Skeletal muscle tissue is made up of muscle fibers, connective tissue, blood vessels and nerves.
Under the control of the somatic nervous system (SNS), skeletal muscle produces force, creates movement. Muscles get bigger and stronger if you exercise, smaller and weaker if you don’t…simple. This is the basic understanding of muscle that most of us have. There is however more benefit to exercising muscle tissue which we are not able to directly observe, and which science is only just beginning to reveal.
It was my recent conversation with Doug McGuff, MD, that lit a fire under my desire to understand myokines better – as they are small proteins with big health benefits. Doug has been ahead of the curve in his passion for the science of myokines writing about them on his blog since at least 2013 and probably earlier.
Myokines are exciting not only for their positive impact on health but also because they reveal that muscle tissue can no longer be perceived as a “dumb” collection of fibers acted upon by the nervous system. In the light of myokine research skeletal muscle can now be viewed as a fully-fledged secretory organ.
The first protein to be labelled as a myokine was myostatin, a mere decade ago in 2008, this is a young and fast developing field. In this post I will summarize current understanding of the impact of the most well-researched myokines so far.
What the heck are Myokines anyway?
Myokines are a type of cytokine, to avoid getting circular let’s start right there.
Cytokines are small proteins that play an important role in cell signalling. Cell signalling is the “talk” or instructions that are sent within and between cells impacting their behaviour. Cytokines can communicate with the originating cell itself (autocrine), with nearby cells (paracrine), and even with distant organs (endocrine). They play a particularly notable role in immune function and therefore in health, wellbeing and disease.
Myokines are a subset of cytokines, ones that are secreted by muscle cells during muscular contractions. The physiological changes stimulated by myokines are widespread, including benefits such as positive metabolic adaptations, tissue repair and immune function enhancement.
More than 100 separate myokines have been identified so far, however not all are understood well or at all and there are likely many, many more, possibly thousands that are currently unknown altogether.
Exercise factors are a subset of myokines. Whilst many myokines act locally within skeletal muscle itself, some known as Exercise Factors, have been proven to release into circulation during exercise, their impact goes beyond muscle cells. There are myokine receptors on muscle, bone, fat, liver, pancreas, heart, immune and brain cells, highlighting a potential for widespread influence.
In this post, we will look primarily at myokines that have been proven to (or have the greatest potential) to be Exercise Factors as these are likely to have the greatest impact on physiology and health.
What stimulates the release of myokines?
As you perform exercise, for example the leg press, and your hip and thigh muscles contract, a stress-like response occurs in skeletal muscle tissue stimulating the secretion of myokines. This results in elevated levels of those myokines in muscle cells, and in the case of Exercise Factors in plasma too. This is the acute effect of a single exercise bout.
Regular exercise (repeated bouts over time) causes a chronic adaptive response, meaning baseline levels of myokines between workouts are altered. The chronic effect may be quite different to the acute effect. For example, acutely levels of a myokine may spike in direct response to exercise, yet chronically levels may be lower at baseline. We will look at both types of response in this post where possible, chronic responses however are less well studied and understood than acute responses.
What’s the big deal with myokines?
In the big picture, myokines are known to behave as anti-inflammatory cytokines important for muscle recovery, repair and hypertrophy and driving the uptake of glucose into skeletal muscle. Beyond muscle, myokines have a positive impact on the prevalent metabolic diseases of today including type 2 diabetes and obesity. They are also known to play a role in bone development, have been shown to slow tumor growth in some cancers and help to stave off sarcopoenia and age-related muscle loss.
If exercise is medicine the active ingredients are myokines.
Without further ado let’s take a closer look at the best understood myokines, starting out with those that are proven Exercise Factors.
Exercise Factor Myokines
Acute response to exercise
Chronic response to exercise
As a cytokine (secreted during sepsis), IL-6 is pro-inflammatory notably associated with auto-immune diseases, its impact as a myokine however is very different.
|Insulin signalling is improved
Skeletal muscle insulin sensitivity is increased
When levels of muscle glycogen and blood glucose are low, exercise stimulates further increased secretion of IL-6
There is a proven increase in plasma levels of IL-6
|Decrease in baseline plasma levels, leading to:
Increased insulin sensitivity in the liver
Increased insulin sensitivity in fat tissue
|INTERLEUKIN-15 (IL-15)||Involved in muscle development, an anabolic/ anti-atrophy agent
Impacts glucose metabolism in skeletal muscle
Assists in muscle-fat cross talk and may play a role in the reduction of fat tissue mass
Signals bone mineral density increases
|C-C MOTIF CHEMOKINE LIGAND 2 (CCL2)||Helps with the repair and hypertrophy of skeletal muscle via infiltration of immune cells
Fat tissue cells shift from an inflammatory to anti-inflammatory state
Helps signal inflammatory and metabolic responses to exercise
Increases in plasma levels occur
|There is a decrease in baseline plasma levels
Fat tissue cells shift from an inflammatory to anti-inflammatory state
Insulin sensitivity improves
|ANGIOPOIETIN-LIKE 4 (ANGPTL4)
It is thought that ANGPTL4 may only enter the bloodstream when exercise is undertaken in a fasted state. It is not fully understood what role ANGPTL4 may play outside of muscle tissue.
|Plays an important role in regulating the use of fat as a fuel during exercise
Sends triglycerides to working skeletal muscle to be used as fuel
At the same time halts inactive skeletal muscle from using triglycerides
|CHEMOKINE (C-X3-X MOTIF) LIGAND 1 (CX3CL1)||Within skeletal muscle tissue, calls on immune cells to assist in repair and hypertrophy
May help prevent Beta cell dysfunction (Beta cells are found in the pancreas and are responsible for producing insulin)
May be beneficial to individuals with type 2 diabetes
|SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE (SPARC)||Enhances glucose metabolism
Plays a role in hypertrophy, particularly of type-2 fiber dominant muscle
May have an important role to play in reversing age-related atrophy
Likely induces apoptosis in colon cancer cells, inhibiting tumor growth during exercise
|Skeletal muscle tissue levels are elevated
Less is known about chronic plasma levels
It is important to note that higher levels of myostatin inhibits both the development of muscle fibers from myoblast cells and Akt -type hypertrophy. Myostatin also promotes the development of low-fatigable, oxidative muscle (type-1) fiber.
|Gene expression and plasma levels decrease after exercise in neophytes, but not trained subjects|
|METEORIN LIKE (METRNL)||Ramps up energy expenditure
Enhances glucose tolerance
|β-AMINOISOBUTYRIC ACID (BAIBA)
Whilst not a typical myokine as it is not a small protein, BAIBA is secreted from muscle cells during contractions and enters circulation, making it a clear Exercise Factor.
|Helps convert white fat tissue to brown (brown = metabolically active heat generating fat)
May play a preventative role in cardiovascular and metabolic risk factors.
|IRISIN *||Helps convert white fat tissue to brown (brown = metabolically active heat generating fat)
Drives up energy expenditure;
Improves the balance of insulin to glucagon (glucose homeostasis)
Correlated with muscle and strength improvements in the elderly, staving off sarcopoenia
|ONCOSTATIN M (OSM) *||Anti-inflammatory in muscle tissue
May induce apoptosis (cell death) in hormone-sensitive breast cancer
* These are probable exercise factors. This means that they are likely to be proven (or have been proven to some extent) to enter the bloodstream after exercise but the evidence needs to be more robust for verification.
Other noteworthy myokines
- Helps in the formation of new blood vessels from existing ones (angiogenesis), in skeletal muscle
- Improves insulin sensitivity in muscle tissue via increasing glucose uptake.
Fibroblast growth factor 21 (FGF21)
Both exercise and fasting help to stimulate the secretion of FGF21
- Plays a role in bodyweight reduction
- Improves plasma insulin, LDL, HDL and triglyceride levels
- May have a beneficial impact on the process of aging
Brain-derived neurotrophic factor (BDNF)
Both acute and long-term exercise stimulate an increase of BDNF levels in muscle tissue. It is worth noting that the brain also secretes BDNF and it is from that source exclusively that BDNF enters the bloodstream.
- BDNF is involved in the repair of muscle tissue, activating satellite cells and signalling AMPK- a fuel sensing enzyme.
Vascular endothelial growth factor (VEGF)
- Critical for the growth of new blood vessels
- Via the above, plays an important role in improving the delivery of oxygen and energy to skeletal muscle tissue.
Leukemia inhibitory factor (LIF)
- Plays a role in muscle regeneration and hypertrophy via cell proliferation
- Increases muscle glucose uptake
Let myokines be your medicine, in strength and health.
Myokines are released by skeletal muscles during contractions/exercise. They communicate an anti-inflammatory message helping locally in the repair, regeneration and hypertrophy of muscle tissue. Beyond that they play an important role in keeping many organs and processes within the body working optimally. Myokines are valuable in the prevention and control of metabolic dysfunction, chronic diseases, and even some cancers.
Myokines are known to help with:
- Metabolic processes
- Musculoskeletal disease
- Type 2 diabetes
- CV disease
Exercise-induced myokines: a brief review of controversial issues of this decade, Jun Seok Son,Song Ah Chae,Eric D. Testroet,Min Du &Hyung-pil Jun, January 2018, Expert Review of Endocrinology & Metabolism 13(1), DOI 10.1080/17446651.2018.1416290. Available here.
The search for exercise factors in humans Milene Catoire and Sander Kersten. Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. The FASEB Journal. Available here.
Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise, Svenia Schnyder and Christoph Handschin. US National Library of Medicine National Institutes of Health. Available here.
Interplay of adipokines and myokines in cancer pathophysiology: Emerging therapeutic implications, Maria Dalamaga. US National Library of Medicine National Institutes of Health. Available here.
Muscles and their myokines. Pedersen BK1. US National Library of Medicine National Institutes of Health. Available here.