Exercise, Skeletal Muscle, and “Hope Molecules”

It is well established both that exercise enhances mood and learning, reduces stress and anxiety, and turbocharges brain function. There is something to be desired about the uplifting effect of exercise and the sense of well-being we inherently feel both from an acute bout of physical activity and while performing any type of physical training program.

An active lifestyle is essential to maintain health into old age; inversely, in inactive lifestyle has been linked to an elevated risk for many chronic diseases.

The discovery of myokines (also referred to as Hope Molecules) are hormones produced by skeletal muscle tissue, suggests the possibility that these might be molecular mediators of the whole-body effects of exercise originating from contracting muscle fibers. Although less is known about the sedentary state, the lack of contraction-induced myokines or the production of a distinct set of hormones in the inactive muscle could likewise contribute to pathological consequences in this context.

Why are myokines called hope molecules?

Myokines are often called “Hope Molecules” because they offer so many benefits for human health and muscle development. By exercising regularly, you can help your body produce more myokines, which can help you feel better and get stronger over time.

It is now firmly established that skeletal muscle tissue produces and secretes cytokines and other proteins, which have been named “myokines”.

Myokines are known to exert endocrine effects, therefore skeletal muscle can be classified as an endocrine organ.

Myokines are essentially all-natural antidepressants: they reduce stress, improve mood and learning, reduce inflammation, control blood sugar levels, combat cancer cells, and turbocharge brain function. Consider them your in-house guardians of mental and physical well-being⁽¹⁾.

Figure: Auto-, para- and endocrine effects of myokines. Selected examples of the physiological consequences of the production and release of myokines on skeletal muscle and other organs are depicted. Adapted from⁽¹⁾

Antidepressive effects of exercise

Antidepressant prescriptions have increased by 35% over the last six years. It seems that somewhere over the last 15 years, we may have started to give the pills a little too much credit. Antidepressants main mechanism is by acting as selective serotonin reuptake inhibitors (SSRIs).

Here is some deflating data on antidepressants:

• - Only 60% of patients respond positively to antidepressants.
• - Antidepressants can help people improve 9.6 points on a depression scale, but a placebo can help them improve 7.8 points.
• - People with depression do not have less serotonin than people without depression⁽²⁾.

This is not to say SSRIs do not work, but essentially that some research indicates that they are only 25% more effective than a piece of candy (i.e., placebo). In addition, they can produce long-term side effects like weight gain or sexual dysfunction.

In order to bridge this gap in treatment, researchers started looking into other options for relief and exercise has emerged as a extremely competent alternative.

In two recent studies, exercise was proven 1.5 times more effective than either therapy or “leading medications” in treating depression^(3,4).

Essentially, evidence indicates that patients can get a handle on their anxiety, distress, or depression in a matter of months and that exercise has moderate to large effects on depressive symptoms and should be offered as an evidence-based treatment option.

Major myokines and their potential applications

Since discovery and describing the first myokines, the list has constantly been growing demonstrating that skeletal muscle can express several myokines, some simultaneously, others are secreted in a time or context-controlled manner. The main catalyst and the key regulatory element for expression and secretion is contractile activity of the muscle. In the following sections, I will describe the functions of some of the major myokines and their potential application in combating metabolic diseases.

Myostatin

The main function of myostatin is to negatively regulate muscle mass. There is evidence that lack of myostatin reduces total and intramuscular body fat. Also, a lack of myostatin increases muscle mass which can lead to increased resting energy expenditure, which also account for reduction in fat mass.

Although it wasn’t’ called a myokine upon its discovery, myostatin is one of the first of this class of proteins. However, since both aerobic exercise and strength training in animals and humans significantly reduce expression in skeletal muscle, myostatin is more like an “inverse” myokine compared to most other family members that are elevated by exercise⁽¹⁾.

Interleukin-6

Interleukin-6 (IL-6) has originally been classified as a classical pro-inflammatory cytokine. Subsequent research has indicated that IL-6 has anti-inflammatory properties. Besides the production of IL-6 in activated immune cells, the systemic elevation of IL-6 in patients with metabolic diseases has supported the link of IL-6 and inflammation. Additional research in a transgenic animal model demonstrated that overexpression of IL-6 results in reduced body mass and impaired insulin-stimulated glucose uptake by skeletal muscle⁽⁵⁾.

Therefore, IL-6 has been indicated as one of the pro-inflammatory factors that promote the development of peripheral insulin resistance.

Conversely, exercise-induced elevation of IL-6 plasma levels increases circulating concentrations of several potent anti-inflammatory cytokines such as IL-1ra and IL-10, suggesting that IL-6 may also have anti-inflammatory properties.

Skeletal muscle fibers also express and release IL-6 during and after exercise.

IL-6 production is likewise boosted in connective tissue, the brain and adipose tissue after an exercise session. Upon discovery, IL-6 was classified as one of the founding members of the myokine class of proteins, and demonstrated characteristics of a true “exercise factor”, which exerts its effects both locally within the muscle and peripherally on distal organs in an endocrine-like fashion⁽⁶⁾.

IL-6 release in response to exercise has multiple positive metabolic effects including enhancing glucose uptake and fatty acid oxidation locally in skeletal muscle and enhancing insulin secretion, which also enhances glucose uptake into muscle cells.

Simultaneously, liver glucose output and fatty acid release from adipose tissue are stimulated and provide energy substrates for exercising muscle.

Brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is strongly expressed in the brain and to a lesser extent in skeletal muscle. In the central nervous system, BDNF regulates neuronal development and modulates synaptic plasticity, playing a role in the regulation of survival, growth, and maintenance of neurons. In addition, hypothalamic BDNF has been identified as a key factor in the control of body mass and energy homeostasis. BDNF also influences learning and memory and brain samples of patients with Alzheimer’s disease demonstrate reduced expression of BDNF.

Correspondingly, BDNF serum levels of patients with depression, obesity and type 2 diabetes are decreased.

Again, exercise has a tremendous positive effect on this myokine by enhancing circulating BDNF levels in humans and recent research indicates that the brain contributes 70-80% of the circulating BDNF in this context.

BDNF levels are also increased in skeletal muscle in response to exercise and contribute to enhanced fat oxidation.

However, muscle-derived BDNF seems not to be released into the circulation in significant amounts indicating that BDNF primarily acts in an auto- and/or paracrine manner, which means it acts locally within the muscle fibers. Accordingly, besides the effects on metabolic properties, the increase of BDNF within the muscle alters myogenesis, satellite cell activation and skeletal muscle regeneration⁽⁷⁾.

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is a mitogen with specificity for vascular endothelial cells and is an essential regulator of embryonic vascular development (vasculogenesis) as well as blood vessel formation (angiogenesis).

In fact, VEGF is most likely the most important pro-angiogenic growth factor in most tissues including skeletal muscle.

Again, exercise upregulates levels of VEGF in skeletal muscle following an acute bout of exercise. Additionally, interstitial VEGF levels likewise increase markedly after exercise⁽¹⁾ suggesting that VEGF is indeed secreted from contracting skeletal muscle fibers.

Therefore, skeletal muscle controls its own capillary supply be secreting VEGF into the extracellular space where VEGF acts on the vascular endothelial cells to increase blood vessel formation, and thus ultimately improve oxygen and energy substrate transport to the exercising muscle.

Anti-tumorigenic myokines

An active life-style is not only associated with a decreased risk for the development of metabolic diseases such as cardiovascular pathologies and type 2 diabetes, research also indicates a possible link between physical activity and certain types of cancer. In fact, the World Cancer Research Fund proposed that exercise reduces the risk for developing breast and colon cancer by 25-30%.

In support, there is a growing list of potential mechanisms how exercise may exhibit anti-tumorigenic effects, even though the molecular pathways are still largely unknown. Recently, two myokines have been identified, secreted protein acidic and rich in cysteine (SPARC) and oncostatin-M (OSM)⁽⁸⁾, which suppress tumor formation in the colon and inhibit mammary cancer cell growth, respectively. Both myokines inhibit proliferation and induce apoptosis (programmed cell death) of cancer cells.

Summary

The discovery of myokines has opened a vast new and exciting field in the study of muscle, and exercise physiology. Even now, members of the myokine group of signaling molecules cover a whole range of effects, both locally and throughout the body. Research on myokines is expanding rapidly. Different analytical techniques are identifying novel potential myokines at a breath-taking pace.

An important area in this line of research should aim at the identification of exercise-induced myokines that may be potentially associated with inactive, sedentary muscle.

Myokines not only provide a molecular explanation for the extensive cross-talk between muscle and other tissues in our body, but also reveal novel therapeutic avenues for the treatment of a myriad of chronic diseases that are associated with a sedentary life-style.

Therefore, the study of myokines will remain an extremely interesting research topic for our understanding of basic as well as translational aspects of skeletal muscle physiology in the years to come.


References:
1.    Schnyder, S. and C. Handschin, Skeletal muscle as an endocrine organ: PGC-1alpha, myokines and exercise. Bone, 2015. 80: p. 115-125.
2.    Moncrieff, J., et al., The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry, 2022.
3.    Singh, B., et al., Effectiveness of physical activity interventions for improving depression, anxiety and distress: an overview of systematic reviews. Br J Sports Med, 2023.
4.    Heissel, A., et al., Exercise as medicine for depressive symptoms? A systematic review and meta-analysis with meta-regression. Br J Sports Med, 2023.
5.    Franckhauser, S., et al., Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia, 2008. 51(7): p. 1306-16.
6.    Pedersen, B.K., et al., Role of myokines in exercise and metabolism. J Appl Physiol (1985), 2007. 103(3): p. 1093-8.
7.    Miura, P., et al., Brain-derived neurotrophic factor expression is repressed during myogenic differentiation by miR-206. J Neurochem, 2012. 120(2): p. 230-8.
8.    Hojman, P., et al., Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab, 2011. 301(3): p. E504-10.