Sarcopenia | |
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Difference between a normal muscle and an atrophied muscle | |
Specialty | Geriatrics Rheumatology |
Sarcopenia (ICD-10 code M62.84) is a type of muscle loss that occurs with aging and/or immobility. It is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss is dependent on exercise level, co-morbidities, nutrition and other factors. The muscle loss is related to changes in muscle synthesis signalling pathways. It is distinct from cachexia, in which muscle is degraded through cytokine-mediated degradation, although the two conditions may co-exist. Sarcopenia is considered a component of frailty syndrome. [1] Sarcopenia can lead to reduced quality of life, falls, fracture, and disability. [2] [3]
Sarcopenia is a factor in changing body composition. When associated with aging populations, certain muscle regions are expected to be affected first, specifically the anterior thigh and abdominal muscles. [2] [4] In population studies, body mass index (BMI) is seen to decrease in aging populations while bioelectrical impedance analysis (BIA) shows body fat proportion rising. [5]
The term sarcopenia stems from Greek σάρξ sarx, "flesh" and πενία penia, "poverty". This was first proposed by Rosenberg in 1989, who wrote that "there may be no single feature of age-related decline that could more dramatically affect ambulation, mobility, calorie intake, and overall nutrient intake and status, independence, breathing, etc".[ citation needed ]
Sarcopenia is distinct from cachexia, in which muscle is degraded through cytokine-mediated degradation, although the two conditions may co-exist.
The hallmark sign of sarcopenia is loss of lean muscle mass, or muscle atrophy. The change in body composition may be difficult to detect due to obesity, changes in fat mass, or edema. Changes in weight, limb or waist circumference are not reliable indicators of muscle mass changes. Sarcopenia may also cause reduced strength, functional decline and increased risk of falling. Sarcopenia may also have no symptoms until it is severe and is often unrecognized. [1] Research has shown, however, that hypertrophy may occur in the upper parts of the body to compensate for this loss of lean muscle mass [2] [6] Therefore, one early indicator of the onset of sarcopenia can be significant loss of muscle mass in the anterior thigh and abdominal muscles. [2]
There are many proposed causes of sarcopenia and it is likely the result of multiple interacting factors. Understanding of the causes of sarcopenia is incomplete, however changes in hormones, immobility, age-related muscle changes, nutrition and neurodegenerative changes have all been recognized as potential causative factors. [7]
The degree of sarcopenia is determined by two factors: the initial amount of muscle mass and the rate at which muscle mass declines. Due to variations in these factors across the population, the rate of progression and the threshold at which muscle loss becomes apparent is variable. [8] Immobility dramatically increases the rate of muscle loss, even in younger people. Other factors that can increase the rate of progression of sarcopenia include decreased nutrient intake, low physical activity, or chronic disease. [1] Additionally, epidemiological research has indicated that early environmental influences may have long-term effects on muscle health. For example, low birth weight, a marker of a poor early environment, is associated with reduced muscle mass and strength in adult life. [9] [10] [11]
There are multiple theories proposed to explain the mechanisms of muscle changes of sarcopenia including changes in myosatellite cell recruitment, changes in anabolic signalling, protein oxidation, inflammation, and developmental factors. The pathologic changes of sarcopenia include a reduction in muscle tissue quality as reflected in the replacement of muscle fibers with fat, an increase in fibrosis, changes in muscle metabolism, oxidative stress, and degeneration of the neuromuscular junction. [12] The failure to activate satellite cells upon injury or exercise is also thought to contribute to the pathophysiology of sarcopenia. [12] Additionally, oxidized proteins can lead to a buildup of lipofuscin and cross-linked proteins causing an accumulation of non-contractile material in the skeletal muscle and contribute to sarcopenic muscle. [8]
In sarcopenic muscle the distribution of the types of muscle fibers changes with a decrease in type II muscle fibers, or "fast twitch," with little to no decrease in type I muscle fibers, or "slow-twitch" muscle fibers. Deinervated type II fibers are often converted to type I fibers by reinnervation by slow type I fiber motor nerves. [13] Males are perhaps more susceptible for this aging-related switching of the myofiber type, as a recent research has shown a higher percentage of "slow twitch" muscle fibers in old compared to young males, but not in old compared to young females. [14]
Aging sarcopenic muscle shows an accumulation of mitochondrial DNA mutations, which has been demonstrated in various other cell types as well. [15] Clones with mitochondrial mutations build up in certain regions of the muscle, which goes along with an about fivefold increase in the absolute mtDNA copy number, that is, these regions are denser. [16] An apparent protective factor preventing cells' buildup of damaged mitochondria is sufficient levels of the protein BNIP3. Deficiency of BNIP3 leads to muscle inflammation and atrophy. [17]
Furthermore, not every muscle is as susceptible to the atrophic effects of aging. For example, in both humans [18] and mice [19] it has been shown that lower leg muscles are not as susceptible to aging as upper leg muscles. This could perhaps be explained by the differential distribution of myofiber type within each muscle group, but this is unknown.
Multiple diagnostic criteria have been proposed by various expert groups and continues to be an area of research and debate. Despite the lack of a widely accepted definition, sarcopenia was assigned an ICD-10 code (M62.84) in 2016, recognizing it as a disease state. [20]
Sarcopenia can be diagnosed when a patient has muscle mass that is at least two standard deviations below the relevant population mean and has a slow walking speed. [21] The European Working Group on Sarcopenia in Older People (EWGSOP) developed a broad clinical definition for sarcopenia, designated as the presence of low muscle mass and either low muscular strength or low physical performance. [7] Other international groups have proposed criteria that include metrics on walking speed, distance walked in 6 minutes, or grip strength. [20] 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. [22]
There are screening tools for sarcopenia that assess patient reported difficulty in doing daily activities such as walking, climbing stairs or standing from a chair and have been shown to predict sarcopenia and poor functional outcomes. [23]
As sarcopenia is a complex clinical diagnosis, circulating biomarkers have been proposed as proxies for early diagnosis and prediction as well as for follow-up and serial assessment of response to interventions.
Aging and sarcopenia are associated with an increase in inflammatory markers ("inflamm-aging") including: C-reactive protein, tumor necrosis factor, interleukin-8, interleukin-6, granulocyte-monocyte colony-stimulating factor, interferons, and serine protease A1. [24]
Changes in hormones associated with aging and sarcopenia include a reduction in the sex-hormones testosterone and dehydroepiandrosterone sulfate, [25] as well as reduced levels of circulating growth hormone and IGF-1. [26]
Circulating C-terminal agrin fragments (CAF) have been found to be higher in accelerated sarcopenic patients. [27]
Lower plasma levels of the amino acids leucine and isoleucine as well as other essential amino acids were found in frail older people compared to non-frail controls. [28] [29]
Alanine aminotransferase (ALT) is responsible for the transfer of the α-amino group from an α-amino acid to an α-keto acid, transforming pyruvate to alanine in skeletal muscle. Low circulating ALT is a marker for low muscle mass and sarcopenia, [30] as well for increased disease activity in patients with inflammatory bowel disease. [31]
Exercise remains the intervention of choice for sarcopenia, but translation of research findings into clinical practice is challenging. The type, duration and intensity of exercise are variable between studies, preventing a standardized exercise prescription for sarcopenia. [32] Lack of exercise is a significant risk factor for sarcopenia and exercise can dramatically slow the rate of muscle loss. [33] Exercise can be an effective intervention because aging skeletal muscle retains the ability to synthesize proteins in response to short-term resistance exercise. [34] Progressive resistance training in older adults can improve physical performance (gait speed) and muscular strength. [35] [36] [37] Increased exercise can produce greater numbers of cellular mitochondria, increase capillary density, and increase the mass and strength of connective tissue. [38]
There are currently no approved medications for the treatment of sarcopenia. [39] 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. [40] [41] Additionally, recent studies suggest testosterone treatments may induce adverse cardiovascular events. [42] [43] [44]
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. [40] 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. [40]
Other medications under investigation as possible treatments for sarcopenia include ghrelin, vitamin D, angiotensin converting enzyme inhibitors, and eicosapentaenoic acid. [40] [41]
Intake of calories and protein are important stimuli for muscle protein synthesis. [45] Older adults may not utilize protein as efficiently as younger people and may require higher amounts to prevent muscle atrophy. [21] A number of expert groups have proposed an increase in dietary protein recommendations for older age groups to 1.0–1.2 g/kg body weight per day. [46] [47] Ensuring adequate nutrition in older adults is of interest in the prevention of sarcopenia and frailty, since it is a simple, low-cost treatment approach without major side effects. [48]
A component of sarcopenia is the loss of ability for aging skeletal muscle to respond to anabolic stimuli such as amino acids, especially at lower concentrations. However, aging muscle retains the ability of an anabolic response to protein or amino acids at larger doses. Supplementation with larger doses of amino acids, particularly leucine has been reported to counteract muscle loss with aging. [49] Exercise may work synergistically with amino acid supplementation. [39]
β-hydroxy β-methylbutyrate (HMB) is a metabolite of leucine that acts as a signalling molecule to stimulate protein synthesis. [21] [39] It is reported to have multiple targets, including stimulating mTOR and decreasing proteasome expression. Its use to prevent the loss of lean body mass in older adults is consistently supported in clinical trials. [50] [51] [52] More research is needed to determine the precise effects of HMB on muscle strength and function in this age group. [51]
The prevalence of sarcopenia depends on the definition used in each epidemiological study. Estimated prevalence in people between the ages of 60-70 is 5-13% and increases to 11-50% in people more than 80 years of age. This equates to >50 million people and is projected to affect >200 million in the next 40 years given the rising population of older adults. [7]
Sarcopenia is emerging as a major public health concern given the increased longevity of industrialized populations and growing geriatric population. Sarcopenia is a predictor of many adverse outcomes including increased disability, falls and mortality. [53] [54] Immobility or bed rest in populations predisposed to sarcopenia can cause dramatic impact on functional outcomes. In the elderly, this often leads to decreased biological reserve and increased vulnerability to stressors known as the "frailty syndrome". Loss of lean body mass is also associated with increased risk of infection, decreased immunity, and poor wound healing. The weakness that accompanies muscle atrophy leads to higher risk of falls, fractures, physical disability, need for institutional care, reduced quality of life, increased mortality, and increased healthcare costs. [21] This represents a significant personal and societal burden and its public health impact is increasingly recognized. [7]
There are significant opportunities to better understand the causes and consequences of sarcopenia and help guide clinical care. This includes elucidation of the molecular and cellular mechanisms of sarcopenia, further refinement of reference populations by ethnic groups, validation of diagnostic criteria and clinical tools, as well as tracking of incidence of hospitalization admissions, morbidity, and mortality. Identification and research on potential therapeutic approaches and timing of interventions is also needed. [55]
As of 2020 [update] , there are no drugs approved to treat muscle wasting in people with chronic diseases, and there is therefore an unmet need for anabolic drugs with few side effects. One aspect hindering drug approval for treatments for cachexia and sarcopenia is disagreement in endpoints. Several clinical trials have found that selective androgen receptor modulators (SARMs) improve lean mass in humans, but it is not clear whether strength and physical function are also improved. After promising results in a phase II trial, a phase III trial of the SARM ostarine was proven to increase lean body mass but did not show significant improvement in function. [56] It and other drugs—such as the growth hormone secretagogue anamorelin—have been refused regulatory approval despite significant increases in lean mass due to a lack of evidence that they increased physical performance. Preventing decline in functionality was not considered an acceptable endpoint by the Food and Drug Administration. It is not known how SARMs interact with dietary protein intake and resistance training in people with muscle wasting. [57] [58]
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain isobutyl group, making it a non-polar aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, and beans and other legumes. It is encoded by the codons UUA, UUG, CUU, CUC, CUA, and CUG. Leucine is named after the Greek word for "white": λευκός (leukós, "white"), after its common appearance as a white powder, a property it shares with many other amino acids.
Cachexia is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and AIDS. Systemic inflammation from these conditions can cause detrimental changes to metabolism and body composition. In contrast to weight loss from inadequate caloric intake, cachexia causes mostly muscle loss instead of fat loss. Diagnosis of cachexia can be difficult due to the lack of well-established diagnostic criteria. Cachexia can improve with treatment of the underlying illness but other treatment approaches have limited benefit. Cachexia is associated with increased mortality and poor quality of life.
Creatine is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. It exists in various tautomers in solutions. Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate (ATP), primarily in muscle and brain tissue. Recycling is achieved by converting adenosine diphosphate (ADP) back to ATP via donation of phosphate groups. Creatine also acts as a buffer.
Skeletal muscle is one of the three types of vertebrate muscle tissue, the other being cardiac muscle and smooth muscle. They are part of the voluntary muscular system and typically are attached by tendons to bones of a skeleton. The skeletal muscle cells are much longer than in the other types of muscle tissue, and are also known as muscle fibers. The tissue of a skeletal muscle is striated – having a striped appearance due to the arrangement of the sarcomeres.
Basal metabolic rate (BMR) is the rate of energy expenditure per unit time by endothermic animals at rest. It is reported in energy units per unit time ranging from watt (joule/second) to ml O2/min or joule per hour per kg body mass J/(h·kg). Proper measurement requires a strict set of criteria to be met. These criteria include being in a physically and psychologically undisturbed state and being in a thermally neutral environment while in the post-absorptive state (i.e., not actively digesting food). In bradymetabolic animals, such as fish and reptiles, the equivalent term standard metabolic rate (SMR) applies. It follows the same criteria as BMR, but requires the documentation of the temperature at which the metabolic rate was measured. This makes BMR a variant of standard metabolic rate measurement that excludes the temperature data, a practice that has led to problems in defining "standard" rates of metabolism for many mammals.
Myostatin is a protein that in humans is encoded by the MSTN gene. Myostatin is a myokine that is produced and released by myocytes and acts on muscle cells to inhibit muscle growth. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.
Bodybuilding supplements are dietary supplements commonly used by those involved in bodybuilding, weightlifting, mixed martial arts, and athletics for the purpose of facilitating an increase in lean body mass. Bodybuilding supplements may contain ingredients that are advertised to increase a person's muscle, body weight, athletic performance, and decrease a person's percent body fat for desired muscle definition. Among the most widely used are high protein drinks, pre-workout blends, branched-chain amino acids (BCAA), glutamine, arginine, essential fatty acids, creatine, HMB, whey protein, ZMA, and weight loss products. Supplements are sold either as single ingredient preparations or in the form of "stacks" – proprietary blends of various supplements marketed as offering synergistic advantages.
β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base, β-hydroxyβ-methylbutyrate, is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wound healing and provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS. In healthy adults, supplementation with HMB has been shown to increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce skeletal muscle damage from exercise, improve aerobic exercise performance, and expedite recovery from exercise. Medical reviews and meta-analyses indicate that HMB supplementation also helps to preserve or increase lean body mass and muscle strength in individuals experiencing age-related muscle loss. HMB produces these effects in part by stimulating the production of proteins and inhibiting the breakdown of proteins in muscle tissue. No adverse effects from long-term use as a dietary supplement in adults have been found.
A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch. Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid and alloisoleucine.
A protein supplement is a dietary supplement or a bodybuilding supplement, and usually comes in the form of a protein bar, protein powder, and even readily available as a protein shake. Usually made from whey, plant, and/or meat sources.
Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weakness and causes disability.
Sports nutrition is the study and practice of nutrition and diet with regards to improving anyone's athletic performance. Nutrition is an important part of many sports training regimens, being popular in strength sports and endurance sports. Sports nutrition focuses its studies on the type, as well as the quantity of fluids and food taken by an athlete. In addition, it deals with the consumption of nutrients such as vitamins, minerals, supplements and organic substances that include carbohydrates, proteins and fats.
Proteins are essential nutrients for the human body. They are one of the building blocks of body tissue and can also serve as a fuel source. As a fuel, proteins provide as much energy density as carbohydrates: 4 kcal per gram; in contrast, lipids provide 9 kcal per gram. The most important aspect and defining characteristic of protein from a nutritional standpoint is its amino acid composition.
Muscle hypertrophy or muscle building involves a hypertrophy or increase in size of skeletal muscle through a growth in size of its component cells. Two factors contribute to hypertrophy: sarcoplasmic hypertrophy, which focuses more on increased muscle glycogen storage; and myofibrillar hypertrophy, which focuses more on increased myofibril size. It is the primary focus of bodybuilding-related activities.
Frailty is a common geriatric syndrome that embodies an elevated risk of catastrophic declines in health and function among older adults. Frailty is a condition associated with ageing, and it has been recognized for centuries. It is a marker of a more widespread syndrome of frailty, with associated weakness, slowing, decreased energy, lower activity, and, when severe, unintended weight loss. As a frequent clinical syndrome in the elderly, various health risks are linked to health deterioration and frailty in older age, such as falls, disability, hospitalization, and mortality. Generally, frailty refers to older adults who lose independence. It also links to the experiences of losing dignity due to social and emotional isolation risk. Frailty has been identified as a risk factor for the development of dementia.
Sarcopenic obesity is a medical condition which is defined as the presence of both sarcopenia and obesity. Sarcopenia refers to the presence of low muscle mass and either low muscular strength or low physical performance. When this is accompanied by a high fat mass the condition is known as sarcopenic obesity.
Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of androgen receptor-positive breast cancer in women and for improvement of body composition in people taking GLP-1 receptor agonists like semaglutide. It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress urinary incontinence, but development for all other uses has been discontinued. Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength. As a result, enobosarm was not approved and development for this use was terminated. Enobosarm is taken by mouth.
Juven is a medical food that is manufactured by Abbott Laboratories and used to provide nutritional support under the care of a physician in individuals with muscle wasting due to AIDS or cancer, to promote wound healing following surgery or injury, or when otherwise recommended by a medical professional. It is a powdered nutritional supplement that contains 3 grams of calcium β-hydroxy β-methylbutyrate, 14 grams of L-arginine, and 14 grams of L-glutamine per two daily servings.
Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD) is an international and multidisciplinary non-profit organization, created in 2008 that focuses on cachexia and sarcopenia. As they are often under-diagnosed, patient groups aim to improve their awareness. Cachexia has been coined the "last illness" and is sometimes called "body wasting". The prevalence of cachexia ranges from 5–15% in end-stage chronic heart failure to 50–80% in advanced malignant cancer. It is estimated that 5 Million Americans have the condition and cachexia frequently occurs in patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD), HIV, Multiple sclerosis, neurological diseases, and rheumatoid arthritis. Mortality rates of cachexia patients range from 15 to 25% per year in severe COPD, 20–40% per year in patients with chronic heart failure or chronic kidney disease, to 20–80% per year in cancer cachexia. The SCWD was founded in 2008 on the initiative of Prof. Stefan D. Anker in Germany and Dr. John E. Morley in the US. It is made up of an international and multidisciplinary group of healthcare professionals in the fields of sarcopenia, cachexia and muscle wasting. As of 2018, the society had 150 members.
Dynapenia is the loss of muscular strength not caused by neurological or muscular disease that typically is associated with older adults.
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