Trait: Muscle Damage (TNF-α)
Dr Haran Sivapalan
June 1, 2020
What is TNF-α?
TNF-α stands for Tumour Necrosis Factor alpha.
It belongs to a class of biological molecules called cytokines – signalling proteins that facilitate communication between cells.
Cytokines help to coordinate complex bodily responses involving multiple cells, such as immune responses and inflammation.
In particular, TNF-α is a pro-inflammatory cytokine: it promotes inflammation.
During an inflammatory response, TNF-α is released by white blood cells (primarily macrophages and T-lymphocytes) and acts to: stimulate the production of other inflammatory molecules; attract other immune cells to a site of tissue injury; and dilate local blood vessels and make them more permeable.
TNF-α is highly involved in diseases characterised by prolonged and excessive inflammation, such as rheumatoid arthritis, psoriasis and inflammatory bowel disease.
- TNF-α is a cytokine that stimulates inflammation.
- TNF-α stimulates the migration of immune cells to a site of tissue injury, increases in local blood flow, and other inflammatory responses.
- TNF-α plays a role in muscle recovery, post-exercise muscle damage, and inflammatory diseases.
What is inflammation?
We’ve encountered inflammation before in the Il-6 and inflammation blog. Readers are encouraged to visit this article for a more thorough overview of inflammation.
To recap briefly, inflammation is the body’s protective response to tissue injury, infection (e.g. bacteria, viruses) and other harmful stimuli/agents. It involves an increase in blood flow and the recruitment of immune cells (e.g. white blood cells) in an effort to remove the harmful agent, prevent further tissue damage and promote healing.
Acute inflammation is a short-term response to tissue injury and is characterised by specific, “cardinal” signs, including:
- Warmness and redness of affected tissue (which is caused by increased blood flow).
- Swelling (due to increased permeability of blood vessels, causing fluid and immune cells to leak into tissues).
- Pain (due to inflammatory molecules causing sensitisation of pain nerves).
- Loss of function (e.g. temporarily reduced muscle strength).
Acute inflammation as a short-term, appropriate response to tissue injury is often beneficial because it helps to clear harmful agents and leads to tissue healing and remodelling. In this respect, mild inflammation is often a beneficial component of recovery from exercise.
By contrast, inflammation that is excessive or persists for a long time (called chronic inflammation) can cause damage to tissues.
- Inflammation is an immune response to tissue injury (e.g. mechanical injury, infection, toxins).
- Inflammation involves: increases in blood flow, increased permeability of blood vessels, recruitment of immune cells to site of tissue injury, pain, temporary loss of function.
- Inflammation is often beneficial as it clears harmful stimuli and promotes healing.
- Excessive or prolonged inflammation can lead to tissue damage.
What is the role of inflammation in recovery from exercise?
Every time we exercise we subject our muscles and other tissues to stress. During recovery after workouts, our tissues rebuild and make neuromuscular changes that aid exercise performances. These changes are collectively referred to as adaptations.
Inflammation is thought to play a key beneficial role in adaptations to muscle during recovery. For example, inflammation leads to remodelling of muscle tissue and promotes hypertrophy (an increase in muscle size) and gains in strength.
If you’ve ever experienced muscle soreness 24-72 hours after unaccustomed exercise, this is likely due to DOMS (Delayed Onset Muscle Soreness). DOMS is caused by inflammation, but ultimately results in recovery, healing and strengthening of muscle tissue.
Furthermore, repeating the same types of exercise leads to reduced inflammation and faster recovery each time. This is known as the “repeated bout effect” and is partly due to decreased expression of pro-inflammatory genes and enhanced expression of anti-inflammatory genes.
- During physical training our muscles make adaptations after we subject them to stress during exercise.
- Inflammation following exercise can aid recovery by causing remodelling of muscle and supporting other adaptations.
- Mild, appropriate inflammation is a key part of recovery from exercise and improvements in exercise performance.
What is the role of TNF-α and inflammation in muscle damage?
Although some degree of inflammation is required for muscle recovery, excessive inflammation has been shown to cause muscle damage, impair healing / remodelling of muscle tissue and prolong recovery time.
Muscle damage resulting from exercise (known as exercise-induced muscle damage) consists of two main phases:
- The first phase involves stress to the muscle during the exercise itself.
- The second phase involves a delayed inflammatory response that occurs after exercise has stopped.
In particular, strenuous exercise involving eccentric muscle contraction is thought to stimulate inflammation in this second phase. Eccentric muscle contraction involves contraction while the muscle is lengthening. For example, slowly lowering a barbell on the downward phase of a bicep curl involves eccentric contraction of the biceps muscle. Studies suggest that older people are more susceptible to muscle damage and excessive inflammation from strenuous, eccentric exercise.
Increased and prolonged production of TNF-α may underlie excessive inflammation following eccentric exercise.
TNF-α acts as a pro-inflammatory cytokine and recruits white blood cells (e.g. neutrophils) to the site of muscle injury. These white blood cells can cause damage and degradation of muscle tissue by producing harmful ROS (reactive oxygen species).
Furthermore, TNF-α stimulates catabolic pathways that break down muscle protein and inhibit muscle protein synthesis. Both these effects can act to delay recovery and regeneration of muscle cells following exercise.
On this note, higher levels of TNF-α in blood plasma have been linked to poorer exercise performance and reduced improvements during physical training.
- Excessive inflammation following exercise can lead to muscle damage and impaired recovery.
- High levels of TNF-α may lead to excessive inflammation and exercise-induced muscle damage.
- Eccentric exercise (contraction while a muscle lengthens) is more likely to cause exercise-induced muscle damage.
- Elderly people are more susceptible to inflammation and muscle damage from eccentric exercise.
How do TNF gene variants affect susceptibility to inflammation?
TNF-α is encoded by your TNF gene.
Variants of this gene can affect the expression of the TNF-α protein, which, in turn, can influence your risk of (excessive) inflammation.
Expression refers to the switching on of genes and production of their protein products. Increased expression of the TNF gene will therefore lead to higher levels of TNF-α within tissues.
One of the most studied TNF gene variants is that created by the rs1800629 SNP. This SNP (Single Nucleotide Polymorphism) causes a ‘G’ to ‘A’ change in the DNA sequence, creating two different TNF gene variants or ‘alleles’ – the “G” allele and the less common “A” allele.
Studies suggest that the “A” allele is associated with increased expression of TNF-α and higher levels of TNF-α in the bloodstream.
Furthermore, carrying one or two copies of the “A” allele has been associated with poorer exercise performance and reduced improvements in response to physical training. Although further studies are needed, both these effects may result from increased inflammation and higher susceptibility to muscle damage following exercise due to higher TNF-α levels in “A” allele carriers.
Other studies have found that “A” allele carriers may be at a moderately increased risk of certain inflammatory conditions, including cardiovascular disease, inflammatory bowel disease (e.g. Crohn’s disease) and asthma.
Your TNF-α, muscle damage and inflammation trait looks at several different SNPs of the TNF gene (including rs1800629) and analyze your risk of excessive inflammation.
- TNF gene variants affect the expression and levels of TNF-α in the body.
- Some TNF gene variants are linked to higher TNF-α levels and greater susceptibility to inflammation.
- These gene variants may increase the risk of exercise-induced muscle damage.
- Gene variants linked to higher TNF-α levels may also be linked to a higher risk of certain inflammatory conditions e.g. cardiovascular disease, inflammatory bowel disease.