Causes and Risk Factors of Muscle Atrophy

Introduction

Muscle atrophy occurs when muscles waste away, either partially or completely, due to the degeneration of muscle cells. The primary causes of muscle wasting include lack of physical activity, nutritional deficiencies, and genetic factors. This condition can arise when disease or injury makes it difficult or impossible to move a body part, such as an arm.

Muscle atrophy results from an imbalance between protein synthesis and degradation, with the latter exceeding the former. Since this condition can significantly impact the quality of life, understanding the mechanisms and factors that contribute to atrophy is crucial for developing effective prevention and management strategies.¹

Types of muscle atrophy

Muscle atrophy can occur due to a variety of underlying causes, each leading to different forms of muscle wasting. Some of the most common types include:

Disuse atrophy

This type occurs when muscles are not used for prolonged periods, often due to immobility from bed rest, casting, or a sedentary lifestyle. Without regular movement or exercise, muscle fibres shrink and weaken over time.

Neurogenic atrophy

Resulting from damage to the nerves that control muscles, neurogenic atrophy can be caused by conditions such as Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), spinal cord injury, or peripheral neuropathies. This type of atrophy is often more severe because it directly impacts the nervous system's ability to stimulate muscle function.

Cachexia

Often associated with chronic diseases like cancer, HIV/AIDS, and heart failure, cachexia leads to significant muscle wasting due to systemic inflammation and metabolic changes, making it difficult for the body to maintain muscle mass even with adequate nutrition.

Sarcopenia 

A natural part of the ageing process, sarcopenia involves the gradual loss of muscle mass and strength, which can affect mobility and overall physical function in older adults.

Other medical conditions

Muscle atrophy can also be triggered by hormonal imbalances (such as hyperthyroidism or Cushing's syndrome), inflammatory conditions like rheumatoid arthritis, or malnutrition and nutrient deficiencies, all of which can disrupt the body’s ability to maintain healthy muscle tissue.

Primary causes of muscle atrophy

The cause of muscle atrophy depends on the type of atrophy one has, which can be either physiological or neurogenic. 

Physiological atrophy is when the muscles are not used enough, leading to their breakdown, weakening, and eventual decrease in size. This can be due to the following:

• Malnourishment 
• Sedentary lifestyle
• Lack of exercise 
• Having a desk job
• Genetic disorders such as muscular dystrophy, Charcot-Marie-Tooth disease or spinal muscular atrophy, which happens on chromosome 5 where the genes in SMN1 are mutated, leading to a deficiency of the survival motor neuron protein
• Stroke, which can render limbs immobile
• Sarcopenia (age-related atrophy)³

Neurogenic atrophy occurs when nerves that connect to muscles are damaged. The nerve damage prevents muscle contractions, leading to the breakdown of these muscles as the body thinks they are no longer needed. This can be due to the following: 

• Polio 
• Spinal cord injury
• Multiple sclerosis (MS)
• Carpal tunnel syndrome 
• Guillain-Barre syndrome 
• Amyotrophic lateral sclerosis (ALS)⁴

Risk factors for muscle atrophy

Several factors can increase the likelihood of developing muscle atrophy, including genetic, lifestyle, and medical influences. By addressing these risk factors through targeted interventions like physical activity, proper nutrition, and medical management, the progression of muscle atrophy can often be slowed or mitigated.

Genetic predisposition

Genetic factors can influence the body’s ability to maintain muscle mass, making some individuals more susceptible to muscle atrophy. Inherited conditions or genetic mutations that affect muscle metabolism or function may predispose individuals to conditions like sarcopenia or neurogenic atrophy earlier in life.

Age

As people age, the body’s ability to repair and regenerate muscle tissue decreases, leading to a gradual loss of muscle mass and strength. This age-related decline in muscle function, known as sarcopenia, can significantly impact mobility and overall quality of life if not managed through proper exercise and nutrition.

Lifestyle factors

Physical inactivity is one of the most important factors that cause muscle atrophy. Prolonged periods of inactivity, such as sedentary behaviour or bed rest, can lead to muscle loss over time. Inadequate intake of protein and essential nutrients can furthermore impair muscle repair and growth, accelerating atrophy.

Medical history

Previous injuries or surgeries that result in extended immobility can lead to muscle degradation due to disuse, while chronic illnesses such as diabetes and chronic obstructive pulmonary disease (COPD) contribute to muscle atrophy through systemic inflammation and metabolic changes.⁵

Mechanisms underlying muscle atrophy

Muscle atrophy occurs when the balance between muscle protein synthesis and degradation is disrupted, leading to a loss of muscle mass. Understanding the underlying mechanisms is crucial for developing effective strategies to prevent or reverse muscle atrophy in various conditions.

Protein degradation pathways

Ubiquitin-proteasome system

The proteasome is a cellular machine that breaks down proteins into smaller pieces. The process, termed proteolysis, helps the body get rid of damaged or unnecessary proteins. Proteolysis is highly regulated, as dysfunction can cause disease. Protein undergoes several steps before being degraded by the proteasome. 

The ubiquitin-proteasome system (UPS) is a crucial cellular mechanism for maintaining healthy cells. It involves tagging damaged or unneeded proteins with ubiquitin, a small regulatory protein.⁶ This tag signals that the protein should be destroyed. The system involves attaching ubiquitin to the target protein, which marks it for breakdown by the proteasome. Ubiquitin attaches to the protein at a specific spot, forming a special bond that leads to the protein’s destruction. This attachment process involves three key enzymes, known as E1, E2, and E3.⁷

To summarize and oversimplify the process: First, the protein is modified through a process called ubiquitination, which tags it for destruction. It is then unfolded and chopped up into short polypeptides by the proteasome. Once the proteasome releases the short polypeptides, they get further broken down into their amino acid building blocks by other enzymes called proteases.⁷

Autophagy-lysosome pathway

Autophagy is the cell's natural and regulated process for eliminating unnecessary or dysfunctional components. This mechanism enables the systematic breakdown and recycling of cellular materials. There are three commonly recognised types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. ​​In macroautophagy, double-membrane vesicles called autophagosomes deliver damaged proteins and organelles to the lysosome for degradation.

In microautophagy, material is delivered to the lysosome via vesicles, but in a slightly more direct manner, using vesicles formed from inward folding of the lysosomal membrane. Chaperone-mediated autophagy (CMA) does not use vesicles but instead uses special proteins called chaperones to guide specific proteins directly to the lysosome for breakdown.⁸

Cytokines inflammatory response

Cytokines are tiny proteins secreted by both immune and non-immune cells to communicate with one another. They attach to specific receptors on target cells and initiate a response. Cytokines facilitate the activation, proliferation, and differentiation of immune cells, and can also perform other functions, such as raising body temperature to induce a fever.

Cytokines signal to other cells mainly through autocrine and paracrine signalling, with a lesser extent of endocrine signalling also being used. In autocrine signalling, the cell producing the cytokine is also the one responding to it.

Diagnostic approaches

Clinicians use various methods to diagnose muscle atrophy. Diagnostic approaches include:¹⁰

• Clinical assessment
• Imaging techniques (e.g. MRI, CT scans)
• Muscle/nerve biopsy
• Electromyography (EMG)
• Nerve conduction studies
• Laboratory tests (e.g. Blood tests for inflammatory markers)

Prevention and management strategies

Preventing muscle atrophy involves a combination of proactive strategies. Regular exercise and physical therapy, including targeted stretches and strengthening exercises, can effectively prevent muscle loss. Nutritional interventions, such as protein supplementation and a well-balanced diet rich in essential vitamins and minerals, support muscle maintenance and recovery. In some cases, medical treatments like anabolic steroids or anti-inflammatory drugs may be prescribed to aid in preserving muscle mass.

FAQs

How long does it take to recover from muscle atrophy?

Recovery is dependent on the type and severity of muscle atrophy. This can often be done by regular exercise and maintaining a healthy diet. It may take a few months to see noticeable changes, and even longer to regain full muscle strength. 

Are muscle loss and muscle atrophy the same?

Yes, muscle loss and muscle atrophy refer to the same condition. "Muscle atrophy" is just another term for muscle loss.

Summary

Muscle atrophy, or muscle loss, often occurs gradually and can be due to various factors including age, nutrition, genetics, and even certain medical conditions such as rheumatoid arthritis. Muscle atrophy can significantly impact an individual's daily life, reducing the overall quality of life. Treatment is dependent on the type and severity of atrophy, but it is always recommended to see a doctor if muscle loss is suspected. Treatments typically involve a combination of exercises, physical therapy, and dietary changes.