Exerkines: The Secret Signaling Molecules That Make Your Muscles Talk to Your Whole Body

2026-02-16

You've probably heard that muscle is metabolically active tissue. But here's what most lifters don't realize: when you train, your muscles become a master signaling hub that communicates with virtually every organ in your body.

This communication happens through molecules called exerkines—a broad term for the peptides, metabolites, and nucleic acids released during and after exercise. Within this family, myokines are the specific signals released by skeletal muscle itself.

The implications for muscle building, fat loss, and overall health are massive. Let's break down what we know.

What Exactly Are Exerkines?

Exerkines are bioactive molecules secreted by contracting muscles (and other tissues) during exercise. They travel through the bloodstream and act on distant organs—your brain, liver, fat, bones, heart, and even other muscle groups.

Think of them as your muscles sending out status updates to the rest of your body: "We're under tension here. Send resources. Activate repair pathways. Boost metabolism."

The term "exerkine" comes from "exercise" + "kine" (as in kinetics or chemical messengers). The more specific term myokine refers specifically to proteins secreted by muscle tissue. Not all exerkines are myokines—some come from fat (adipokines), liver (hepatokines), and other tissues—but myokines are the heavy hitters for lifters.

Key Myokines Every Lifter Should Know

1. Interleukin-6 (IL-6): The Archetype

IL-6 was the first myokine discovered and remains the most studied. During intense resistance training, muscle IL-6 expression can increase 20-100x above resting levels.

But here's the counterintuitive part: IL-6 isn't just an inflammatory marker. In the context of exercise, it acts as a metabolic regulator that:

Increases glucose uptake in muscles
Enhances fat oxidation
Stimulates muscle protein synthesis (MPS)
Modulates the immune response

The key difference between exercise-induced IL-6 and chronic inflammation: acute IL-6 spikes are short-lived and followed by anti-inflammatory responses. It's the pattern of repeated exercise that matters, not the individual spikes.

2. Irisin: The Brown Fat Activator

Irisin is perhaps the most famous exerkine, named after the Greek goddess Iris (messenger). It's released from muscle tissue in response to exercise and converts white fat into brown fat—the metabolically active kind that burns calories for heat.

For muscle builders, irisin is exciting because it:

Enhances glucose metabolism
Increases energy expenditure
May improve muscle regeneration
Potentially supports bone health

Research from 2024-2025 shows irisin levels rise within 30 minutes of moderate-intensity exercise and remain elevated for up to 24 hours. High-volume training with shorter rest periods tends to produce greater irisin responses.

3. Brain-Derived Neurotrophic Factor (BDNF)

BDNF is a neurotrophin—a protein that supports neuron survival and growth. Muscle release of BDNF during resistance training has major implications beyond the gym:

Cognitive function: Higher BDNF is linked to improved memory and learning
Mood regulation: BDNF has antidepressant-like effects
Neuroprotection: May help prevent age-related cognitive decline

For older lifters, this is particularly relevant. Sarcopenia (age-related muscle loss) is accompanied by reduced myokine signaling. Exercise reverses this by boosting BDNF and other neuroprotective exerkines.

4. Myostatin: The Growth Brakes

Myostatin is a negative regulator of muscle growth—it's literally the molecule that tells your muscles when to stop growing. Some people have genetic myostatin mutations that cause massive muscle hypertrophy (the "double muscle" phenomenon in cattle and mice).

Here's the key insight: heavy resistance training suppresses myostatin expression. While the effect is transient (myostatin rebounds between sessions), consistent training keeps the brakes partly off.

This is why some researchers are interested in myostatin-inhibiting compounds—the theory being that blocking myostatin could unlock additional muscle growth potential. However, the long-term effects aren't fully understood, and natural training remains the best approach.

5. IGF-1: The Growth Messenger

Insulin-like growth factor-1 (IGF-1) is released by muscle and acts as a key regulator of muscle protein synthesis. It's one of the primary mechanisms through with resistance training stimulates muscle growth.

Recent research (2025) shows different exercise modalities produce different IGF-1 responses:

Moderate-intensity continuous training (MICT): Higher muscle IGF-1 expression
High-intensity interval training (HIIT): More systemic IGF-1 release

For hypertrophy, this suggests both approaches have merit—MICT may build local muscle protein machinery while HIIT provides systemic growth signals.

6. FGF21: The Metabolic Regulator

Fibroblast growth factor 21 (FGF21) is a hepatokine that's also released by muscle during exercise. It improves insulin sensitivity, enhances fat burning, and may have anti-aging effects.

What's interesting about FGF21 is its nutrient-dependent release. Fasting amplifies the exercise-induced FGF21 response, suggesting that training in a fasted state might maximize this particular exerkine (though the practical implications are still being studied).

How Exercise Modality Affects Exerkine Release

Not all training produces the same exerkine profile. Research shows:

| Training Type | Primary Exerkine Response | |--------------|---------------------------| | Heavy resistance training | IL-6, IGF-1, myostatin suppression | | High-volume training | Greater IL-6, irisin, BDNF | | HIIT | Systemic IGF-1, FGF21, irisin | | Endurance | IL-6, BDNF, FGF21 |

Practical takeaway: For maximum exerkine signaling, incorporate both heavy lifting and higher-volume sessions. Varying your training stimulus creates different molecular environments that collectively support muscle growth, metabolism, and recovery.

The Anti-Aging Implications

Here's where exerkines get really interesting: they're a primary mechanism through which resistance training combats aging.

As we age, a phenomenon called sarcopenia occurs—progressive loss of muscle mass and function. Research shows this is accompanied by:

Reduced myokine production
Impaired inter-organ communication
Chronic low-grade inflammation
Mitochondrial dysfunction

Exercise reverses this cascade. Resistance training in older adults has been shown to:

Restore myokine secretion to youthful levels
Improve satellite cell function
Enhance mitochondrial quality
Reduce systemic inflammation

A 2026 meta-analysis of 40 randomized controlled trials confirmed that exercise training significantly alters exerkine profiles, with the most consistent changes in adiponectin, IL-6, and BDNF.

Optimizing Your Exerkine Response

Based on current research, here's how to maximize exerkine signaling:

1. Train with Sufficient Volume

Higher-volume sessions produce greater myokine responses. This doesn't mean endless sets, but it does suggest including some higher-rep work alongside your heavy lifting.

2. Incorporate Compound Movements

Exercises that recruit more muscle mass (squats, deadlifts, rows, presses) produce greater systemic exerkine release than isolation movements.

3. Vary Intensity and Modality

Alternating between heavy days and higher-rep sessions creates varied exerkine profiles. Both matter.

4. Don't Neglect Recovery

Exerkines are part of the adaptive response, but they need recovery time to do their work. Overtraining suppresses myokine function.

5. Consider Training Fasted (Cautiously)

The data on fasted exercise amplifying certain exerkines (like FGF21) is intriguing, but this isn't for everyone. If you train well fasted, you're likely leaving some gains on the table; if you need food to train, don't force it.

The Future: Exerkines as Therapeutics

This is where it gets futuristic. Researchers are exploring whether exerkines could be isolated and administered as drugs—essentially creating an "exercise pill."

Early animal studies show promise: injecting certain myokines can partially replicate exercise benefits in sedentary mice. However, we're years (possibly decades) from human applications.

The more immediate reality: you already have the technology to produce these molecules. Every hard set, every rep to failure, every challenging workout triggers this sophisticated signaling cascade.

The Big Picture

Your muscles aren't just contractile tissue—they're an endocrine organ that shapes your entire physiology. When you lift, you're not just damaging fibers and eating protein. You're initiating a complex conversation between your muscles and nearly every system in your body.

Understanding exerkines helps explain why resistance training does so much more than build muscle: it improves brain function, strengthens bones, enhances metabolic health, and even influences how your body stores fat.

The research is clear: the best way to optimize your exerkine profile is simply to train consistently with intensity and variety. No supplement, no hack, no shortcut replicates what a well-designed training program accomplishes.

Now go lift something heavy. Your whole body will thank you.

References

Exerkines and myokines in aging sarcopenia. Frontiers in Endocrinology, 2025.
Decoding the Endocrine Code of Skeletal Muscle: Myokines, Exerkines, and Inter-Organ Crosstalk. Cells, 2026.
Exercise, Exerkines, and Sarcopenia. Diabetes & Metabolism Journal, 2026.
Transcriptomic adaptation of skeletal muscle in response to MICT and HIIT. PLOS ONE, 2025.
Exploring SPARC as a leading exerkine candidate. Biomedicines, 2026.