Muscle Building Myokines | What Are They?

myokines

The myokines are a group of cytokines and interleukins that help to increase muscle mass. Myokines are vital because they play an essential role in developing and maintaining lean body tissue (muscle), bone, skin, cartilage, tendons, and ligaments.

What is a Myokine? Myokines Definition

cytokines and myokines

Myokines are a type of cytokine. The signaling process within cells is regulated by cytokines, which are small proteins. Cellular signaling is the exchange of information within and between cells, affecting how they behave. Cytokines can communicate with the originating cell itself, referred to as autocrine. They can also talk with nearby cells, referred to as paracrine, and even with distant organs, called endocrine. 

Over 100 distinct myokines have been discovered to date. However, most are poorly understood, and scientists speculate that hundreds or possibly thousands are left undiscovered.

Skeletal muscles release myokines during muscle contractions and exercise. They communicate an anti-inflammatory message that starts the repair process in the damaged muscle fibers and leads to regeneration and hypertrophy of muscle tissue. Beyond repairing and growing skeletal muscles, they are crucial to the optimal functioning of many internal organs. Myokines play an essential role in protecting against metabolic dysfunction, chronic diseases, and cancer.[1] It is believed that myokines kill cancer cells, reduce inflammation, boost immunity, regulate blood sugar, and have the most significant effect on the brain.

As already mentioned, resistance training stimulates the creation and release of myokines from within the skeletal muscle. The release of these myokines has the unique ability to directly control anabolic and catabolic processes within the body and the muscles.[2]

Myokines and their actions are claimed to be biphasic. They bind first to the cell receptor and then regulate the signal transduction through an array of transcription factors and intracellular messengers.[3]

Myokines involved in muscle growth

muscle growth

There are dozens, even hundreds, of known myokines, but we will focus on the known ones that play a significant role in skeletal muscle growth.

Below is a list of the key myokines produced by the human skeletal muscle cells that affect muscle hypertrophy.

  • Mechano growth factor (MGF)
  • Interleukin-4 (IL-4)
  • Interleukin-6 (IL-6)
  • Interleukin-7 (IL-7)
  • Interleukin-8 (IL-8)
  • Interleukin-10 (IL-10)
  • Interleukin-15 (IL-15)
  • Myostatin
  • Hepatocyte growth factor (HGF)
  • Leukemia inhibitory factor (LIF)

How do myokines increase muscle growth?

build muscle

It is important to note that not all myokines produced by the skeletal muscle cells are anabolic; some are catabolic or inhibitory. An excellent example of this is myostatin; when released, it has an inhibitory effect on muscle growth, but when myostatin is inhibited, it can increase protein synthesis and muscle growth.

The majority of the myokines are anabolic in nature, which means they stimulate or upregulate protein synthesis or start the process of bringing the required substances to the muscle fibers so repair, healing, and muscle hypertrophy can begin.

Below we will break down each of the key myokines and explain how they affect skeletal muscle cells.

Mechano Growth Factor (MGF)

mechano growth factor

Mechano growth factor, also known as MGF, is thought to initiate the skeletal muscle growth process after resistance training. MGF downregulates specific catabolic processes and at the same time upregulates anabolic processes. MGF is believed to be essential in the early stages of the skeletal muscle cell’s response to mechanical stimuli and the reaction by satellite cells. researchers speculate that the muscle loss and wasting seen in old age is related to an impaired ability of the skeletal muscle cells to express MGF.[4]

Interleukin-4 (IL-4)

Interleukin 4, also referred to as IL-4, is thought to play a role in skeletal muscle hypertrophy via myogenic differentiation.[5]

Interleukin-6 (IL-6)

interleukin-6

Interleukin 6 is one of the most researched interleukins that affects human skeletal muscle hypertrophy. IL-6 affects hypertrophy by stimulating satellite cells to proliferate.[6] IL-6 also plays a crucial role in myonuclear accretion via signaling satellite cells.[7] Evidence suggests that interleukin-6 can directly stimulate protein synthesis via specific signal transduction pathways.[8]

In addition to its ability to affect muscle mass, IL-6 has been well documented to play a role in the energy demands of working skeletal muscle cells. According to scientists, IL-6 functions as an energy sensor. It is secreted to stimulate glycogenolysis in the liver and lipolysis in fat tissue to meet the muscle’s demands during exercise.[9]

Interleukin-7 (IL-7)

Interleukin-7 increases the migration of satellite cells and affects myogenesis and protein synthesis.[10][11]

Interleukin-8 (IL-8)

Interleukin-8 does not directly stimulate muscle growth. But instead, IL-8 works by exhibiting an anticatabolic effect. IL-8 stops muscle fibers from being broken down and affects muscle in similar ways to those seen with IGF-1.[12]

Interleukin-10 (IL-10)

Interleukin-10 plays a secondary role in increasing muscle mass. IL-10 works by improving insulin resistance and making your muscles more sensitive to insulin.[13] Increasing the skeletal muscle’s insulin sensitivity means they will be able to take up more glucose, amino acids, and nutrients key to muscle repair and growth.

Interleukin-15 (IL-15)

Interleukin-15 is highly sensitive to resistance training, and its levels increase substantially in response to resistance training, inflammation, and oxidative stress. IL-15 can increase protein synthesis and myotube differentiation, which leads to an anabolic environment within the muscle.[14] In addition to upregulating anabolism, it has also been shown to reduce muscle breakdown by as much as 3 times.[15]

Myostatin

myostatin bull

Myostatin is a potent negative regulator of muscle mass. The myostatin gene is almost entirely expressed within muscle fibers.[16] By inhibiting myostatin in mice, researchers observed increased myofiber hypertrophy by 20 to 30 percent in both old and young mice in the absence of exercise.[17][18] Myostatin inhibits protein synthesis and muscle building by inhibiting satellite cell activation.[19]

Research shows that resistance training downregulates myostatin. If the resistance training is done consistently, it can downregulate myostatin by up to 3 times.[20]

Hepatocyte growth factor (HGF)

Hepatocyte growth factor is believed to help build muscle mass by activating dormant (quiescent) satellite cells. Scientists believe that HGF is activated by calcium-calmodulin and nitric oxide synthase.[21]

Leukemia inhibitory factor (LIF)

Leukemia inhibitory factor stimulates muscle mass by activating satellite cells and inducing satellite cell proliferation. LIF is believed to be released in response to the influx of intracellular calcium within the muscle related to resistance exercise.[22]

Leukemia inhibitory factors importance in building muscle mass was demonstrated in a study using mice. Mice missing the LIF gene were completely unable to build muscle mass in response to muscular overload. When the mice were given exogenous LIF, their ability to gain muscle mass was restored.[23]

What does it all mean?

As you can see, myokines play many crucial roles in the anabolic process. Without proper stimulation and release of adequate amounts of these myokines, the muscle hypertrophy process and protein synthesis grinds to a halt or is severely impaired.

References

References
1Exercise-induced myokines and their effect on prostate cancer | Nature Reviews Urology
2The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15 – PubMed (nih.gov)
3Eccentric Exercise Activates Novel Transcriptional Regulation of Hypertrophic Signaling Pathways Not Affected by Hormone Changes – PMC (nih.gov)
4Mechanical Signals, IGF-I Gene Splicing, and Muscle Adaptation | Physiology
5Differentially Activated Macrophages Orchestrate Myogenic Precursor Cell Fate During Human Skeletal Muscle Regeneration | Stem Cells | Oxford Academic (oup.com)
6Localization of leukemia inhibitory factor and interleukin‐6 messenger ribonucleic acids in regenerating rat skeletal muscle – Kami – 1998 – Muscle & Nerve – Wiley Online Library
7Satellite cell and myonuclear accretion is related to training-induced skeletal muscle fiber hypertrophy in young males and females | Journal of Applied Physiology
8, 9Interleukin-6: possible biological roles during exercise – PubMed (nih.gov)
10IL-7 is expressed and secreted by human skeletal muscle cells | American Journal of Physiology-Cell Physiology
11Muscles, exercise and obesity: skeletal muscle as a secretory organ | Nature Reviews Endocrinology
12Interleukin-8 enhances myocilin expression, Akt-FoxO3 signaling and myogenic differentiation in rat skeletal muscle cells – PubMed (nih.gov)
13Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance – PMC (nih.gov)
14, 15Interleukin-15: a muscle-derived cytokine regulating fat-to-lean body composition – PubMed (nih.gov)
16Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child | NEJM
17Molecular, cellular and physiological investigation of myostatin propeptide-mediated muscle growth in adult mice – Neuromuscular Disorders (nmd-journal.com)
18Myostatin propeptide gene delivery by adeno-associated virus serotype 8 vectors enhances muscle growth and ameliorates dystrophic phenotypes in mdx mice – PubMed (nih.gov)
19Myostatin negatively regulates satellite cell activation and self-renewal – PMC (nih.gov)
20Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy | Journal of Applied Physiology
21Nitric oxide modulates hepatocyte growth factor/scatter factor-induced angiogenesis – PubMed (nih.gov)
22Leukaemia inhibitory factor–an exercise-induced myokine – PubMed (nih.gov)
23Changes in muscle mass with mechanical load: possible cellular mechanisms This paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process. (cdnsciencepub.com)