coexistence of sarcopenia and obesity results in adverse cardiometabolic as well as functional outcomes [26, 27], although it is uncertain whether the process is sarcopenia leading to obesity or obesity leading to sarcopenia, and the term obese sarcopenia instead of sarcopenia obesity has been proposed to reflect the pathological sequence [28]. Current literature continues to use the term sarcopenic obesity, although there is no universal consensus definition to capture both conditions. Nevertheless, composite measures of both total body fat as well as sarcopenia measures predict mortality, incident mobility limitations, as well as cardiovascular diseases. However, the threshold values are different for different outcomes [29–31].
SECONDARY SARCOPENIA
The term secondary sarcopenia refers to loss of muscle mass as a result of disuse (for example, stroke or prolonged bedrest), and/or the presence of chronic diseases with varying degrees of upregulation of inflammatory cytokines, but distinct from the condition of cachexia. For example, the prevalence of sarcopenia in patients with heart failure (HF) is 20% higher compared with healthy subjects of the same age, and not confined only to the older age groups. There is increased catabolic stress in the skeletal muscle of HF patients, presenting clinical as reduced exercise tolerance, ventilator inefficiency, as well as inefficient chronotropic response. Malnutrition as a result of anorexia caused by inflammatory cytokines also aggravates muscle loss. Both malnutrition and sarcopenia are commonly observed among patients undergoing rehabilitation, the prevalence of both conditions ranging from 40 to 67% [32].
The relationship between secondary sarcopenia and cachexia is not distinct and may be viewed as a transition between the two states. While muscle loss occurs in cachexia, the underlying disease state plays a prominent role with its associated anorexia, weight loss, fatigue, and reduced physical activity. Anorexia, inflammation, insulin resistance, and increased muscle breakdown are more marked in cachexia, while inflammatory cytokines such as interleukin‐6 and tumor necrosis factor are highly elevated compared with sarcopenia [33].
CONTROVERSIES
Recently, there are ongoing discussions examining the role of functional outcomes of sarcopenia and muscle mass in the definition of sarcopenia itself. If the purpose of diagnosis of sarcopenia is to predict adverse outcomes so that interventional measures may be implemented (non‐pharmacological or pharmacological), then measures that actually predict adverse outcomes should be used. A community study of older adults with a mean age of 81.2 years showed that strength measures are better than muscle mass measures in predicting health‐related outcomes in older people [34]. Similarly, the Sarcopenia Definitions and Outcomes Project (supported by the National Institute on Aging and the Foundation for the National Institute of Health United States) analyzed pooled data from 10 prospective studies of community‐living older people in United States, Sweden, Amsterdam, and Hong Kong concluded that lean mass measured by dual energy x‐ray absorptiometry was not predictive of physical function, falls, or mortality, whereas more accurate estimation of muscle mass by isotope dilution method (D3Cr) was predictive (unpublished data presented at the SDOC conference in Boston in November 2018). However, use of this method would be difficult in community and clinical settings. Furthermore, some measures currently proposed to be incorporated into the definition of sarcopenia such as grip strength, may actually influence outcomes not via muscle but through neurological pathways that represent brain health [35].
CONCLUSION
Multiple pathways lead to age‐related muscle loss, which include poor nutrition, physical inactivity, oxidative damage to mitochondrial energy metabolism, upregulation of inflammatory cytokines, hormone resistance syndromes, protein anabolic failure, neurodegeneration, and changes in muscle fiber structure and the neuromuscular junction. Sarcopenia in turn leads to reduction in VO2 peak, reduced physical activity, mobility limitations, and consequent downstream adverse outcomes such as falls and fractures, disability and dependency, poor quality of life, use of hospital services, as well as mortality, contributing to a downward spiral of decline.
Strategies for early detection and intervention would be of public health and clinical importance.
REFERENCES
1 1. Beaudart C, Zaaria M, Pasleau F, Reginster JY, Bruyere O. Health outcomes of sarcopenia: A systematic review and meta‐analysis. PLoS One 2017; 12(1):e0169548.
2 2. Liu P, Hao