Harman Patil (Editor)

Sarcopenia

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Covid-19
ICD-10  M62.84
ICD-9-CM  xxx

Sarcopenia is the degenerative loss of skeletal muscle mass (0.5–1% loss per year after the age of 50), quality, and strength associated with aging. Sarcopenia is a component of the frailty syndrome. It is often a component of cachexia. It can also exist independently of cachexia; whereas cachexia includes malaise and is secondary to an underlying pathosis (such as cancer), sarcopenia may occur in healthy people and does not necessarily include malaise. The term is from Greek σάρξ sarx, "flesh" and πενία penia, "poverty".

Contents

Classification

Sarcopenia received the International Classes of Disease (ICD) code M62.84 on 1 October 2016.

The European Working Group on Sarcopenia in Older People (EWGSOP) developed a clinical definition and consensus diagnostic criteria for age-related sarcopenia, using the presence of low muscle mass and either low muscular strength or low physical performance. Severe sarcopenia requires the presence of all three conditions.

Signs and symptoms

Sarcopenia is characterized first by a muscle atrophy (a decrease in the size of the muscle), along with a reduction in muscle tissue quality, characterized by such factors as replacement of muscle fibres with fat, an increase in fibrosis, changes in muscle metabolism, oxidative stress, and degeneration of the neuromuscular junction and leading to progressive loss of muscle function and frailty. Sarcopenia is determined by two factors: initial amount of muscle mass and rate at which aging decreases muscle mass. Due to the loss of independence associated with loss of muscle strength, the threshold at which muscle wasting becomes a disease is different pathologically from person to person.

Simple circumference measurement does not provide enough data to determine whether or not an individual is suffering from severe sarcopenia. Sarcopenia is also marked by a decrease in the circumference of distinct types of muscle fibers. Skeletal muscle has different fiber-types, which are characterized by expression of distinct myosin variants. During sarcopenia, there is a decrease in "type 2" fiber circumference (Type II), with little to no decrease in "type I" fiber circumference (Type I), and deinervated type 2 fibers are often converted to type 1 fibers by reinnervation by slow type 1 fiber motor nerves.

Causes

Satellite cells are small mononuclear cells that abut the muscle fiber. Satellite cells are normally activated upon injury or exercise. These cells then differentiate and fuse into the muscle fiber, helping to maintain its function. One theory is that sarcopenia is in part caused by a failure in satellite cell activation.

Extreme muscle loss is often a result of both diminishing anabolic signals, such as growth hormone and testosterone, and promotion of catabolic signals, such as pro-inflammatory cytokines.

Oxidized proteins increase in skeletal muscle with age and leads to a buildup of lipofuscin and cross-linked proteins that are normally removed via the proteolysis system. These proteins compile in the skeletal muscle tissue, but are dysfunctional. This leads to an accumulation of non-contractile material in the skeletal muscle. This helps explain why muscle strength decreases severely, as well as muscle mass, in sarcopenia.

One group has suggested that the evolutionary basis for the failure of the body to maintain muscle mass and function with age is that the genes governing these traits were selected in a Late Paleolithic environment in which there was a very high level of obligatory muscular effort, and that these genetic parameters are therefore ill-matched to a modern lifestyle characterized by high levels of lifelong sedentary behavior.

Epidemiological research into the developmental origins of health and disease has shown that early environmental influences on growth and development may have long-term consequences for human health. Low birth weight, a marker of a poor early environment, is associated with reduced muscle mass and strength in adult life. One study has shown that lower birth weight is associated with a significant decrease in muscle fibre score, suggesting that developmental influences on muscle morphology may explain the widely reported associations between lower birth weight and sarcopenia.

Diagnosis

A working definition for diagnosis was proposed in 1998 by Baumgartner et al which uses a measure of lean body mass as determined by dual energy X-ray absorptiometry (DEXA) compared to a normal reference population. His working definition uses a cut point of 2 standard deviations below the mean of lean mass for gender specific healthy young adults.

Since Baumgartner's working definition first appeared, some consensus groups have refined the definition, including the European Working Group on Sarcopenia in Older People (EWGSOP). Their consensus definition is:

  • Low muscle mass, (e.g. >2 standard deviations below that mean measured in young adults [aged 18–39 years in the 3rd NHANES population] of the same sex and ethnic background).
  • And either:

  • Low gait speed (e.g. a walking speed below 0.8 m/s in the 4-m walking test)
  • Or:

  • Low muscular strength (e.g. grip strength: <30 kg in males, <20 kg in females)
  • Severe sarcopenia requires the presence of all three conditions.

    Exercise

    Lack of exercise is thought to be a significant risk factor for sarcopenia. Even highly trained athletes experience its effects; master-class athletes who continue to train and compete throughout their adult lives exhibit a progressive loss of muscle mass and strength, and records in speed and strength events decline progressively after age 30.

    Master-class athletes maintain a high level of fitness throughout their lifespan. Even among master athletes, performance of marathon runners and weight lifters declines after approximately 40 years of age, with peak levels of performance decreased by approximately 50% by 80 years of age. However a gradual loss of muscle fibres begins only at approximately 50 years of age.

    Exercise is of interest in treatment of sarcopenia; evidence indicates increased ability and capacity of skeletal muscle to synthesize proteins in response to short-term resistance exercise. A 2009 Cochrane review also found evidence that in older adults progressive resistance training can improve physical performance (gait speed) and muscular strength, which are two key components of sarcopenia.

    Medication

    As of July 2015, there are no approved medications for the treatment of sarcopenia; however, β-hydroxy β-methylbutyrate (HMB), a metabolite of leucine which is sold as a dietary supplement, has demonstrated efficacy in preventing the loss of muscle mass in individuals with sarcopenia. A growing body of evidence supports the efficacy of HMB as a treatment for reducing, or even reversing, the loss of muscle mass, muscle function, and muscle strength in hypercatabolic disease states such as cancer cachexia; consequently, as of June 2016 it is recommended that both the prevention and treatment of sarcopenia and muscle wasting in general include supplementation with HMB, regular resistance exercise, and consumption of a high-protein diet. Based upon a meta-analysis in 2015, HMB supplementation appears to be useful as a treatment for preserving lean muscle mass in older adults. More research is needed to determine the precise effects of HMB on muscle strength and function in this age group.

    DHEA and human growth hormone have been shown to have little to no effect in this setting. Growth hormone increases muscle protein synthesis and increases muscle mass, but does not lead to gains in strength and function in most studies. This, and the similar lack of efficacy of its effector insulin-like growth factor 1 (IGF-1), may be due to local resistance to IGF-1 in aging muscle, resulting from inflammation and other age changes.

    Testosterone or other anabolic steroids have also been investigated for treatment of sarcopenia, and seem to have some positive effects on muscle strength and mass, but cause several side effects and raise concerns of prostate cancer in men and virilization in women. Additionally, recent studies suggest testosterone treatments may induce adverse cardiovascular events. Other approved medications under investigation as possible treatments for sarcopenia include ghrelin, vitamin D, angiotensin converting enzyme inhibitors, and eicosapentaenoic acid.

    Epidemiology

    A study, in community dwelling older adults with an average age of 67 years, found the UK prevalence of sarcopenia to be 4.6% in men and 7.9% in women using the EWGSOP approach. Another study, conducted in the United States among older adults with an average age of 70.1 years, found the prevalence of sarcopenia to be 36.5%.

    Society and culture

    Due to the lessened physical activity and increased longevity of industrialized populations, sarcopenia is emerging as a major health concern. Sarcopenia may progress to the extent that an older person may lose his or her ability to live independently. Furthermore, sarcopenia is an important independent predictor of disability in population-based studies, linked to poor balance, gait speed, falls, and fractures. Sarcopenia can be thought of as a muscular analog of osteoporosis, which is loss of bone, also caused by inactivity and counteracted by exercise. The combination of osteoporosis and sarcopenia results in the significant frailty often seen in the elderly population.

    Research directions

    Many opportunities remain for further refinement of reference populations by ethnic groups, and to further correlate the degrees of severity of sarcopenia to overt declines in functional performance (preferably using verified functional tests), as well as incidence of hospitalization admissions, morbidity, and mortality. The body of research points toward severe sarcopenia being predictive of negative outcomes, similar to those already shown to exist with frailty syndrome, as defined by the criteria set forth in 2001 by Fried et al.

    Future research should aim to gain a deeper understanding of the molecular and cellular mechanisms of sarcopenia and the application of a lifecourse approach to understanding aetiology as well as to informing the optimal timing of interventions.

    New pharmaceutical therapies in clinical development include myostatin and the selective androgen receptor modulators (SARMs). Nonsteriodal SARMs are of particular interest, given they exhibit significant selectivity between the anabolic effects of testosterone on muscle, but with little to no evidence of androgenic effects (such as prostate stimulation in men).

    MT-102, the first-in-class anabolic catabolic transforming agent (ACTA), has recently been tested in a Phase-II clinical study for treating cachexia in late-stage cancer patients. The study data show significant increases in body weight in patients treated with 10 mg of MT-102 twice daily over the study period of 16 weeks compared to significant decrease in body weight in patients receiving placebo treatment. In preclinical models, MT-102 has also shown benefits in reversing sarcopenia in elderly animals. Future clinical studies will investigate sarcopenia as potential second indication for MT-102.

    Novartis proposes the use of a new molecule BYM338 Bimagrumab for treatment of sarcopenia and plans to make a FDA submission in 2019.

    Clinical practice

    However, diagnosis can be difficult due to the comprehensive measurements used in research that are not always practical in healthcare settings. Hand grip strength alone has also been advocated as a clinical marker of sarcopenia that is simple and cost effective and has good predictive power, although it does not provide comprehensive information.

    Exercise remains the intervention of choice for sarcopenia but translation of findings into clinical practice is challenging. The type, duration and intensity of exercise are variable between studies, so an ‘off the shelf’ exercise prescription for sarcopenia remains an aspiration.

    The role of nutrition in preventing and treating sarcopenia is less clear. Large, well-designed studies of nutrition particularly in combination with exercise are needed, ideally across healthcare settings. For now, basing nutritional guidance on the evidence available from the wider health context is probably the best approach with little contention in the goals of replacing vitamin D where deficient, and ensuring an adequate intake of calories and protein, although there is debate about whether currently recommended protein intake levels are optimal.

    References

    Sarcopenia Wikipedia


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