Peptide Hormones in Exercise Physiology Research

Every time you exercise, your body launches a coordinated chemical response involving dozens of peptide hormones. Growth hormone surges. Insulin shifts. Endorphins flood the bloodstream. And peptides discovered only in the last decade — MOTS-c, irisin — are released from muscles and mitochondria to communicate with nearly every organ in the body.

Understanding these peptide responses isn't just academic. It explains why exercise works as medicine. It informs how therapeutic peptides like CJC-1295 and semaglutide interact with the body's natural systems. And it's reshaping how researchers think about the link between physical activity, metabolism, and aging.

This article breaks down the major peptide hormones involved in exercise — what they do, how exercise changes them, and what that means for both athletic performance and human health.

Growth Hormone: The Exercise-Responsive Giant
IGF-1: Local Muscle Signaling vs. Circulating Levels
MOTS-c: The Mitochondrial Exercise Mimetic
Irisin: The Browning Peptide and Beyond
Insulin Dynamics During Exercise
Endorphins and Enkephalins: The Opioid Peptides of Exercise
Atrial Natriuretic Peptide and Cardiovascular Exercise
GLP-1: How Exercise Changes Gut Peptide Signaling
How This Informs Therapeutic Peptide Research
FAQ
The Bottom Line
References

Growth Hormone: The Exercise-Responsive Giant {#growth-hormone}

Growth hormone (GH) is probably the most studied peptide hormone in exercise physiology. Released from the anterior pituitary gland, GH drives tissue repair, fat metabolism, and protein synthesis. It's a potent anabolic signal — and exercise is one of the strongest natural triggers for its release.

How Exercise Triggers GH Release

Physical activity is a potent physiological stimulus for GH secretion in both aerobic and resistance exercise. Aerobic exercise stimulates GH release after roughly 15 minutes of activity, and the response scales with intensity — harder workouts produce more GH.

Resistance training triggers GH through a different pattern. The type of workout matters: high-volume protocols with moderate loads and short rest periods (the kind that produce significant metabolic stress) tend to generate the largest GH spikes. Heavy, low-rep strength training with long rest periods produces less.

Several factors affect the GH response:

Intensity — Higher intensity = more GH
Duration — Longer sessions generally produce more total GH
Fitness level — Trained individuals may have a blunted acute GH response to the same absolute workload, though the response to relative intensity is preserved
Age — GH response to exercise declines with age
Gender — Women show different GH kinetics than men, partly due to estrogen's role in GH regulation

The GH Superfamily

Recent research has complicated the simple story of "exercise raises growth hormone." GH exists as multiple molecular isoforms — including 20 kDa, non-22 kDa, 44 kDa, and 66 kDa variants — each potentially serving different functions during recovery (Journal of Applied Physiology, 2017). The classic immunoassay measures primarily the 22 kDa form, meaning we may have been measuring only part of the picture.

This has implications for peptides like sermorelin and CJC-1295 that stimulate GH release through growth hormone-releasing hormone (GHRH) pathways, and for growth hormone secretagogues like ipamorelin and MK-677 that work through the ghrelin receptor. Understanding which GH isoforms are released — and which matter most for tissue repair, fat loss, or muscle growth — is an active area of investigation.

The Mixed Evidence on Training and Hormones

A 2025 study in Frontiers in Physiology found that while exercise programs improved body composition, muscle strength, and both aerobic and anaerobic capacity, they did not always produce significant changes in anabolic hormones like GH, IGF-1, and testosterone. This finding underscores an important point: the acute hormonal spike during a workout and the long-term hormonal adaptation to training are different things. You can get stronger and fitter without persistent elevations in resting GH levels.

IGF-1: Local Muscle Signaling vs. Circulating Levels {#igf-1}

Insulin-like growth factor 1 (IGF-1) is produced primarily in the liver in response to GH, but also locally in skeletal muscle. It drives cell growth, protein synthesis, and tissue repair. For years, researchers focused on blood levels of IGF-1 as a marker of anabolic status. That picture has changed.

The Local vs. Systemic Distinction

One of the most important developments in exercise endocrinology is recognizing that local muscle IGF-1 matters more than what's circulating in the blood. Increased expression of IGF-1 within muscle tissue leads to muscle hypertrophy in mice independently of circulating levels. This means serum IGF-1 — the number on a blood test — may not reflect what's happening inside the muscle itself.

Exercise consistently upregulates local IGF-1 in muscle, and training-induced increases in muscle IGF-1 are correlated with gains in muscle strength (Physiological Reviews, 2024). The splice variants of IGF-1 are particularly interesting: mechano-growth factor (MGF), a splice variant produced in response to mechanical loading, is thought to play a role in satellite cell activation and muscle repair.

Exercise Type Matters

A 2025 review covering evidence from 2000-2025 examined how different training modalities affect the insulin/IGF-1 axis. Resistance training, sprint work, power training, high-intensity interval training, and aerobic exercise at various intensities all influence IGF-1 differently. Resistance training with higher volumes appears to produce the most consistent local IGF-1 response. Dietary protein intake also modulates the IGF-1 response to exercise, with higher protein intake supporting greater IGF-1 signaling.

Relevance to Therapeutic Peptides

This research context helps explain why peptide researchers study compounds like IGF-1 LR3 and CJC-1295/ipamorelin combinations. They're attempting to augment the same pathways that exercise naturally activates. Understanding the natural system — particularly the importance of local vs. systemic signaling — is essential for evaluating whether exogenous peptides can meaningfully replicate exercise-induced IGF-1 effects.

MOTS-c: The Mitochondrial Exercise Mimetic {#mots-c}

MOTS-c is one of the most exciting peptide discoveries in exercise science. First identified in 2015 by Lee et al., MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial genome — not the nuclear genome. This makes it a primary signaling molecule for communication from mitochondria to the rest of the cell and the entire body.

MOTS-c and Exercise: A Direct Connection

Exercise dramatically increases MOTS-c production. In muscle cells, MOTS-c levels increased nearly 12-fold after exercise and remained partially elevated after four hours of rest. Blood plasma levels increased by approximately 50% during and after exercise (Nature Communications, 2021).

This makes MOTS-c a true exercise-responsive peptide — a molecule your mitochondria produce more of when you're physically active. The profile has led researchers to call it an "exercise mimetic," meaning it may reproduce some effects of exercise even without physical activity.

What MOTS-c Does

MOTS-c activates AMPK — the same energy-sensing enzyme activated by exercise and by the diabetes drug metformin. Through AMPK activation, MOTS-c:

Improves glucose metabolism and increases GLUT4 (the glucose transporter that moves sugar into muscle cells)
Increases exercise endurance in animal models
Prevents skeletal muscle atrophy
Promotes mitochondrial biogenesis
Supports muscle fiber-type changes toward oxidative (Type I) fibers

The CK2 Discovery (2024)

A landmark 2024 study published in iScience identified casein kinase 2 (CK2) as a direct molecular target of MOTS-c. When researchers gave MOTS-c to mice, it prevented muscle atrophy and improved glucose uptake — effects that were blocked when CK2 was suppressed. This was the first identification of a direct binding target for MOTS-c, moving beyond the general "AMPK activation" story to a specific molecular mechanism.

Beyond Muscle: Expanding Roles

Recent research has expanded MOTS-c's story beyond exercise and muscle:

A 2025 study in Scientific Reports showed MOTS-c combats diabetic liver fibrosis through the Keap1-Nrf2-Smad2/3 pathway
Research in Frontiers in Physiology (2025) demonstrated MOTS-c restores mitochondrial respiration in type 2 diabetic hearts
Blood MOTS-c levels are lower in people with type 2 diabetes, gestational diabetes, coronary endothelial dysfunction, and in obese children

Anti-Doping Status

MOTS-c is banned by the World Anti-Doping Agency (WADA) as of 2024. It is not approved to treat any medical condition. Its prohibition reflects WADA's concern about its performance-enhancing potential — a concern that, ironically, is itself evidence of how seriously the athletic and regulatory communities take this peptide's biological effects.

Irisin: The Browning Peptide and Beyond {#irisin}

Irisin made headlines in 2012 when it was identified as a myokine (muscle-derived hormone) that could convert white fat into calorie-burning brown fat. The initial excitement was followed by controversy over whether irisin actually existed in human blood at meaningful levels. A decade later, the evidence has largely supported irisin's existence and expanded its role far beyond fat browning.

How Exercise Releases Irisin

During exercise, the transcriptional co-activator PGC-1-alpha is upregulated in skeletal muscle. PGC-1-alpha drives expression of FNDC5, a membrane protein. FNDC5 is cleaved, and the released fragment — irisin — enters the bloodstream.

A 2024 meta-analysis of nine randomized controlled trials involving 264 participants found that concurrent training (combined aerobic and resistance exercise) moderately increased circulating irisin levels (SMD = 0.56, 95% CI 0.33-0.80), published in PeerJ (2024). The effect was strongest in the 45-60 age group.

What Irisin Does: The Expanding Picture

Fat browning — Irisin's original claim to fame. It activates UCP1 (uncoupling protein 1) in white adipose tissue, converting it to metabolically active beige/brown fat that burns calories through thermogenesis.

Anti-thrombotic effects — A 2025 presentation at the American Society of Hematology revealed that irisin functions as a multi-target anti-thrombotic myokine, modulating platelet, monocyte, and endothelial cell function through distinct integrin receptors (Blood, 2025).

Anti-cancer potential — A 2025 review found that irisin has dose- and time-dependent anti-proliferative effects in cancer cell lines, primarily through PI3K/Akt/mTOR inhibition and AMPK activation. It also inhibits epithelial-mesenchymal transition, suppressing cancer cell migration. This connects to the broader question of how exercise reduces cancer risk — irisin may be one of the molecular mediators. (For more on peptides in cancer research.)

Brain effects — Research in Scientific Reports (2024) confirmed that irisin can cross the blood-brain barrier, influencing central nervous system signaling — which may help explain some of the cognitive benefits of exercise.

Renal anti-aging — A 2025 study showed that irisin modulates renal expression of Klotho (an anti-aging protein) and HSP70, suggesting exercise-released irisin may help protect kidneys from age-related decline.

The Broader Concept: Exerkines

Both MOTS-c and irisin belong to the growing category of "exerkines" — signaling molecules released during exercise that mediate the systemic health benefits of physical activity. A 2024 review in The Journal of Physiology highlighted that small peptides, including mitochondrial-derived peptides like MOTS-c and humanin, could play outsized roles in exercise-mediated metabolic regulation. This reframes exercise not just as mechanical work, but as a signal that triggers whole-body communication through a network of peptide messengers.

Insulin Dynamics During Exercise {#insulin-dynamics}

Insulin is a 51-amino-acid peptide hormone, and its behavior during exercise is one of the most well-studied — and counterintuitive — aspects of exercise physiology.

The Paradox: Insulin Falls, Glucose Uptake Rises

During exercise, plasma insulin levels decrease. Your pancreas produces less insulin while you're active. Yet skeletal muscle glucose uptake increases dramatically. How?

The answer is GLUT4. In resting muscle, glucose transport depends on insulin signaling to move GLUT4 transporters to the cell surface. During exercise, muscle contractions activate a completely separate pathway — involving AMPK, calcium signaling, and nitric oxide — that translocates GLUT4 to the membrane independently of insulin (Physiological Reviews, 2024).

These two pathways — insulin-dependent and contraction-dependent — are synergistic. That's why exercise improves insulin sensitivity: it adds a second, parallel route for glucose to enter muscle cells.

The Post-Exercise Window

After exercise, muscle remains more sensitive to insulin for 24-48 hours. This isn't primarily about increased insulin signaling (proximal signaling like Akt phosphorylation is only modestly elevated). Instead, the enhancement appears to involve greater phosphorylation of TBC1D4 (a downstream signaling molecule) and activation of glycogen synthase — the enzyme that stores glucose as glycogen.

Muscle glycogen levels also play a regulatory role. Surface membrane GLUT4 content after exercise is negatively associated with initial glycogen levels. In other words, depleted muscles ramp up glucose transporters more aggressively than full ones. This is the molecular basis for why exercise helps manage blood sugar — and why it matters for conditions like type 2 diabetes and insulin resistance.

A New Discovery: REPS1 (2025)

A 2025 phosphoproteomics study identified REPS1 as a novel regulator of muscle glucose uptake, involved in both insulin- and exercise-induced signaling (ScienceDirect, 2025). This finding shows that even for the most-studied pathways in exercise physiology, new molecular players are still being discovered.

Endorphins and Enkephalins: The Opioid Peptides of Exercise {#endorphins-and-enkephalins}

The "runner's high" is real, and peptide hormones are behind it. The endogenous opioid system — beta-endorphin, enkephalins, and dynorphins — are peptides with biochemical properties similar to morphine and heroin. They bind to mu, kappa, and delta opioid receptors throughout the nervous system.

Beta-Endorphin Response to Exercise

Beta-endorphin is a 31-amino-acid peptide synthesized in the anterior pituitary gland, cleaved from pro-opiomelanocortin (POMC). Exercise of sufficient intensity and duration reliably increases circulating beta-endorphin levels.

The threshold is roughly 60% VO2 max for aerobic exercise — below that, beta-endorphin doesn't rise consistently. Higher intensity produces greater increases. High-intensity anaerobic exercise and high-volume resistance training also trigger beta-endorphin release (PubMed, 1997).

Trained athletes need to work at greater absolute workloads to produce similar beta-endorphin increases compared to untrained individuals — the system adapts, requiring more stimulus over time.

What Endorphins Do During Exercise

Exercise-induced endorphin release is primarily associated with:

Pain modulation — Elevated endorphins raise the pain threshold, allowing athletes to push through discomfort
Mood elevation — The euphoria associated with sustained exercise (the "runner's high") correlates with endorphin levels
Cardiovascular regulation — Endogenous opioids influence heart rate and blood pressure during exercise
Substrate metabolism — There are indications that endorphins may influence fuel selection during prolonged activity

The Therapeutic Connection

The exercise-endorphin pathway has been proposed as a mechanism for exercise's benefits in conditions including depression, addiction, chronic pain, and hypertension (PubMed, 1990). Prolonged rhythmic exercise activates central opioid systems by triggering increased discharge from mechanosensitive Group III (A-delta) afferent nerve fibers in contracting skeletal muscle.

This opioid peptide response connects to the broader GLP-1 and addiction research — the brain's reward system is modulated both by exercise-induced endorphins and by GLP-1 receptor activation, raising interesting questions about overlapping mechanisms.

Atrial Natriuretic Peptide and Cardiovascular Exercise {#anp}

Atrial natriuretic peptide (ANP) is a 28-amino-acid peptide hormone released from the heart's atrial walls in response to stretching — which occurs during exercise when blood volume returning to the heart increases. (For more on natriuretic peptides, see the natriuretic peptides profile.)

ANP Response to Exercise

During maximal ergometer exercise, plasma ANP levels rise substantially — from roughly 5.9 to 35.1 pmol/L at sea level in one study of young athletes. The response is driven by increased atrial filling pressure as cardiac output rises during intense cardiovascular exercise (PubMed, 1992).

ANP promotes:

Natriuresis — Sodium excretion via the kidneys, helping regulate blood pressure
Vasodilation — Relaxation of blood vessel walls
Inhibition of aldosterone — Reducing fluid retention
Lipolysis — ANP is increasingly recognized as a fat-mobilizing signal during exercise

Interestingly, ANP's role in exercise-induced lipolysis connects it to the broader metabolic peptide network. During exercise, the combination of falling insulin and rising ANP creates a powerful fat-mobilizing environment.

Altitude Blunts the Response

In simulated altitude conditions (3,000 meters), the ANP response to maximal exercise is blunted (rising to only 22.3 pmol/L compared to 35.1 at sea level), likely due to changes in blood volume distribution and ANP clearance mechanisms. This has implications for athletes training at altitude.

GLP-1: How Exercise Changes Gut Peptide Signaling {#glp-1-exercise}

GLP-1 (glucagon-like peptide-1) is best known as the target of blockbuster drugs like semaglutide and tirzepatide. But before it was a drug target, it was an exercise-responsive gut peptide.

Exercise Stimulates GLP-1

Both acute exercise and endurance training increase GLP-1 secretion. In mice, exercise-induced GLP-1 production was associated with improved endurance capacity, and overexpression of GLP-1 in skeletal muscle enhanced glycogen synthesis, glucose uptake, Type I fiber proportion, and mitochondrial biogenesis (ScienceDirect, 2022).

In humans with type 2 diabetes, some evidence suggests exercise may improve GLP-1 sensitivity rather than raw GLP-1 secretion. Exercise also increases gut microbiota diversity, which could improve GLP-1 signaling — an emerging area linking the gut microbiome, exercise, and metabolic health (PMC, 2018).

GLP-1 Agonists and Exercise: Better Together

Recent research makes a strong case for combining GLP-1 agonist therapy with exercise rather than treating them as alternatives:

A 2024 randomized controlled trial found that combining liraglutide with structured exercise reduced metabolic syndrome severity, abdominal obesity, and inflammation more than either treatment alone
Stopping GLP-1 therapy alone leads to regaining roughly two-thirds of lost weight within a year. Adding exercise helps sustain the loss
GLP-1 agonist-induced weight loss includes 26-40% lean mass loss in recent trials. Resistance training helps preserve muscle during treatment
A 2025 review in Frontiers in Clinical Diabetes argued that the future of obesity management should prioritize integrated approaches combining pharmacotherapy with lifestyle interventions

This is particularly relevant for patients considering peptides for bodybuilding or athletic performance — natural GLP-1 pathways respond to exercise, and exogenous GLP-1 agonists work better when combined with training.

How This Informs Therapeutic Peptide Research {#therapeutic-implications}

Understanding the body's natural peptide response to exercise provides the foundation for evaluating therapeutic peptides. Here's how these connections work:

Growth hormone secretagogues — Peptides like CJC-1295, ipamorelin, sermorelin, and MK-677 aim to augment the same GH/IGF-1 axis that exercise naturally stimulates. The research on local vs. systemic IGF-1 signaling suggests that compounds boosting circulating GH may not fully replicate the local muscle effects of exercise-induced GH release.

MOTS-c as exercise in a peptide — MOTS-c research is built entirely on the exercise connection. Its AMPK activation, glucose regulation, and muscle-preservation effects mirror exercise adaptations. Whether exogenous MOTS-c can meaningfully substitute for exercise — or should be viewed as a complement — is an active research question.

Recovery peptides — Compounds like BPC-157 and TB-500 are studied for tissue repair, an area where the natural exercise-induced peptide response (GH, IGF-1, various growth factors) provides the biological context. Understanding the body's own repair signaling helps researchers evaluate whether exogenous peptides add meaningful benefit.

Metabolic peptides — The relationship between insulin, GLP-1, and exercise-induced glucose regulation informs the use of GLP-1 agonists, retatrutide, and other metabolic peptides. Patients using these medications while exercising are engaging both natural and pharmacological versions of overlapping pathways.

FAQ {#faq}

What peptide hormones increase during exercise?

The major peptide hormones that increase during exercise include growth hormone (GH), beta-endorphin, MOTS-c, irisin, atrial natriuretic peptide (ANP), and GLP-1. Insulin typically decreases during exercise even as muscle glucose uptake increases through insulin-independent mechanisms. The specific pattern depends on exercise type, intensity, duration, and individual fitness level.

Does exercise increase growth hormone permanently?

No. Exercise causes acute spikes in GH that return to baseline within hours. Regular training does not consistently elevate resting GH levels. The benefits of exercise-induced GH release come from the repeated acute exposures and their effects on tissue repair and metabolism over time, not from a persistent elevation.

What is MOTS-c and why do athletes care about it?

MOTS-c is a mitochondrial-derived peptide that increases nearly 12-fold in muscle during exercise. It activates AMPK, improves glucose metabolism, increases endurance capacity, and prevents muscle atrophy. It's sometimes called an "exercise mimetic" because it reproduces several exercise adaptations. WADA banned it in 2024, reflecting its potential as a performance-enhancing substance.

How does irisin help with fat loss?

Irisin converts white adipose tissue (fat storage) into brown/beige adipose tissue (fat burning) by activating UCP1, a protein that generates heat from stored fat. Exercise — particularly concurrent aerobic and resistance training — reliably increases irisin release. Beyond fat browning, irisin also has anti-inflammatory, anti-thrombotic, and anti-cancer properties.

Why does insulin drop during exercise if muscles need more glucose?

During exercise, muscles activate an insulin-independent pathway for glucose uptake using GLUT4 transporters driven by AMPK, calcium signaling, and nitric oxide. Lower insulin during exercise actually helps mobilize fat for fuel while muscles still take up glucose through the contraction pathway. This dual mechanism is why exercise is so effective for improving insulin sensitivity.

Can peptide supplements replace exercise?

No current peptide can replicate the full spectrum of exercise benefits. Exercise triggers responses across dozens of peptide systems simultaneously — GH, IGF-1, MOTS-c, irisin, endorphins, ANP, GLP-1, and hundreds of other myokines. Individual peptide therapies target one or a few of these pathways. They may complement exercise or support specific aspects of recovery, but they cannot substitute for the systemic effects of physical activity.

The Bottom Line {#the-bottom-line}

Exercise is the most powerful peptide-release trigger the human body has. A single workout activates growth hormone, MOTS-c, irisin, endorphins, ANP, GLP-1, and hundreds of other signaling peptides in a coordinated wave that reaches nearly every organ. No drug or supplement comes close to replicating this breadth of response.

The research on exercise-induced peptides is doing two things. First, it's explaining how exercise works at a molecular level — not just "it's good for you" but specifically what molecules are released, where they act, and what they do. Second, it's giving therapeutic peptide researchers their blueprints. Every synthetic peptide being studied for muscle growth, fat loss, metabolic health, or tissue repair is, in some way, attempting to tap into pathways that exercise activates naturally.

For anyone interested in peptide research — whether as a clinician, researcher, athlete, or patient — understanding the body's own peptide response to exercise isn't optional. It's the foundation everything else is built on.

References {#references}

Kraemer WJ, et al. Recovery responses of testosterone, growth hormone, and IGF-1 after resistance exercise. Journal of Applied Physiology. 2017. Link
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Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021. Link
Kim SJ, et al. MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience. 2024. Link
MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3. Scientific Reports. 2025. Link
MOTS-c restores mitochondrial respiration in type 2 diabetic heart. Frontiers in Physiology. 2025. Link
A comprehensive view of muscle glucose uptake: regulation by insulin, contractile activity, and exercise. Physiological Reviews. 2024. Link
Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake. ScienceDirect. 2025. Link
The role of irisin in exercise-induced muscle and metabolic health: a narrative review. PubMed. 2025. Link
Irisin acts as an endogenous anti-thrombotic agent. Blood. 2025. Link
Goldfarb AH, Jamurtas AZ. Beta-endorphin response to exercise: an update. Sports Medicine. 1997. Link
Shyu BC, et al. Endorphins and exercise: physiological mechanisms and clinical implications. PubMed. 1990. Link
Effect of physical exercise in hypobaric conditions on atrial natriuretic peptide secretion. PubMed. 1992. Link
GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway. Biochimica et Biophysica Acta. 2022. Link
Exercise and glucagon-like peptide-1: does exercise potentiate the effect of treatment? PMC. 2018. Link
GLP-1 agonists and exercise: the future of lifestyle prioritization. Frontiers in Clinical Diabetes and Healthcare. 2025. Link
Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation. PubMed. 2023. Link
Frontiers in Physiology: Exercise effects on hormones and body composition. Frontiers in Physiology. 2025. Link

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