Muscle atrophy

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.

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Muscle atrophy
The size of the muscle is reduced, as a consequence there is a loss of strength and mobility.
Specialty	Physical medicine and rehabilitation

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Disuse causes rapid muscle atrophy and often occurs during injury or illness that requires immobilization of a limb or bed rest. Depending on the duration of disuse and the health of the individual, this may be fully reversed with activity. Malnutrition first causes fat loss but may progress to muscle atrophy in prolonged starvation and can be reversed with nutritional therapy. In contrast, cachexia is a wasting syndrome caused by an underlying disease such as cancer that causes dramatic muscle atrophy and cannot be completely reversed with nutritional therapy. Sarcopenia is age-related muscle atrophy and can be slowed by exercise. Finally, diseases of the muscles such as muscular dystrophy or myopathies can cause atrophy, as well as damage to the nervous system such as in spinal cord injury or stroke. Thus, muscle atrophy is usually a finding (sign or symptom) in a disease rather than being a disease by itself. However, some syndromes of muscular atrophy are classified as disease spectrums or disease entities rather than as clinical syndromes alone, such as the various spinal muscular atrophies.

Muscle atrophy results from an imbalance between protein synthesis and protein degradation, although the mechanisms are incompletely understood and are variable depending on the cause. Muscle loss can be quantified with advanced imaging studies but this is not frequently pursued. Treatment depends on the underlying cause but will often include exercise and adequate nutrition. Anabolic agents may have some efficacy but are not often used due to side effects. There are multiple treatments and supplements under investigation but there are currently limited treatment options in clinical practice. Given the implications of muscle atrophy and limited treatment options, minimizing immobility is critical in injury or illness.

The hallmark sign of muscle atrophy is loss of lean muscle mass. This change 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.^[1]

The predominant symptom is increased weakness which may result in difficulty or inability in performing physical tasks depending on what muscles are affected. Atrophy of the core or leg muscles may cause difficulty standing from a seated position, walking or climbing stairs and can cause increased falls. Atrophy of the throat muscles may cause difficulty swallowing and diaphragm atrophy can cause difficulty breathing. Muscle atrophy can be asymptomatic and may go undetected until a significant amount of muscle is lost.^[2]

Skeletal muscle serves as a storage site for amino acids, creatine, myoglobin, and adenosine triphosphate, which can be used for energy production when demands are high or supplies are low. If metabolic demands remain greater than protein synthesis, muscle mass is lost.^[3] Many diseases and conditions can lead to this imbalance, either through the disease itself or disease associated appetite-changes, such as loss of taste due to Covid-19. Causes of muscle atrophy, include immobility, aging, malnutrition, certain systemic diseases (cancer, congestive heart failure; chronic obstructive pulmonary disease; AIDS, liver disease, etc.), deinnervation, intrinsic muscle disease or medications (such as glucocorticoids).^[4]

Intrinsic muscle diseases

Muscle diseases, such as muscular dystrophy, amyotrophic lateral sclerosis (ALS), or myositis such as inclusion body myositis can cause muscle atrophy.^[13]

Muscle atrophy occurs due to an imbalance between the normal balance between protein synthesis and protein degradation. This involves complex cell signalling that is incompletely understood and muscle atrophy is likely the result of multiple contributing mechanisms.^[19]

Mitochondrial function is crucial to skeletal muscle health and detrimental changes at the level of the mitochondria may contribute to muscle atrophy.^[20] A decline in mitochondrial density as well as quality is consistently seen in muscle atrophy due to disuse.^[20]

The ATP-dependent ubiquitin/proteasome pathway is one mechanism by which proteins are degraded in muscle. This involves specific proteins being tagged for destruction by a small peptide called ubiquitin which allows recognition by the proteasome to degrade the protein.^[21]

Screening for muscle atrophy is limited by a lack of established diagnostic criteria, although many have been proposed. Diagnostic criteria for other conditions such as sarcopenia or cachexia can be used.^[3] These syndromes can also be identified with screening questionnaires.^{[citation needed]}

Muscle mass and changes can be quantified on imaging studies such as CT scans or Magnetic resonance imaging (MRI). Biomarkers such as urine urea can be used to roughly estimate muscle loss during circumstances of rapid muscle loss.^[22] Other biomarkers are currently under investigation but are not used in clinical practice.^[3]

Muscle atrophy can be delayed, prevented and sometimes reversed with treatment. Treatment approaches include impacting the signaling pathways that induce muscle hypertrophy or slow muscle breakdown as well as optimizing nutritional status.^{[citation needed]}

Physical activity provides a significant anabolic muscle stimulus and is a crucial component to slowing or reversing muscle atrophy.^[3] It is still unknown regarding the ideal exercise "dosing." Resistance exercise has been shown to be beneficial in reducing muscle atrophy in older adults.^[23][24] In patients who cannot exercise due to physical limitations such as paraplegia, functional electrical stimulation can be used to externally stimulate the muscles.^[25]

Adequate calories and protein is crucial to prevent muscle atrophy. Protein needs may vary dramatically depending on metabolic factors and disease state, so high-protein supplementation may be beneficial.^[3] Supplementation of protein or branched-chain amino acids, especially leucine, can provide a stimulus for muscle synthesis and inhibit protein breakdown and has been studied for muscle atrophy for sarcopenia and cachexia.^[3][26] 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 several muscle wasting conditions in humans, particularly sarcopenia.^[26][27][28] Based upon a meta-analysis of seven randomized controlled trials that was published in 2015, HMB supplementation has efficacy as a treatment for preserving lean muscle mass in older adults.^[29] More research is needed to determine the precise effects of HMB on muscle strength and function in various populations.^[29]

In severe cases of muscular atrophy, the use of an anabolic steroid such as methandrostenolone may be administered to patients as a potential treatment although use is limited by side effects. A novel class of drugs, called selective androgen receptor modulators, is being investigated with promising results. They would have fewer side effects, while still promoting muscle and bone tissue growth and regeneration. These effects have yet to be confirmed in larger clinical trials.^[30]

Outcomes of muscle atrophy depend on the underlying cause and the health of the patient. Immobility or bed rest in populations predisposed to muscle atrophy, such as the elderly or those with disease states that commonly cause cachexia, can cause dramatic muscle atrophy and impact on functional outcomes. In the elderly, this often leads to decreased biological reserve and increased vulnerability to stressors known as the "frailty syndrome."^[3] 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.^[3]

Inactivity and starvation in mammals lead to atrophy of skeletal muscle, accompanied by a smaller number and size of the muscle cells as well as lower protein content.^[31] In humans, prolonged periods of immobilization, as in the cases of bed rest or astronauts flying in space, are known to result in muscle weakening and atrophy. Such consequences are also noted in small hibernating mammals like the golden-mantled ground squirrels and brown bats.^[32]

Bears are an exception to this rule; species in the family Ursidae are famous for their ability to survive unfavorable environmental conditions of low temperatures and limited nutrition availability during winter by means of hibernation. During that time, bears go through a series of physiological, morphological, and behavioral changes.^[33] Their ability to maintain skeletal muscle number and size during disuse is of significant importance.^{[citation needed]}

During hibernation, bears spend 4–7 months of inactivity and anorexia without undergoing muscle atrophy and protein loss.^[32] A few known factors contribute to the sustaining of muscle tissue. During the summer, bears take advantage of the nutrition availability and accumulate muscle protein. The protein balance at time of dormancy is also maintained by lower levels of protein breakdown during the winter.^[32] At times of immobility, muscle wasting in bears is also suppressed by a proteolytic inhibitor that is released in circulation.^[31] Another factor that contributes to the sustaining of muscle strength in hibernating bears is the occurrence of periodic voluntary contractions and involuntary contractions from shivering during torpor.^[34] The three to four daily episodes of muscle activity are responsible for the maintenance of muscle strength and responsiveness in bears during hibernation.^[34]

Muscle-atrophy can be induced in pre-clinical models (e.g. mice) to study the effects of therapeutic interventions against muscle-atrophy. Restriction of the diet, i.e. caloric restriction, leads to a significant loss of muscle mass within two weeks, and loss of muscle-mass can be rescued by a nutritional intervention.^[35] Immobilization of one of the hindlegs of mice leads to muscle-atrophy as well, and is hallmarked by loss of both muscle mass and strength. Food restriction and immobilization may be used in mouse models and have been shown to overlap with mechanisms associated to sarcopenia in humans.^[36]