Sarcopaenia

Introduction

Different body systems become dysregulated on anatomic, molecular and physiologic levels as people reach old age. There is a decline in humoral and cell-mediated immunity with advancing age. There is over expression of cytokines, decline in the level of hormones, immune senescence, loss of muscle mass (LMM) and muscle strength (MS).

Sarcopaenia

Aged population exhibit loss of functional muscle. Sarcopaenia (Gk. Sarx- flesh; penia-loss) is age-related LMM that is responsible for the decline in MS. It affects physical performance and quality of life. The term, sarcopaenia was first used in 1988 at a meeting in Albuquerque, USA, while discussing assessment of health and nutrition in elderly population. Elderly persons with sarcopaenia exhibit decreased lean body mass and MS. Ageing is associated with a marked uncoupling of muscle cross-sectional area and muscle fibre strength. The condition has drawn greater attention with increase in aged population.

In the past, sarcopenia was typically diagnosed by assessing low muscle mass using bioimpedance analysis and either low MS as indicated by grip strength, or reduced physical performance as indicated by slow gait speed. It was recognized based on age, grip strength and calf circumference. Irwin Rosenberg proposed the term in 1989 to describe age-related LMM. In his description, he pointed that there might not be a single aspect of age-related decline that could have a more significant impact on walking ability, mobility, calorie intake, overall nutrient intake and status, and functional independence.1

There can also be accumulation of fat in the muscle (myosteatosis). Myosteatosis refers to accumulation of fat in muscle and causes a decline in MS leading to functional impairment and physical disability, bringing about changes in gait and balance.²

The decline in muscle mass and function affects ambulation, mobility, nutrient intake and status and functional independence.³ In contrast to this condition, obese persons often have a greater lean body mass than persons with normal weight. However, within this group, a minority displays sarcopenia, known as "sarcopenic obesity" or "frailty with excess fat." These persons can become frail if they do not exercise adequately and eventually develop disability.⁴

Definition

Initially the term sarcopaenia was used to refer LMM, function and physical disability. Later the use of this term was restricted to LMM.

The Society for Sarcopaenia, Cachexia and Wasting Disorders in 2011 proposed the term ‘Sarcopaenia with limited mobility’ to define persons with a need for therapeutic intervention.⁵ The condition exhibits LMM and low walking speed (1 m/s or less during a four-metre walking test or less than 400 m during a six-minute walking test).

The European Working Group on Sarcopaenia in Older People (EWGSOP) included loss of muscle function in the definition. Sarcopenia was defined as, "a syndrome marked by the gradual and widespread reduction in skeletal muscle mass and strength, carrying the potential for adverse consequences such as physical disability, diminished quality of life, and mortality."⁶ Thus, there is presence of both low muscle mass and low muscle function.

Thus, sarcopaenia is a progressive and generalized skeletal muscle disorder associated with LMM and function.

Prevalence

Muscles grow from birth to third decade of life. Then there is a decline in muscle mass. This decline in muscle mass in physically active persons is 3-5 percent per decade. Relatively, the loss is greater in physically inactive persons. LMM is greater in elderly persons. Prevalence of sarcopaenia in an elderly population aged above 60 years in rural South India was 14.2% and it was higher in females.⁷

Aetiology

There are many causes for development of sarcopaenia (Table 1).⁸

Classification

Sarcopenia may be primary or secondary.⁶ Primary sarcopenia is age-related without any obvious cause. The secondary sarcopenia may be related to activity, disease or nutrition (Table 2).⁶

Sarcopaenia may be acute (duration lasting for <6 months) or chronic (lasting for >6 months). Age-related sarcopaenia is chronic.

Risk factors

It has been considered that sarcopaenia is inevitable with aging. It should be noted that it is variable and is dependent on the presence of certain risk factors as follows:⁹

1. Lack of exercise: There is a gradual decline in the number of muscle fibres with aging (>50 years). The decrease in muscle fibre and strength is more noticeable in individuals leading a sedentary lifestyle as opposed to those who are more physically active. 
2. Imbalance of hormone and cytokine: There is age-related decline in the levels of hormones such as growth hormone, testosterone, thyroid hormone and insulin-like growth factor. It leads to a decline in muscle mass and strength. The levels of pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin (IL)-6 are elevated. They mediate a combination of decreasing hormonal anabolic signals and increasing catabolic signals leading to extreme muscle loss.
3. Protein synthesis and regeneration: With aging, the body shows a decline in its ability to synthesize proteins. There is insufficient consumption of calories and/or protein to preserve muscle mass, alongside an accumulation of non-contractile dysfunctional proteins in skeletal muscles due to an increase in oxidized proteins as people age. It leads to decreased MS.
4. Motor unit remodelling: With aging, there is reduction in motor nerve cells leading to a reduction in signals to the muscles to initiate movement. There is presence of satellite cells (small mononuclear cells) on muscle fibres that get activated following injury or exercise. These signals enable satellite cells to differentiate and fuse into muscle fibres and help to maintain muscle function. It is likely there is a failure in satellite cell activation.
5. Evolutionary basis: There appears to be a failure of the body to maintain muscle mass and function with aging on genes that govern these traits.
6. Early developmental influences: Having a low birth weight is linked to reduced muscle mass and strength in adulthood.

Pathophysiology

The pathophysiology of sarcopaenia exhibits great complexity involving muscle and associated neural and hormonal regulation.¹⁰ Muscle tissue is not static. It exhibits a continuous process of atrophy and hypertrophy. It is a cyclical process of death and rejuvenation. Muscle proteins undergo degradation when they unfold and it leads to atrophy. The cells also undergo apoptosis. However, there is rejuvenation of the cells following incorporation of amino acids. It causes synthesis of protein leading to muscle hypertrophy. There is also stimulation of stem cells leading to production of satellite cells that are capable of repairing damaged muscle and subsequently growth of the muscle.¹¹

The intake of food must be adequate to maintain proper function of muscle. Protein and creatine play an important role.¹² Motor unit acuity gets diminished with advancing age. There is fall in the ciliary neurotrophic factor (CNTF) levels which is associated with decreased MS.¹³ The raised levels of cytokines, such as tumour-necrosis factor, alpha and interleukin-6, are associated with decreased MS.14 Diabetes mellitus is associated with decreased MS. With the development of atherosclerosis, muscle rejuvenation is affected as it leads to reduced blood supply to muscle.

The anabolic hormones such as growth hormone and testosterone activate insulin growth factor (IGF)-1 gene within the muscle. IGF-1 stimulates protein synthesis and muscle hypertrophy. It is under growth hormone regulation.¹⁵ The production of satellite cells is activated by mechano-growth factor (MGF) leading to an increase in muscle mass. In the absence of resistance exercise, the muscle fails to acquire strength. Growth hormone exhibits its action after the process is initiated by resistance exercise.¹⁶ Ghrelin, a growth hormone secretagogue can increase muscle mass and food intake.¹⁷

There is a fall in the concentration of testosterone with advancing age and it is associated with a decrease in MS and function. The level of testosterone falls with aging at the rate of nearly 1% per year.¹⁸ There is loss of anabolic stimuli. Muscle mass shows atrophy with androgen deprivation.¹⁹ Testosterone stimulates protein synthesis and satellite cell production.²⁰ Administration of large doses of testosterone can improve muscle mass and strength in hypogonadal men.²¹

The quality of muscle fibres slowly gets deteriorated with normal aging process. Along with that, the power shortening speed and elasticity show a slow decline.²² With advancing age, there is reduction in the number and activation of satellite cells. It may reduce the regenerative capacity of muscle fibres. In addition, the levels of myostatin increase with age. Myostatin is considered a negative regulator of muscle mass. Its increased levels may cause muscle atrophy.¹⁵

Clinical features

In the early stages of the course of sarcopaenia, no loss of physical or functional independence is observed. It gives a valuable opportunity to carry out interference to decelerate its progression of sarcopaenia and prevent physical disability.¹ Generally, the patients with sarcopaenia show progressive disability. However, these patients are generally unaware of their sarcopaenic state. There is a gradual decline in muscle function. Only when it becomes severe, they become physically and functionally dependent.

Patients with sarcopaenia exhibit low muscle mass with either low MS or low physical performance. The hand grip strength becomes poor implying poor MS. There is poor physical performance which is associated with a markedly decreased gait speed.

Cruz-Jentoft and Sayer summarized the consequences of sarcopaenia as falls and fractures, frailty, functional decline, loss of independence, lower quality of life, increasing risk of hospitalization and mortality.²³

Diagnosis

European Working Group on Sarcopaenia on Older People (EWGSOP) has given the following diagnostic criteria for sarcopaenia (Table 3).⁶

Staging of sarcopaenia

In addition, EWGSOP suggested staging of sarcopaenia into three different categories based on the presence of low physical performance and presence or absence of functional impairment (Table 4).⁶ Pre-sarcopaenia is characterized by low muscle mass only without influence on muscle function. Sarcopaenia exhibits low muscle mass with low MS, with or without low physical performance. Severe sarcopaenia exhibits low muscle mass with low MS and physical performance (low muscle function).

The diagnosis of sarcopaenia is based on the presence of low muscle mass. It may be associated either with low MS or low physical performance. Sarcopaenia is considered present in an elderly person >65 years if the gait speed is 0.8 m/s or less in presence of low muscle mass.²²

Prominent muscle wasting is encountered in situations of malnutrition and cachexia, in addition to sarcopaenia. These conditions are to be differentiated as the treatment approach varies. Malnutrition occurring due to starvation results in a loss of body fat. There is also loss of non-fat mass due to an inadequate intake of protein and energy. It should be noted that body fat in sarcopaenia is preserved. Body fat may even be increased as in sarcopaenic obesity.

Cachexia is associated with severe muscle wasting. It involves fat and non-fat mass. Such a condition is associated with disease states such as tuberculosis, heart diseases (cardiac cachexia), thyrotoxicosis, type-1 diabetes mellitus, and cancer. Inflammation underlies the occurrence of muscle wasting. Many of these individuals also have sarcopaenia. However, it must be noted that most patients with sarcopaenia are not cachectic.

Physical frailty is strongly associated with sarcopenia. Frailty is a consequence of age-related cumulative decline across multiple physiological systems with impaired homeostatic reserve and increased vulnerability to adverse health outcomes.⁸ Frailty and sarcopaenia frequently overlap. Most frail elderly persons exhibit sarcopenia. Some elderly persons with sarcopaenia are also frail.²³

Diagnostic methods

Many tests have been devised to screen elderly for the presence of sarcopenia. They include measurement of muscle mass, MS, and physical performance. There is also a quick and easy-to-use questionnaire to identify the population to be screened for the diagnosis of sarcopaenia as mentioned:

1. Anthropometric measurements: Weight and height, body mass index (BMI), mid-arm circumference (measurement of flexed biceps at its greatest girth), calf circumference (measurement of calf circumference at its greatest girth when the individual stands with feet apart), and skin-fold thickness. With advancing age, there are changes in the distribution of fat and loss of skin elasticity. It results in a loss of accuracy and precision in the measures of circumference and skin fold in elderly persons.
2. Mini Sarcopaenia Risk Assessment (MSRA) questionnaire: The test is used as a pre-screening tool for sarcopaenia risk assessment. The full version of the MSRA questionnaire (MSRA-7) comprises seven questions such as age, number of hospitalizations in the previous year, level of physical activity, number of meals per day and their regularity, consumption of protein and dairy products, and weight loss >2 kg in the last year. It helps in assessment of anatomic and nutritional characteristics related to risk of sarcopaenia onset. This is an inexpensive, first line instrument. An arbitrary score is assigned to each item. Rossi and colleagues have found low values of MSRA score to be associated with a greater number of sarcopaenic persons. Sarcopaenic persons are likely to have a score of 30 or less.²⁴ There is a short version (MSRA-5) that excludes protein and dairy consumption. A score of 45 or less indicates risk of sarcopenia.

Gait-speed test: It is tested by 4 m walk test. The subject is asked to walk on a flat surface at their usual pace for a distance of four meters, and the time is recorded. A normal person can cover this distance in less than five seconds (<0.8m/s). A person with sarcopaenia takes longer than this. It indicates low physical performance.²⁵

1. SARC-F test: This is a first level screening questionnaire for sarcopenia. It elicits answers for five muscle functions such as, strength (S), ambulation (A), rising up from a chair (R), climbing up a set of stairs ©, and falls (F).²⁶ A score of 4 out of the maximum 10 points indicates risk of sarcopaenia.
2. SARC-CalF questionnaire: SARC-CalF consists of six items, the first five items being and scored the same as the SARC-F and the sixth additional item is the calf circumference (CC) where the right calf is measured in standing position. This test has been considered to be an optimal choice for screening sarcopaenia in community dwelling older adults.²⁷
3. Sarcopaenia-specific health-related quality of life (HRQoL) questionnaire was developed by Beaudart and colleagues to accurately assess the impact of sarcopaenia on quality of life. This can be used for initial screening. Initially it was developed as a self-administered Sarcopaenia QoL (SarQoL) in French, consisting of 55 items condensed into 22 questions. The questionnaire has demonstrated clarity, validity, coherence, and reliability. It is recommended for clinical and research purposes. Its translations are available in many languages and can be answered in 10-15 minutes.²⁸
4. Grip strength: The hand grip strength is measured from each hand by a hand-held dynamometer. Voluntary isometric strength of the dominant arm extensors can be tested by asking the person to lift 1 kg weight. He has to perform it with the arm lifted above the shoulder, with the elbow being fully extended for a period of 30 seconds. If the person succeeds in performing it, grip strength is considered normal.²⁵
5. Rising to a standing position: The proximal muscles of the lower limb can be tested by asking the person to rise to a standing position from a standard chair without arm support within 30 s. Normally an individual is able to rise from a chair five times in 30s.
6. Dual-energy X-ray absorptiometry (DXA): The appendicular fat-free skeletal muscle mass is assessed by using DXA. Since the equipment is not available everywhere, the skeletal muscle mass can be determined by the mid-arm circumference and calf circumference.
7. Skeletal mass index (SMI): SMI is obtained by dividing appendicular skeletal muscle mass measured with DXA by height expressed in meters squared (kg/m² ). Baumgartner and colleagues found individuals with low muscle mass exhibited <7.26 kg/ m² for men and <5.5 kg/m2 for women.²⁹
8. Imaging studies: Computed tomography (CT) and magnetic resonance imaging (MRI) have been utilised to measure the skeletal muscle mass. Then the muscle mass so measured is divided by weight square (kg/m² ). There are also alternate methods to estimate muscle mass like the bioelectrical impedance analysis, mid-thigh imaging, third lumbar vertebral imaging, and Psoas muscle measurements. Even ultrasound is utilised to measure the thickness and cross-sectional area of quadriceps muscle.
9. Red flag method: Red flags on sarcopenia have been identified by clinician’s observation (general weakness of the subject, visual identification of LMM, and low-walking speed), subject’s presenting features (loss of weight, loss of MS, in arms or in legs, general weakness, fatigue, falls, mobility impairment, loss of energy, difficulties in physical activities or activities of daily living), and clinician’s assessment (nutrition, body weight, physical activity).³⁰
10. Gender specific model: Ischii and colleagues have introduced a new screening tool for sarcopenia in Japan. Their approach defines sarcopenia based on low muscle mass measured using Bio-electrical impedance analysis (BIA), low muscle strength characterized by handgrip, or low physical performance characterized by slow gait speed. This model is specific to gender and incorporates three variables: age, handgrip strength, and calf circumference. They have developed a gender-specific scoring chart with discriminative ability. Scores are calculated using the following formulas: for men, 0.62 x (age-64) - 3.09 x (grip strength - 50) - 4.64 x (calf circumference - 42); for women, 0.80 x (age-64) - 5.09 (grip strength - 34) - 3.28 x (calf circumference - 42).³⁰
11. Bio-electrical impedance analysis (BIA): With BIA, it is possible to estimate the volume of fat and lean body mass by analyzing the relationship between the volume of a conductor and its electrical resistance. Reference values are available for older adults.³¹ 
12. Inexpensive methods: Beaudart and colleagues have suggested several user-friendly and cost-effective approaches for assessing sarcopenia in real-world environments. These methods include the red flag method, the SARC-F questionnaire, the SMI method, and various prediction equations.²⁹

Geriatric syndrome

Cruz-Jentoft and colleagues have considered sarcopaenia as a geriatric syndrome. It is a state of impaired health condition in elderly persons.⁶ They share the common risk factors such as old age, impaired cognition, impaired function and impaired mobility. Sarcopaenia increases risk of falls and fractures, impairs ability to undertake activities of daily living. Further it is associated with cardio respiratory disorders, cognitive impairment. It results in mobility issues and contributes to a decreased quality of life, loss of self-sufficiency, potential requirement for long-term care placement, and ultimately mortality.³²

Management

Nutrition and physical exercise have been considered as cornerstones in the management of sarcopaenia.33 A decline in the musculoskeletal system and physical capabilities is observed as age advances.

Exercise: Management of sarcopaenia is essentially focused on physical therapy for MS and gait training. A properly supervised exercise program if carried out for a long period of time has beneficial effect. MS and mass increases by undertaking resistance exercise training. It also improves protein accumulation in skeletal muscles. Aerobic exercise training may help ageing skeletal muscles and improve insulin sensitivity.⁸ The capability of person to undertake exercise should be determined. The program should be initiated from whatever level the person can undertake. It should be started slowly. To begin, there should be low intensity exercises which should be gradually increased depending on the tolerance shown by the person.

Resistance exercises involve weight lifting, pulling against resistance band, or moving body parts against gravity. Such exercises put tension on muscle fibres. There is initiation of growth signals to the muscle cells enabling them to grow and undertake repair process. The ‘satellite cells’ show activity. They reinforce the muscle and increase the muscle mass and strength.

Aerobic and resistance exercises including jogging, cycling, treadmill show a beneficial effect. Walking has influence on preventing or reversing effects of sarcopaenia.

Nutrition: Nutritional deficiencies must be corrected. Caloric intake should be increased to cope with the increased demands from exercise. The intake of protein must be increased. It should be more than 1.2 g per kilogram of body weight per day. Caution must be exercised to curtail the intake of protein in presence of renal insufficiency. The protein balance in skeletal muscles will improve with addition of leucine, beta-hydroxy –beta-meth butyrate, creatine and some milk-proteins. There is need to correct vitamin D deficiency to improve muscle function.

Medication: No specific medication is available for the treatment of sarcopaenia. Attempts are made to inhibit myostatin and manipulation of neuromuscular junction. Anabolic hormones have not shown any beneficial response. While human growth hormone does enhance muscle protein synthesis and augment muscle mass, it does not succeed in improving MS and functionality. Similarly, insulin-like growth factor-1 is not efficacious in aging muscle. Testosterone, an anabolic steroid though has some effect on MS and mass, is not recommended due to its adverse effects.³⁴

Myostatin impedes satellite cell production, thereby inhibiting muscle rejuvenation. A double-deletion of the myostatin gene can prompt muscle hypertrophy.⁶ Poor muscle function is associated with vitamin D deficiency. Elderly individuals demonstrate a longitudinal change in serum 25-hydroxy vitamin D. The vitamin D levels show gradual reduction throughout the life time.³⁴ Research has demonstrated that supplementation of vitamin D in elderly can result in a reduced rate of fall and decreased functional impairment.³⁵ Adequate food intake including creatine maintains muscle quality. Elderly individuals often report decline in appetite. Many of them consume less amounts of food, resulting in insufficient intake of protein, which can deleteriously affect the muscle maintenance. Reduced MS is noted with a fall in the level of ciliary neurotrophic factor. With aging, an increase in cytokines (TNF-alpha and IL-6) is observed and this in turn is associated with decline in MS and frailty.

New insights³²

1. It was thought sarcopaenia is an aging phenomenon associated with older people. The condition makes it beginning early in life. Sarcopaenia phenotypes has many contributory causes beyond aging. This knowledge enables us to intervene to prevent or delay development of sarcopenia.
2. Sarcopenia is a progressive and widespread skeletal muscle disorder characterized by reduced muscle strength (MS). It represents a state of muscle dysfunction and has surpassed low muscle mass as a primary determinant. This facilitated the identification of the condition in clinical practice.
3. Sarcopenia is linked to both decreased muscle quantity and quality. These features are difficult to identify in clinical practice. 
4. Diagnostic methods are available to recognise sarcopaenia.

Revised guidelines³² In the updated guidelines, there is a focus on muscle strength which has now become the primary parameter for diagnosing sarcopenia. The emphasis is on the idea that strength is a better predictor of adverse outcomes than muscle mass. Muscle strength has emerged as the most dependable measure of muscle function. The structure and makeup of muscles, and thus their quality, are affected. Low physical performance is indicative of the severity of sarcopenia and predicts adverse outcomes.

Sarcopaenia is probable when there is low MS. The confirmation of sarcopenia diagnosis hinges on identifying the presence of reduced muscle quantity or quality. Sarcopenia is classified as severe when there is a combination of low MS, diminished muscle quantity/ quality, and impaired physical performance.

EWGSOP2 updated the classification in 2019 as ‘probable’, ‘confirmed’, or ‘severe’. It emphasizes low MS as a pivotal attribute of sarcopenia. Elevated low MS has been regarded as a primary indicator for potential sarcopenia rather than low muscle mass. It employs the identification of reduced muscle quantity and quality to validate the diagnosis of sarcopenia. Poor physical performance serves as an indicator of severe sarcopenia (Table 5).³²

Diagnostic tools

In clinical practice, certain important diagnostic tools are utilised to determine the presence of sarcopenia (Table 6). The measurements involve muscle mass, MS and physical performance. 

Clinically sarcopenia must be suspected when a patient exhibits features like falling, feeling weak, slow walking speed, difficulty rising from a chair or weight loss/ muscle wasting.

Sarcopenia cases

Case finding

The SARC-F questionnaire gathers self-reported information from patients regarding the presence of indicators associated with sarcopenia. Consisting of five items that assess limitations in strength, walking ability, rising from a chair, stair climbing, and falls, it serves as a screening tool to identify individuals at risk of sarcopenia. This method of sarcopenia risk screening is highly convenient.³³

Measurement of sarcopenia parameters

Muscle Strength

Muscle grip strength, evaluated using a calibrated handheld dynamometer, is a straightforward and cost-effective procedure. However, it may not be applicable in cases of hand disability resulting from advanced stages of rheumatoid arthritis or stroke.

The chair stand test, also known as the chair rise test, evaluates the strength of the leg muscles by timing how long it takes a patient to stand up five times from a seated position without using their arms. Another version of this test, called the chair stand count test, records how many times a patient can rise and sit in the chair within a 30-second timeframe.

Muscle quantity

Skeletal muscle quantity is estimated non-invasively by CT or MRI. DXA measures the overall lean tissue mass of the body. Bioelectrical impedance analysis (BIA) indirectly calculates muscle mass based on the body's total electrical conductivity. CT imaging of lumbar 3rd vertebra can be utilized to detect low muscle mass.

Physical performance

Physical performance encompasses the overall functioning of the body related to movement and locomotion, involving not just muscles but also the functioning of the central and peripheral nervous systems, including balance. It is evaluated using different metrics such as gait speed, the short physical performance battery, and the timed-up and go test. Gait speed, measured through the 4-meter usual walking speed test, is a fast, safe, and dependable assessment. The Short Physical Performance Battery (SPPB) evaluates gait speed, balance, and the ability to stand from a chair. The assessment has a maximum score of 12, and a core score of 8 or lower suggests inadequate physical performance. The Timed Up and Go (TUG) test assesses physical function by instructing the individual to stand up from a regular chair, walk to a point 3 meters away, turn around, return, and sit back down. During the 400-meter walk test, an individual's walking capacity and stamina are assessed along a corridor spanning more than 20 meters.

Prevention

As various pathways contribute to the onset of sarcopenia, a critical factor in the development of frailty, research has demonstrated that this condition can be prevented through strategies such as muscle-strengthening exercises, a nutritious diet, sufficient sleep, administration of hormones and growth factors, and lifestyle interventions. There is need to reduce the number of drugs taken, to train balance and gait, to correct postural hypotension by rationalizing medication, adequate hydration and use of non-steroidal anti-inflammatory drugs that cause salt and water retention, thus increasing the circulating volume, and to direct attention to those factors to reduce risk of falls.

Conclusion

Sarcopenia is a geriatric condition linked to the gradual and widespread reduction of skeletal muscle mass and strength. Its pathophysiology involves muscle, neural and hormonal alterations. The condition should be differentiated from starvation and cachexia. Multiple aetiological factors are to be carefully evaluated. Nutrition and physical exercise form the main interventions. There is no specific treatment.

Conflict of Interest

Nil