Exercise as Medicine: How Movement May Act Like a Drug at the Cellular Level
Not a motivational text. Instead, the signalling pathways through which a muscle contraction reaches metabolism, immune system, blood vessels and brain. With numbers, with mechanisms, and with the places where the evidence ends.
The sentence “move more” sounds like a lecture. At the cellular level it is something else: a prescription of signals. Muscle is not an engine that burns calories. It is an organ that releases messengers.
I do not want to sell you motivation here. You have probably heard motivation often enough, and it rarely lasts longer than three weeks.
What interests me is a different question. Why does physical activity appear in the recommendations for so many completely different conditions? In type 2 diabetes. In heart failure. In depression. In cancer aftercare. In dementia prevention.
No drug covers such a broad list of indications. And that is exactly what makes one suspicious. Either the recommendation is unspecific and therefore turns up everywhere. Or physical activity acts at a point that all these conditions share.
The second explanation is the more interesting one. And by now it is quite well studied.
What awaits you in this article
- Muscle as an endocrine organ and what myokines are
- IL-6, BDNF, SPARC, decorin and the special case of irisin
- Mitochondrial biogenesis via AMPK and PGC-1alpha
- GLUT4 translocation: sugar without insulin
- Autophagy as the cellular waste disposal
- Silent inflammation, CRP and immune cell redistribution
- Neuroplasticity, hippocampus and depression
- Vascular endothelium, shear stress and nitric oxide
- Documented dose-response data from WHO to step count
- Where the mechanisms come from animal models
Muscle is not only an engine. It also transmits.
For a long time skeletal muscle was seen as a pure organ of movement. Contraction, force, consumption. Done.
That has shifted since the late nineties. The Copenhagen group around Bente Pedersen described that muscle fibres produce proteins during contraction and release them into the bloodstream. For these substances the term myokines was coined.
Picture the muscle like a radio set. It does not only move, it also transmits. And the receivers sit in adipose tissue, liver, pancreas, bone and brain.
Pedersen and Febbraio summarised in 2012 in Nature Reviews Endocrinology what was known until then about the secretory function of skeletal muscle. Their central statement: the muscle secretome consists of several hundred secreted peptides.
Some of them stay locally in the muscle. Myostatin, LIF, IL-6 and IL-7 are involved in muscle growth and myogenesis. Others travel further. IL-6 can reach liver, adipose tissue and the immune system. IGF-1 and FGF-2 support bone formation, and FSTL-1 can influence the endothelial function of blood vessels.
What this may mean for you: If many of these proteins depend on contraction, then physical inactivity is not simply the absence of sport. It is an altered signalling pattern. That is exactly what the authors propose as an explanation for the link between sitting and chronic disease.
Pedersen BK, Febbraio MA, Nat Rev Endocrinol, 2012. DOI: 10.1038/nrendo.2012.49Interleukin-6: the same molecule, two completely different stories
The first and to this day best studied myokine is interleukin-6. And it is a nice example of why biology is rarely black or white.
You probably know IL-6 as an inflammatory marker. It rises in sepsis, it rises in rheumatic disease, and in visceral obesity it is chronically slightly elevated. In that role it counts as problematic.
During exercise something else happens. Pedersen and Febbraio describe in their review in Physiological Reviews that IL-6 in blood can rise up to a hundredfold during physical exertion. The source is not the immune system but the working muscle itself.
The decisive difference lies in the context. In chronic inflammation IL-6 comes predominantly from immune cells and is part of a pattern in which TNF-alpha goes first and stays elevated over time. During exercise it comes from the muscle fibre, rises steeply, falls quickly again, and in the recovery phase anti-inflammatory signals such as IL-10 and the IL-1 receptor antagonist rise. According to what Pedersen and Febbraio describe, muscle-derived IL-6 may even dampen TNF-alpha production.
Many people believe sport is healthy because it “lowers inflammation”. Physiologically that holds true only with an intermediate step. Exercise first creates a short, controlled inflammatory impulse. The dampening response comes afterwards.
This is the same basic idea as with a vaccine or with any training stimulus at all: a dosed disturbance to which the body answers with an adaptation. Not rest, but rhythm.
The other messengers: BDNF, SPARC, decorin
IL-6 is only the best known representative. A few others are particularly interesting for the topic of chronic disease.
| Myokine | What has been described so far | Level of evidence |
|---|---|---|
| IL-6 | Rise of up to a hundredfold during exertion, involvement in fat oxidation via AMPK, crosstalk to liver and adipose tissue | Human, well documented |
| BDNF | Neurotrophic factor, in muscle involved in AMPK-mediated fat oxidation, in the brain in neuroplasticity | Human plus animal model |
| SPARC | Released from muscle after a single bout of exertion, in the mouse model linked to fewer colon cancer precursors | Release human, effect mouse |
| Decorin | Released from contracting muscle cells, binds myostatin, possible role in muscle hypertrophy | Human plus mouse |
| Irisin | PGC-1alpha-dependent cleavage product of FNDC5, in the mouse model conversion of white towards brown fat | Disputed in humans |
The group around Aoi searched specifically by DNA microarray for new muscle-dependent secretory proteins. They found SPARC, a cysteine-rich secretory protein. A single bout of exertion increased expression and release of SPARC in skeletal muscle, in mice as well as in humans.
In the next step a mouse model of chemically induced colon tumours was used. Regular low intensity exertion clearly reduced the number of aberrant crypt foci in normal mice, but not in SPARC-deficient mice. In cell culture SPARC inhibited the growth of colon cancer cells and promoted their programmed cell death.
What this may mean for you: Here you can see a possible molecular bridge between physical activity and cancer prevention. The release in humans is documented. The tumour effect comes from the mouse model. In humans it is therefore not yet proven.
Aoi W et al., Gut, 2013. DOI: 10.1136/gutjnl-2011-300776The group around Kanzleiter investigated decorin, a small leucine-rich proteoglycan. They showed that decorin is released from contracting human muscle cells and that the decorin concentration in blood rises after an acute strength training session in humans.
It becomes interesting at the target molecule. Decorin binds myostatin directly, the body's strongest brake on muscle growth. In the mouse, overexpression of decorin promoted the pro-myogenic factor Mighty and reduced the muscle-degrading enzymes atrogin-1 and MuRF1.
What this may mean for you: Strength training does not appear to build up mechanically alone. Via decorin it could release a brake that favours muscle breakdown. That is relevant for everyone whose muscle mass is dwindling anyway, for instance in older age.
Kanzleiter T et al., Biochem Biophys Res Commun, 2014. DOI: 10.1016/j.bbrc.2014.06.123Irisin: why I tell this mechanism with a caveat
If you have read anything about sport and cell biology in recent years, you have probably come across irisin. Usually as the “fitness hormone” said to turn white fat into brown fat.
The story began in 2012 with a paper by Boström and colleagues in Nature. They described that the expression of PGC-1alpha in muscle stimulates the formation of the membrane protein FNDC5. Part of it is cleaved off and released as a hormone: irisin. In mice, irisin increased the expression of UCP1 in white fat cells and raised energy expenditure, without any change in movement or food intake.
That sounded like a breakthrough. And then measurement technology got in the way.
The group around Albrecht examined in 2015 four commercial polyclonal antibodies used to determine irisin in blood samples. In Western blot all four showed a marked cross-reactivity with non-specific serum proteins in humans and animals.
Using recombinant irisin as a positive control, the authors found no specific band of the expected size in any biological sample. A mass spectrometrically detectable FNDC5 signature at around 20 kilodaltons was not captured by the tested antibodies.
What this may mean for you: A considerable part of the published irisin values in humans rests on measurements whose specificity is questionable. A methodological analysis in Trends in Endocrinology and Metabolism reached the same result independently.
Albrecht E et al., Sci Rep, 2015. DOI: 10.1038/srep08889I could simply leave irisin out and make the text smoother. I think that would be wrong. Irisin shows in exemplary fashion how a mechanism can become popular before the measurement method is reliable.
The debate is not settled to this day. There are mass spectrometry papers that argue for the existence of circulating irisin, and there is continued scepticism. What I can say: the mechanism is described in the animal model, in humans it is not established. If someone sells you irisin as a proven reason to exercise, that is a shortcut.
The power plant rebuilds itself: AMPK and PGC-1alpha
Now we go one level deeper, into the cell itself.
When a muscle works, it consumes ATP, the energy currency of the cell. The ratio of ADP and AMP to ATP shifts. At the same time calcium streams out of the sarcoplasmic reticulum. Both are alarm signals, and both are read by sensors.
The most important of these sensors is called AMPK, the AMP-activated protein kinase. Picture it like the fuel attendant who notices that the tank is running empty and then calls the workshop.
Contraction consumes energy
ATP is split, the ratio of AMP to ATP rises. At the same time intracellular calcium rises, because every contraction is triggered by it.
Sensors switch on
AMPK responds to the energy shortage, calcium-dependent kinases such as CaMKII respond to the calcium signal. Both routes run in parallel and complement each other.
PGC-1alpha is activated
This transcriptional coactivator is regarded as the central switch of mitochondrial biogenesis. It coordinates genes for the respiratory chain, mitochondrial proteins and fat burning.
The cell builds more and better power plants
Mitochondrial density and oxidative enzyme equipment can increase. The cell can then deliver the same performance with less stress. That is one of the cores of training adaptation.
And it does not stay in the muscle
PGC-1alpha might in addition influence the local inflammatory milieu and the formation of several myokines. That is the proposal by Handschin and Spiegelman, and it rests mainly on mouse models. If it holds, power plant remodelling and distant effects hang on the same switch.
Handschin and Spiegelman formulated in 2008 in Nature a thesis that sums up this whole article. They proposed that PGC-1alpha governs the plasticity of muscle, dampens a broad inflammatory response and thereby mediates an essential part of the favourable effects of physical activity.
Their starting point was an observation that may surprise you: insufficient physical activity is linked with many chronic diseases, but the connecting mechanisms were unclear for a long time. PGC-1alpha could be one such connecting point.
What this may mean for you: If a single molecular switch jointly influences mitochondrial construction, muscle fibre type and the tendency to inflammation, then that explains why one single intervention turns up in very different disease patterns.
Handschin C, Spiegelman BM, Nature, 2008. DOI: 10.1038/nature07206Autophagy: the waste disposal that starts up under exertion
A mitochondrion is not good forever. Damaged power plants produce more free radicals and less energy. The cell therefore needs a route for breakdown. It is called autophagy, literally self-digestion.
The group around He and Levine showed in 2012 in Nature that acute exertion triggers autophagy in skeletal and cardiac muscle in fed mice. To test the significance, they generated mice with normal basal but impaired stimulus-dependent autophagy. For this, three phosphorylation sites in the protein BCL2 were mutated.
These animals showed reduced endurance capacity, an altered glucose metabolism during acute exertion, and no protection against glucose intolerance on a high fat diet, although they were chronically trained.
What this may mean for you: The cellular waste disposal appears to be part of the reason why physical activity can favourably influence sugar metabolism. That is a very elegant experiment. But it is a mouse model with genetic manipulation, not a human finding.
He C et al., Nature, 2012. DOI: 10.1038/nature10758Sugar into the cell, even without insulin
For me this is the most impressive point of the whole topic. And the least known.
Glucose does not enter the muscle cell on its own. It needs a transporter, GLUT4. At rest it is parked in vesicles inside the cell and first has to travel to the cell surface.
Normally insulin gives the signal for this. In insulin resistance exactly this signal works less well, and the sugar stays in the blood.
Muscle contraction uses a second, separate route.
Richter and Hargreaves describe in their review how glucose enters the cell during muscle contraction. GLUT4 moves from intracellular stores to the plasma membrane and into the T-tubules. In the proximal part of the signalling cascade AMPK, calcium and nitric oxide synthases are involved among others, in the distal part GTPases, Rab and SNARE proteins as well as components of the cytoskeleton.
Beyond the acute relocation they describe a second effect: training increases the amount of GLUT4 in muscle in the first place. AMPK and CaMKII are key kinases here, influencing the readability of the GLUT4 gene via the HDAC4/5-MEF2 axis.
What this may mean for you: Muscle work can bring sugar into the cell even when the insulin route works poorly. And regular training raises the number of transporters, which is likely to be part of the improved insulin action after training phases.
Richter EA, Hargreaves M, Physiol Rev, 2013. DOI: 10.1152/physrev.00038.2012The working muscle appears to have a second key to the sugar door. That could explain why a walk after a meal is physiologically something different from a walk at some other time.
Knowler and colleagues randomly assigned 3,234 people with elevated fasting and post-load glucose values to three groups: placebo, the active substance metformin at the study dose of 850 mg twice daily, or a lifestyle programme with the goal of at least 7 per cent weight loss and at least 150 minutes of physical activity per week.
After an average of 2.8 years, diabetes incidence was 11.0 cases per 100 person-years on placebo, 7.8 on metformin and 4.8 in the lifestyle group. That corresponds to a risk reduction of 58 per cent versus placebo for lifestyle and 31 per cent for metformin. The difference between lifestyle and metformin was statistically significant.
What this may mean for you: This is perhaps the closest the data come to the question in the title. In this trial a structured lifestyle intervention performed better at preventing type 2 diabetes than the comparator arm with the drug. Important for context: it was a combined intervention of physical activity and nutrition, not physical activity alone. And the figures refer to people with elevated glucose values, not to people with already treated diabetes. What was compared here was prevention, not treatment.
On the active substance metformin: Metformin is a prescription-only medicine in Germany. It has its own contraindications and risks, among them markedly reduced kidney function, severe liver impairment and situations with tissue oxygen shortage, because lactic acidosis can occur then. Gastrointestinal complaints are common, and with longer use a vitamin B12 deficiency can develop. Interactions are described among others with iodine-containing contrast media and with diuretics. The dose figure above is the study dose, not a recommendation. Whether, when and how the substance is used is decided by the doctor treating you.
Knowler WC et al., N Engl J Med, 2002. DOI: 10.1056/NEJMoa012512This one is important, and I mean it seriously: if a medicine has been prescribed for you, please do not stop it because of an article and do not reduce it on your own. Exercise can contribute a great deal within treatment. Whether anything changes about your medication belongs in the consultation that treats you.
Silent inflammation: the common denominator of many chronic diseases
Type 2 diabetes, atherosclerosis, depression, many cancers and most rheumatic diseases share one feature: a low grade, persistent inflammatory activity. In clinical psychoneuroimmunology this is one of the central lenses.
This is exactly where one of the better documented effects of physical activity comes in.
Fedewa, Hathaway and Ward-Ritacco evaluated 83 randomised and non-randomised controlled trials with a total of 143 effect estimates and 3,769 participants. The condition was an intervention duration of at least two weeks.
The mean effect size was 0.26 with a confidence interval of 0.18 to 0.34, in the sense of a CRP reduction after training programmes. If body mass index fell at the same time, the effect was larger at 0.38. If weight stayed the same, the effect was still statistically detectable at 0.19.
What this may mean for you: The inflammation-dampening share does not depend on weight loss alone. Part of it appears to come directly from the working muscle. That fits the myokine hypothesis.
Fedewa MV, Hathaway ED, Ward-Ritacco CL, Br J Sports Med, 2017. DOI: 10.1136/bjsports-2016-095999Benatti and Pedersen describe in Nature Reviews Rheumatology how this connection could look in inflammatory rheumatic diseases. Their model is a vicious circle: chronic inflammation promotes muscle breakdown and metabolic disturbance, this leads to less movement, which in turn sustains the inflammation. Myokines could interrupt this circle at several points, directly after each bout of exertion and indirectly through the improvement of cardiovascular risk factors.
And what about the weakened immune system after exercise?
You may have heard of the “open window”: the idea that after intense exertion you are more susceptible to infection for one to two hours because the lymphocyte count in blood drops.
Campbell and Turner took this hypothesis apart in 2018 in Frontiers in Immunology. Their core statement: the strong fall in lymphocyte count in blood one to two hours after exertion reflects a time-limited redistribution of immune cells into peripheral tissues, not their disappearance.
The authors argue that this creates a state of heightened immune surveillance rather than immune weakness. They also point to vaccination studies in which exertion before or after vaccination was associated with stronger antibody responses, and to indications that regular activity could slow the ageing of the immune system.
What this may mean for you: After training the immune cells go on patrol, so to speak, rather than clocking off. This is not an all clear for training with a fever. But it puts the widespread fear of every intense session into perspective.
Campbell JP, Turner JE, Front Immunol, 2018. DOI: 10.3389/fimmu.2018.00648The four KPNI lenses on a single muscle contraction
In clinical psychoneuroimmunology we do not look at one organ but at four interwoven systems. During physical activity they react at the same time, and that is exactly what makes the topic so layered.
Nervous system
Every contraction begins with a nerve impulse. At the same time exertion shifts the balance between sympathetic and parasympathetic activity, and in the brain neurotrophic signals such as BDNF rise.
Immune system
A short IL-6 rise from the muscle, followed by anti-inflammatory counter-regulation. Immune cells are temporarily redistributed into tissues. Over weeks, meta-analyses show a lower CRP.
Metabolism
GLUT4 can move to the membrane independently of insulin, AMPK can switch to energy generation, PGC-1alpha can trigger the building of new mitochondria. For autophagy the evidence so far comes from the mouse model, in humans this step has not been shown in the same way yet.
Hormonal system
The muscle itself releases messengers and thereby becomes an endocrine organ. In parallel, cortisol rhythm, growth hormone release and insulin sensitivity can shift.
The brain is listening: BDNF, hippocampus, mood
The hippocampus is the brain region central to memory formation and spatial orientation. It shrinks in older age, and this shrinking is linked with memory problems and dementia risk.
For a long time the question was whether anything can change that.
Erickson and colleagues randomised 120 older adults into an endurance training group and a control group. The volume of the hippocampus was measured by magnetic resonance imaging.
Training increased the anterior hippocampus by 2 per cent, which arithmetically offset the age-related volume loss of one to two years. In parallel, spatial memory improved. The volume gain was associated with higher BDNF levels in serum. In the control group volume decreased, with a higher baseline fitness partly attenuating the decline.
What this may mean for you: Structural change in the brain through physical activity has been shown in humans in a randomised design. The study was not large, and the effect size is modest. But it was really measured, not extrapolated.
Erickson KI et al., Proc Natl Acad Sci U S A, 2011. DOI: 10.1073/pnas.1015950108How robust is the BDNF rise itself? The meta-analysis by Szuhany, Bugatti and Otto summarised 29 studies with 1,111 participants. For a single bout of exertion a Hedges' g of 0.46 emerged. In people who already trained regularly, the response to a single session was stronger at 0.59. For the resting value of BDNF after a training programme the effect was 0.27. Notable and honestly stated: in studies with more women the BDNF rise was smaller.
Noetel and colleagues published in 2024 in the BMJ the most extensive evaluation to date on exercise in diagnosed depression: 218 studies, 495 study arms, 14,170 participants.
Compared with active control conditions, moderate effects appeared for walking or jogging with a Hedges' g of minus 0.62, for yoga minus 0.55, for strength training minus 0.49, for mixed aerobic exercise minus 0.43 as well as for tai chi or qigong minus 0.42. Effects were larger with higher prescribed intensity. Strength training and yoga were accepted best.
What this may mean for you: The authors recommend considering these forms of exercise alongside psychotherapy and medication as core treatment. But they name the weakness themselves: only a single one of the 218 studies met the Cochrane criteria for low risk of bias. Confidence was rated low to very low.
Noetel M et al., BMJ, 2024. DOI: 10.1136/bmj-2023-075847Many people with depression hear “why don't you do some sport” and experience it as a devaluation of their suffering. I understand that well. The sentence sounds as if the problem were a lack of effort.
At the cellular level the statement is a different one. Exertion changes neurotrophic signals, inflammatory markers and stress axes. That does not make it a substitute for treatment. But it does make it more than a well meant piece of advice.
If low mood will not let go of you, or you have thoughts of not wanting to live any more, please do not wait for the next walk. Get medical or psychotherapeutic help soon. In Germany, Telefonseelsorge is available around the clock, free and anonymous, on 0800 111 0 111 or 0800 111 0 222. In an emergency, call 112.
The vessel lining senses the blood flow
One last level that is often underestimated: the endothelium. This is the single cell layer lining your blood vessels. How large this surface is in total is estimated very differently. All that is clear: it is huge, and it is not a passive pipe.
Endothelial cells are not just wallpaper. They measure the friction with which blood flows past them. This friction is called shear stress. When it rises, the cells release nitric oxide among other things, which relaxes the vascular muscle.
During exertion the blood flow in the working regions rises considerably. With it the shear stress rises, repeatedly, in intervals, over years.
Green and colleagues describe in Physiological Reviews how arteries in humans adapt to repeated haemodynamic stimuli. Exertion changes blood flow, shear stress at the vessel wall, blood pressure and tangential wall stress. Each of these stimuli can change the function, diameter and wall thickness of the artery.
The authors argue that the direct mechanical action of blood flow on the vessel wall contributes to the well documented risk reduction through physical activity. This concerns large conduit arteries as well as resistance vessels and the microcirculation.
What this may mean for you: Part of the vascular protection through physical activity does not arise via cholesterol or blood pressure, but via the mechanics themselves. The vessel trains along with you.
Green DJ et al., Physiol Rev, 2017. DOI: 10.1152/physrev.00014.2016The dose question: what is documented in numbers
Mechanisms are nice. But the practical question is: how much, how often, of what?
Here the data are surprisingly concrete.
- Guideline, WHO 2020. 150 to 300 minutes of moderate intensity or 75 to 150 minutes of vigorous intensity aerobic activity per week for all adults, plus regular muscle-strengthening activity for all age groups.
- Observational data, not causality: steps per day. In the meta-analysis across 15 cohorts and 47,471 adults, the hazard ratio for all-cause mortality in the highest quartile was 0.47 compared with the lowest. The curve flattened at 6,000 to 8,000 steps from the age of 60, and between 8,000 and 10,000 in younger people.
- Observational data, not causality: cardiovascular events. In the harmonised meta-analysis across 8 studies and 20,152 adults, in people aged 60 and older the risk in the highest step quartile fell to a hazard ratio of 0.51. In younger adults the association was not significant.
- Observational data, not causality: strength training. Across 16 cohort studies, muscle-strengthening activity was associated, independently of endurance activity, with a 10 to 17 per cent lower risk of all-cause mortality, cardiovascular disease, total cancer, diabetes and lung cancer. For colon, kidney, bladder and pancreatic cancer the same paper found no association. The greatest risk reduction was at around 30 to 60 minutes per week.
- Observational data from a clinically referred group: cardiorespiratory fitness. In a cohort of 122,007 people referred for symptom-limited exercise testing, mortality was inversely proportional to fitness, with no discernible upper limit of benefit. That is a selected clinical group, not the general population.
The point about steps is important because it contradicts the popular narrative. The 10,000 steps do not come from research. In the meta-analysis by Paluch and colleagues the median values of the four groups were 3,553, 5,801, 7,842 and 10,901 steps per day. The largest jump happened between the first and the second quartile, that is between roughly 3,500 and 5,800 steps.
Someone at 3,000 steps gains considerably more from 3,000 additional steps than someone going from 9,000 to 12,000. The greatest leverage lies at the lower end.
That is the genuinely good news in these data. You do not have to become athletic to take along a relevant part of the effect. You have to stop being completely immobile.
Colon cancer: what a randomised trial has reported
I am reporting a study here, I am not making you an offer. Exercise is not a cancer therapy and it does not replace oncological treatment. Benefit, timing and how much you can tolerate are always decided by the oncology team treating you, not by a text on the internet.
Courneya and colleagues randomised 889 patients with resected colon cancer after completed adjuvant chemotherapy. One group received a structured, medically supervised exercise programme over three years, the other health education material alone. Recruitment ran from 2009 to 2024.
After a median follow-up of 7.9 years, the exercise programme in this group was associated with longer disease-free survival. Musculoskeletal complaints occurred more often in the exercise group.
How I read this: Until 2025 the statement that physical activity may influence cancer prognosis rested on observational data and animal models. This work is the first large randomised data set on it. It applies to this one situation, that is colon cancer after completed chemotherapy, and cannot be transferred to other tumour types, other stages or ongoing treatment.
Courneya KS et al., N Engl J Med, 2025. DOI: 10.1056/NEJMoa2502760Dementia: an association that remains even after 20 years
In dementia there is a well known methodological problem. People in whom a dementia is developing often move less already years beforehand. If a study follows up for only five years, it easily confuses cause and early symptom. That is called reverse causality.
Iso-Markku and colleagues examined exactly this. Their systematic review with meta-analysis included 58 studies and specifically tested whether study length changes the result. Physical activity was associated with a relative risk of 0.80 for dementia overall, in 257,983 people. For Alzheimer's disease the value was 0.86, for vascular dementia 0.79. Crucially: for dementia overall and for Alzheimer's disease the association persisted even in follow-ups of 20 years and longer. The authors name possible publication bias themselves.
Where the evidence ends, and why I say so
Now the uncomfortable part. And for me the most important one.
First: many mechanisms come from animal or cell models. The autophagy work by He and colleagues is a mouse model with genetic manipulation. The SPARC effect on colon tumours is a mouse model. The irisin effect on brown fat is a mouse model. That does not devalue these papers. But it means: biologically plausible, in humans not yet conclusively established.
Second: irisin is disputed in humans. The measurement methods with which a large part of the human data was collected have been called into question in their specificity. As long as that is unresolved, irisin belongs in the category of interesting hypothesis, not established mechanism.
Third: observational studies carry a healthy user effect. People who take many steps are often healthier in other respects too, smoked less, have more income and better care. The studies adjust for many of these factors. But they cannot adjust for what they have not measured. And the reverse direction remains: those who are ill walk less.
Fourth: the randomised evidence has weaknesses too. In the BMJ network analysis on depression only a single one of 218 studies met the Cochrane criteria for low risk of bias. Exercise studies are hard to blind. Everyone knows which group they are in, and that creates expectation effects.
What I consider documented: muscle is a secretory organ. GLUT4 moves independently of insulin. AMPK and PGC-1alpha govern mitochondrial biogenesis. Training programmes are associated with lower CRP. Physical activity is associated with lower mortality, less diabetes, less dementia and better mood, and for diabetes prevention as well as for the one situation studied after colon cancer surgery randomised data exist.
What I consider plausible but not proven: that exactly the myokines described here are the bridge between muscle and organ protection. The mechanism fits the observations. That does not yet make it their explanation.
The sentence “move more” can do harm when it is given as a blanket statement. These situations belong clarified beforehand:
- Acute infection with fever. Especially when involvement of the heart muscle is suspected, exertion belongs on pause, not on a dose.
- Unstable angina, recent myocardial infarction, decompensated heart failure. New chest pain or breathlessness during exertion also belongs assessed before training.
- Dizziness, blacking out or loss of consciousness during exertion. That is a red flag and always belongs assessed, among other things because of hypertrophic cardiomyopathy, a narrowed aortic valve or arrhythmia. With loss of consciousness, severe chest pain or severe breathlessness, call 112 and do not wait for a practice appointment.
- Long inactivity plus risk factors. If you have barely moved for years and also bring high blood pressure, diabetes, high blood lipids or a family history of heart disease, a sports medicine check-up before returning to intense training can make sense.
- Abruptly increased, unaccustomed exertion. Very hard sessions without preparation can damage muscle cells, in extreme cases up to rhabdomyolysis. Under statins the risk of muscle pain and muscle damage can be additionally raised. Dark urine, severe muscle pain and weakness after training belong assessed medically without delay.
- Pregnancy and breastfeeding. The WHO recommends regular activity in pregnancy as well. With complications such as pre-eclampsia, bleeding or cervical insufficiency, exertion belongs medically assessed beforehand.
- Post-exertional symptom worsening. In ME/CFS and in post-COVID with exercise intolerance, an increase can worsen the condition. Here the usual training recommendations expressly do not apply.
- Pronounced anaemia, marked underweight, fresh injuries or operations. First clarify the basis, then the dose.
- Diabetes with insulin therapy. Because muscle work can bring glucose into the cell independently of insulin, the risk of hypoglycaemia rises. Adjusting dose and timing belongs in the treating consultation.
Three levers that follow from the mechanisms
If you take the signalling pathways seriously, a few very concrete consequences follow. Not training plans, but directions.
Lever 1: frequency before intensity, because myokines are released acutely
- The myokine response appears to hang on the single bout, not on the weekly volume. From that one can suspect that several short sessions set more signal impulses than one long one. To my knowledge this has not been compared directly. So it is a deduction from the mechanism, not a study finding.
- The step data show the largest relative gain in the jump from the lowest into the second quartile. That is roughly 2,000 additional steps a day.
- In practice this means: become regular first, then more intense. Not the other way round.
Lever 2: strength and endurance are two stimuli, not one
- Endurance mainly addresses mitochondrial biogenesis and the vascular endothelium.
- Strength training additionally acts on muscle mass, decorin, myostatin and GLUT4 storage capacity.
- The WHO recommends both. In the cohort data, people who combined strength and endurance had a lower risk than people who did neither of the two. A direct comparison against just one component is not contained in these data. The focus was at around 30 to 60 minutes of strength training per week.
Lever 3: use the moment when the second key fits
- The contraction-dependent GLUT4 relocation happens during and shortly after muscle work.
- Movement close in time to larger meals could make use of exactly this window.
- With insulin therapy or sulfonylureas this counts the other way round as a risk of hypoglycaemia and belongs discussed beforehand.
And now you know why physical activity appears in the recommendations for so many different conditions. Not because it is unspecific. But because it acts at switching points that these conditions share.
Frequently asked questions about exercise as medicine
What does “exercise as medicine” actually mean at the cellular level?
It means that muscle contraction itself is a biochemical signal, not merely calorie expenditure. A working muscle releases messenger substances called myokines that can reach other organs. At the same time, energy sensors inside the cell such as AMPK shift, and they can trigger the building of new power plants via PGC-1alpha. Sugar transporters move to the cell membrane independently of insulin. Part of these signalling pathways overlaps with targets that drugs also act on, AMPK is one example. That is why the comparison with a drug is physiologically understandable. It remains a comparison. Exercise is not a medicine, and it does not replace one.
What are myokines and why is muscle described as an endocrine organ?
Myokines are peptides and cytokines produced by muscle fibres and released during contraction. The Copenhagen group around Pedersen coined the term and describes in their review in Nature Reviews Endocrinology that the muscle secretome comprises several hundred secreted peptides. Among them are interleukin-6, BDNF, IL-7, LIF, myostatin, IGF-1, FGF-2, follistatin-like protein 1, decorin and SPARC. Because these substances can act via the bloodstream on adipose tissue, liver, pancreas, bone and brain, skeletal muscle is today described as a secretory and endocrine organ. For some of these myokines the release in humans is well documented, for the downstream effects often not yet.
Is irisin really established in humans?
No, caution is appropriate here. The group around Boström described in Nature in 2012 a PGC-1alpha-dependent myokine cleaved from the membrane protein FNDC5 that can reprogramme white adipose tissue towards brown adipose tissue in the mouse model. Shortly afterwards the group around Albrecht showed in Scientific Reports that four commercial polyclonal antibodies used to measure irisin in blood cross-react markedly with non-specific serum proteins. An analysis in Trends in Endocrinology and Metabolism reached the same conclusion: many of the contradictory human findings go back to measurement problems. Irisin is therefore a good example of how a mechanism can become popular before the measurement method is reliable.
How can exercise improve insulin sensitivity?
Via two separate routes. Acutely, the glucose transporter GLUT4 moves during muscle contraction from intracellular stores to the cell membrane and into the T-tubules. The review by Richter and Hargreaves in Physiological Reviews describes that AMPK, calcium and nitric oxide synthases, among others, are involved in this pathway. This route is independent of insulin, which is why muscle work can bring glucose into the cell even in insulin resistance. In the long run the amount of GLUT4 in muscle also rises, because training changes gene expression. Clinically this is mirrored in the Diabetes Prevention Program: there, diabetes incidence in the lifestyle group was 4.8 cases per 100 person-years compared with 11.0 on placebo.
How much physical activity does the WHO recommend?
The 2020 WHO guideline recommends that all adults do 150 to 300 minutes of moderate intensity or 75 to 150 minutes of vigorous intensity aerobic activity per week, or an equivalent combination of both. In addition, regular muscle-strengthening activity is recommended for all age groups. Also new is the recommendation to reduce sedentary behaviour, although the evidence was not sufficient to quantify a threshold. For the first time there are separate recommendations for pregnant women, for women after giving birth and for people living with chronic conditions or disability. The core message of the guideline is: some activity is better than none, and more activity is more favourable for most people.
How many steps per day make sense?
The 10,000 are a marketing figure, not a research figure. The meta-analysis by Paluch and colleagues in Lancet Public Health evaluated 15 cohorts with a total of 47,471 adults and 3,013 deaths. Compared with the lowest quartile, the hazard ratio for all-cause mortality was 0.60 in the second quartile, 0.55 in the third and 0.47 in the fourth. The median values of the quartiles were 3,553, 5,801, 7,842 and 10,901 steps per day. The risk curve flattened between 6,000 and 8,000 steps in people aged 60 and older, and between 8,000 and 10,000 in younger people. The largest relative gain therefore lies at the lower end, not at the upper end.
Is endurance training enough, or do I also need strength training?
The data speak for both. A systematic review with meta-analysis by Momma and colleagues in the British Journal of Sports Medicine evaluated 16 prospective cohort studies. Muscle-strengthening activity was associated, independently of aerobic activity, with a 10 to 17 per cent lower risk of all-cause mortality, cardiovascular disease, total cancer, diabetes and lung cancer. Notably there was a J-shaped pattern with the greatest risk reduction at around 30 to 60 minutes per week. People who did both, strength and endurance, had a lower risk in these cohorts than people who did neither of the two. A direct comparison against just one of the two activities is not contained in these data. The authors also state themselves that for some cancers, among them colon, kidney, bladder and pancreatic cancer, no association was found. From a cell biology perspective it is plausible to do both, because strength and endurance stimuli partly address different signalling pathways.
Can exercise play a role in depression?
The largest evaluation so far is the network meta-analysis by Noetel and colleagues in the BMJ with 218 studies, 495 study arms and 14,170 participants. Compared with active control conditions, moderate effects appeared for walking or jogging with a Hedges' g of minus 0.62, for yoga minus 0.55, for strength training minus 0.49, for mixed aerobic exercise minus 0.43 and for tai chi or qigong minus 0.42. Effects were larger with higher prescribed intensity. Important is the limitation named by the authors themselves: only a single study met the Cochrane criteria for low risk of bias, and confidence was rated low to very low. Exercise is therefore an option to take seriously alongside psychotherapy and medication, not a substitute for professional assessment.
Can exercise lower inflammatory markers such as CRP?
There are good indications for this. The meta-analysis by Fedewa, Hathaway and Ward-Ritacco in the British Journal of Sports Medicine included 83 randomised and non-randomised controlled trials with 143 effect estimates and 3,769 participants. The mean effect size was 0.26 in favour of a CRP reduction after training programmes. The effect was more pronounced when body mass index or body fat percentage fell at the same time, with an effect size of 0.38. It remained measurable without weight loss as well, at 0.19. That is the interesting point: part of the inflammation-dampening signals appears to come directly from the working muscle and not only from a decrease in fat mass.
Can exercise influence the prognosis in cancer?
I am reporting a study here, I am not making you an offer. Exercise is not a cancer therapy and it does not replace oncological treatment. Benefit, timing and how much you can tolerate are always decided by the oncology team treating you, not by a text on the internet. What the CHALLENGE trial was able to show in 2025 in the New England Journal of Medicine: in 889 people with resected colon cancer after completed adjuvant chemotherapy, a structured, medically supervised exercise programme over three years was associated with longer disease-free survival across a median follow-up of 7.9 years. Musculoskeletal complaints occurred more often in that group. These data apply to this one situation and cannot be transferred to other tumour types, other stages or ongoing treatment.
When is exercise not the right recommendation?
There are situations in which the blanket advice “move more” can do harm. In acute febrile infections, especially when involvement of the heart muscle is suspected, exertion belongs on pause. In unstable angina, recent myocardial infarction, decompensated heart failure or unexplained chest pain during exertion, the question belongs in the cardiology consultation before training. Particularly important is exercise intolerance in ME/CFS and in post-COVID with post-exertional symptom worsening: here an increase in exertion can worsen the condition, and the usual training recommendations do not apply. In marked underweight, pronounced anaemia or fresh injuries the rule is: clarify first, then dose. And one red flag that is often forgotten: dizziness, blacking out or loss of consciousness during exertion always belongs assessed, in an emergency via 112.
Further reading in the Sport guide and beyond
This article describes the mechanisms. The following texts go into individual applications, and two of them deliberately lead out of the sport cluster, because the same stimulus principles turn up there again.
Exercise as Medicine: Effects at the Cellular Level
Myokines, mitochondria, GLUT4, BDNF and the limits of the evidence.
You are hereStrength Training from 40: Muscle as a Longevity Organ
What follows in practice from the endocrine muscle once mass begins to dwindle.
VO2max and Life Expectancy
Why cardiorespiratory fitness is so closely linked with mortality in cohort data.
Zone 2 Training and Fat Metabolism
The intensity at which mitochondrial biogenesis and fat oxidation take centre stage.
Exercise in Chronic Exhaustion
When movement can help and when it harms. Important in exercise intolerance.
Ice Bathing for Beginners
Cluster Forces of Nature: another dosed stimulus with a similar logic of adaptation.
All articles in the Sport guide
Movement, training, recovery and performance at a glance.
Guide Forces of Nature
Heat, cold and light as medical stimuli, thought across clusters.
Sources
All details were cross-checked against title, journal, year and DOI via PubMed. The study type is given in square brackets. Numbers are taken as they appear in the respective abstract.
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