Myokines: the signals working muscle sends to the body

Muscle as a secretory organ

Hormones usually bring to mind glands such as the thyroid or adrenals. From the 2000s, Bente Klarlund Pedersen’s group at the University of Copenhagen gathered evidence that skeletal muscle also secretes. In a 2012 review with Mark Febbraio, they proposed that cytokines and peptides produced and released by muscle fibres, acting on the muscle itself, on nearby tissue or on distant organs, be called myokines.

According to that review, the muscle secretome runs to several hundred peptides and may connect muscle with adipose tissue, the liver, pancreas, bone and brain. The idea offered a lead on why exercise affects so many organs.

The first case: IL-6

Interleukin-6 (IL-6) was known as a signal released by immune cells during inflammation. Then blood IL-6 was seen to rise sharply during exercise, and the question became where it came from.

In a 2000 study, six healthy men did light one-legged knee-extension exercise for five hours. Arterial IL-6 rose 19-fold over rest. Blood leaving the exercising leg carried more IL-6 than blood entering it; across the resting leg there was no such difference. Contracting muscle was releasing IL-6 itself. The authors suggested it helps maintain blood glucose during prolonged exercise.

The same molecule means different things in different settings. IL-6 that rises in infection or chronic inflammation is not the same context as a brief rise from working muscle. Pedersen’s group describes muscle-derived IL-6 as affecting fat oxidation, the liver, adipose tissue and the immune system.

Irisin and the controversy

In 2012, Bruce Spiegelman’s group in Boston reported a new muscle hormone in Nature. In mouse muscle, a membrane protein called FNDC5 is cleaved and released into the blood as irisin. Irisin gave white fat cells brown-fat-like features and, in mice, raised energy expenditure and improved glucose control. It was quickly nicknamed the exercise hormone.

In 2015, researchers in Germany, Norway and elsewhere pushed back. They found that antibodies in the commercial ELISA kits used to measure irisin cross-reacted with other blood proteins, and argued that all data from those kits needed re-examining. Their paper was titled “Irisin: a myth rather than an exercise-inducible myokine”.

The same year, Spiegelman’s group measured human plasma irisin directly by mass spectrometry: about 3.6 ng/mL in sedentary people and about 4.3 ng/mL in people doing aerobic interval training. That settled that irisin circulates in humans. What it does at those levels in people is still unclear.

Other myokines

• Myostatin: a myokine involved in regulating muscle hypertrophy and the formation of muscle cells.
• BDNF: a protein tied to neural plasticity in the brain; it is also made in muscle, where it has been linked to fat oxidation.
• IL-7 and LIF: involved in the formation and growth of muscle cells.
• Others on the list include IGF-1 and FGF-2, linked to bone formation, and FSTL-1, linked to blood-vessel lining function.

What is known, and what is not

What is known: muscle does secrete many substances, and many of them depend on contraction. Pedersen and Febbraio therefore proposed that inactivity probably alters the myokine response, which could be one mechanism linking sedentary life to many chronic diseases. That is offered as a hypothesis.

Much is unknown. A 2020 review from Pedersen’s group noted that although muscle secretes hundreds of myokines, only a few have been assigned a specific function in humans. Even measuring blood levels can be contested, as irisin showed. Supplements or devices claimed to “boost” a given myokine, or to deliver the benefits of exercise without exercise, are not supported by current research. Where myokine research points, so far, is using muscle. Muscle loss itself is covered in the article on sarcopenia.

Before you start exercising

If you have heart or lung disease, or have had chest pain, severe breathlessness or dizziness during exercise, talk to a doctor before increasing intensity. With joint pain or sarcopenia, too, it is safer to start with a plan suited to your condition.