Written by: Colin Champ, MD
Several years back a scientific article revealed that those of us with high “muscular strength” have a lower risk of becoming a victim to cancer – a 40% lower risk to be exact.1 After assessment of almost 9,000 men aged 20-82, scientists found that men with a stronger one-rep max on bench press and leg press have a 40% reduction in their risk of dying from cancer. They adjusted for body mass index (BMI), body fat, and cardiorespiratory fitness and the results still held strong (pun intended).2 In other words, there is something about simply being stronger that can lower our risk of getting cancer. Many felt as though there was something innately healthy about having more muscles, but another study associated weak hand grip strength with an increased risk of cancer, even regardless of muscle size.3 So is it all about strength or do muscles fight cancer?
Strength goes beyond lowering our risk of dying from cancer; it lowers our risk of dying from most major health issues. For instance, men exhibiting a lower vertical leap, less sit-ups, and decreased grip strength have a higher risk of dying period.4Men and women with moderate and high bench press and sit-up scores have lower risks of death,5 while men with a higher 1-repetition bench and leg press apparently live longer (even when we account for other health issues, like cardiovascular disease, smoking, obesity, etc.).6
Muscles Fight Cancer – More Muscles = More Health?
The first thought that comes to mind is that more muscles means more strength, and both are a result of more exercise. Sure enough, when we take a close look through these studies, we do see that the strongest among us have less body fat, are in better shape, and have better “good” cholesterol values with lower blood sugar and triglycerides.1 This is not surprising.
However, in nearly all these “muscles fight cancer” studies, other health issues were adjusted for and the findings still held. In other words, these studies seem to suggest that strength is independently associated with a lower risk of cancer and a higher change of avoiding an untimely death, regardless of age, smoking, alcohol usage, or other health issues. But as we know, associations can only take us so far, before we must explore the mechanism that support these associations.
Muscles Fight Cancer – It’s the Muscles!
In the study above, the scientists found some intriguing results: the benefits of muscular strength overlap with cardiovascular fitness, but the benefits of muscular strength in decreasing the risk of cancer death work through different mechanisms.1Perhaps the synergy exists, or in other words, having more muscle and strength is good, and exercising them is better.
For instance, we know that exercising our muscles leads to:
- Improved insulin sensitivity (less insulin needed to remove sugar from our blood)
- More sugar extracted from our blood by skeletal muscle and used for energy during exercise
- Less cancer-promoting sugar and insulin floating around our blood
- A decrease in the levels of hormones that, over a prolonged period, can lead to cancer. For instance, resistance training increases IGFBP-3, which binds to insulin-like growth factor (IGF), decreasing its ability to promote cancer (growth factors are normal within the human body, but too many can lead to excessive cellular growth, including cancer growth)7
- Decreased inflammation (which when present, serves as a fertilizer for cancer)
- Increased antioxidant defense, which helps fight potential cancer-causing free-radicals
- Less inflammation-producing body fat
However, recent studies have changed much of our thinking when it comes to muscle. There are many organs in our body that respond to stimuli and secrete hormones, which serve as messages to direct remote parts of the body. We are recently starting to find some more unconventional organ-like structures in the body. For instance, it is now well-established that our adipose tissue works like an endocrine organ – albeit a bad one – secreting inflammatory hormones and an excess of potentially cancer-stimulating hormones.8 Take estrogen for example, which is a hormone that both men and women require to function normally. However, when supplied in higher than physiologically normal amounts from excess body fat, it can increase a woman’s risk of breast cancer. When women lose theses additional pounds through dietary changes and exercise, estrogen levels decrease.9
Studies have now shown that fat is not the only recently discovered endocrine organ. Muscle may act similarly, though this time to the benefit of our health. The metabolic muscular organ within us secretes IL-6, an important cytokine that was once felt to be a bad guy that caused inflammation. Newer studies reveal that IL-6 has a healthy role and is actually a myokine, which is an endocrine hormone produced by muscle (myo = muscle) and released during contraction. In other words, while fat secretes harmful hormones, muscles squeeze out some healthy hormones during lifting.
Muscles Fight Cancer – The Physiologic Benefits of Having More Muscle
As discussed above, exercise has plenty of benefits. However, contracting our muscles during running, resistance training, or simply heavy lifting provides benefits that are entirely separate from those of exercise.
For instance, while fat tissue secretes the pro-inflammatory cytokine TNF-α (which stands for tumor necrosis factor since our immune cells secrete it in the presence of tumor cells), our muscles secrete IL-6, which fights inflammation. As bad as fat is generally considered, muscle seems to stand in direct opposition to fat physiologically, and TNF versus IL-6 further embodies this difference.
- Adipose-derived TNF is inflammatory, while muscle-derived IL-6 is anti-inflammatory.
- Muscle-derived IL-6 signals to our body to break down lipids and burn fat.10
- Adipose-derived TNF causes insulin resistance and impairs glucose uptake by our cells (both leading to increased blood sugar).11
- While serious and often fatal events like septic shock cause a sudden release of TNF, excess adipose tissue causes the chronic release of harmful TNF.
- Muscle-derived IL-6 helps regulate AMPK (while muscle contraction directly activates AMPK), which stimulates the breakdown of fat and cholesterol, stimulates our mitochondria, and potentially fights cancer.12
AMPK, or AMP-activated protein kinase, is an enzyme extensively expressed in our muscles, liver, and brain. It serves as an energy sensor and regulator and closely monitors changes in energy status based on our dietary and lifestyle habits. ATP, the energy currency of our cells, is broken down to AMP by our cells. ATP has three phosphates (the T is for tri) and when it loses one becomes ADP (the D is for di, or two) and when it loses two phosphates it becomes AMP (the M is for mono). Without dipping too deep into boredom territory:
ATP → ADP + P
ATP → AMP + 2P
AMPK works to supply more ATP and increase our available energy molecules. AMPK achieves this through several mechanisms described in the picture below. The dark blue mechanisms involve breaking down glucose (sugar) to burn for energy. This can be done by pulling glucose out of our blood stream and into our cells to be consumed. The aqua circles represent the breaking down of cholesterol and fat to be used as an efficient source of energy. The purple includes building more mitochondria to use these fats and sugars to make more energy, and the light blue mechanisms turn off cell building and replication.
Basically, AMPK signals to our body and cells that it is not a time for building, but rather for breaking down.
AMPK and Cancer
AMPK is, in essence, the antithesis of cancer. While cancer cells are burning large amounts of glucose and nutrients, this is mostly to build up biomass – or simply put to keep growing and spreading. AMPK, on the other hand, shuts off this process, blocking cancer growth so we can feed our own cells.12,13 As you can see in the picture to the right, AMPK actually blocks mTOR, a pathway that leads to cancer survival and growth.14 This is the same pathway that is blocked with targeted cancer drugs. You will also notice that the pathways are all affected by intermittent fasting, labeled as “IF,” as this is a state of energy scarcity. You may also notice that increased insulin sensitivity, which happens though exercise and muscle contraction, also appears to upregulate AMPK.
AMPK and Warburg
The Warburg hypothesis is something that comes up often when dealing with cancer and metabolism. Briefly put, Warburg showed that regardless of the presence of oxygen, cancer cells prefer to use glucose for energy derivation (through a process known as glycolysis). In our normal cells, preference is given to the mitochondria for energy production, as it is significantly more efficient. While AMPK may stop several pro-cancer pathways, newer data shows that it actually blocks the Warburg Effect, by blocking the ability of cancer cells to use sugar for energy.15
AMPK is upregulated via several mechanisms (in no apparent order):
- Muscle contraction during exercise,16,17 with the more intense exercise resulting in increased expression of AMPK18
- Carbohydrate restriction (with or without fasting and even in the face of an increase in calories)19
- Intermittent fasting20
Inflammation is the fertilizer of cancer cells; it fosters an environment where normal cells can turn cancerous and cancer cells can grow with less effort. Inflammation has recently been labeled a “hallmark of cancer cells.”21 Any method to decrease this inflammation can provide health benefits, and even decrease the risk of cancer. When muscles are contracted, they release IL-6 and several other hormonal signals that act to decrease inflammation. These “signals” alert other organs that energy status is down, stimulating processes like AMPK,22 leading to a state of breaking down components for energy instead of stimulating growth processes like cancer. In other words, our muscles are creating signals that act at distant places within the body. These signals are plenty, but one of the more famous is when muscles signal to our bones to grow stronger23 – one of the many reasons why weight training strengthens bones.24 In a sense, the way in which our muscles “talk” with the rest of our body is only one of the many ways in which they improve our health, and ultimately, help in the fight against cancer.
Muscles Fight Cancer – The Physiologic Benefits of Lifting Weights
While our muscle cells (myocytes) secrete IL-6 at baseline, exercise increases this release up to 100 times.25 Those of us that exercise and contract our muscles frequently experience a sensitization to IL-6 when not exercising and at rest.26 While excess fat tissue desensitizes us to the action of insulin (i.e. more insulin is needed to get rid of extra blood sugar), increasing harmful amounts of blood sugar, contracting our muscle sensitizes us to the benefits of muscle-derived IL-6.
The amount of IL-6 produced depends on several factors,27 including:
- Intensity of the exercise
- Duration of the exercise
- Endurance capacity
- Size of muscle contracting
As a side note, carb-loading before exercise appears to oppose this effect, blunting IL-6 release from the muscle, perhaps paying homage to our ancient times of exercise, which was often hunting for wild game on an empty stomach.28
Countering the benefits of weight-lifting are the harms of inactivity, which, much like excess body fat, increases background inflammation.29 Exercise is such a powerful anti-inflammatory, that it offsets the potential inflammatory damage from injection of the toxin E. coli into healthy volunteers. For instance, while E. coli normally causes doubling or tripling of harmful TNF, when injected during exercise, no increase occurs.30 Not surprisingly, trained athletes have lower levels of several inflammatory factors.31
Inflammation is the likely cause of or contributor to many diseases, including atherosclerosis, diabetes, and cancer. Oxidative (free radical) damage is also considered a major cause of disease and cancer.32 Much like inflammation, high levels of free radicals can damage our cells and DNA, exposing us to a higher risk of cancer. To counter this potential damage, our cells have spent millions of years developing a defense mechanism against free radicals – known as the antioxidant defense system – that creates a plethora of antioxidant compounds that can offset the harm of radicals.
When we place men on a regimen of muscle-activating resistance training twice a week, many of these antioxidant defense mechanisms are activated. For instance, glutathione peroxidase, which defuses the potential damage from free radicals that are bound to lipids, is increased. Mitochondrial and cytosolic superoxide dismutase – which break apart, or dismutase the potentially harmful free radical superoxide – are amplified. Interestingly, when weight lifting was compared to endurance training, the latter antioxidant mechanism was only increased by weight training.33 Muscle biopsies of legs after unilateral resistance training shows similar findings, that antioxidant defense mechanisms are boosted.34
Finally, while muscle and fat can be considered opposites by the hormones they produce, the same can be said about stimulated muscle versus inactivity. Muscle contraction releases large amounts of IL-6, which sensitizes our cells to its effect, resulting in less IL-6 circulating at rest. In other words, our cells get better at dealing with IL-6 and inflammation from exercise. Muscle-derived IL-6 is beneficial, but a constantly elevated amount of IL-6 can be inflammatory.
High levels of adipose tissue and inactivity lead to an opposite state when it comes to insulin. Both decrease insulin sensitivity, or in other words, more insulin is required to rid the blood of sugar, which eventually results in chronically elevated levels of circulating insulin and sugar within our blood. Both are unhealthy and can lead to cancer.35 Further closing the loop of association, exercise-derived IL-6 increases insulin sensitivity and can prevent this damaging state from inactivity and excessive body fat.
Muscles Fight Cancer – A Final Comment of Exercise, Blood Sugar and Cancer
Many people have recently questioned the benefit of exercise before or after a cancer diagnosis since it can result in elevated levels of blood glucose. This occurs when our body mobilizes available stores of glucose (from glycogen within the liver and muscles). As increased blood glucose levels correlate with an increased risk of several cancers,36 this may seem concerning on the surface. Furthermore, while IL-6 secreted from muscle increases the breakdown of fats and activation of the AMPK energy sensor can reduce the risk of cancer,37–39 the increase in PI3K, another pro-cancer pathway, is concerning.
Yet, these changes primarily occur in the muscle, which is using the mobilized glucose. Furthermore, the rise in blood sugar is transient (glucose levels drop by 30 minutes afterwards40), and as exercise and resistance training increases insulin sensitivity, overall we are left with a lower blood glucose and insulin level.41 The multitude of other physiologic changes that occur listed above provide an overwhelming anti-cancer benefit. This has played out in several recent studies, showing a decreased risk of breast cancer in women who exercise, with some data suggesting additional benefit from strenuous exercise.42,43 The benefits appear to be similar for women who were already diagnosed with breast cancer.44
Muscles Fight Cancer – Conclusions
Muscles fight cancer and strength is associated with a decreased risk of cancer. The conclusions are obvious: if you are physically able, lift more weights, build more muscle, and increase your strength. Do it safely, do it right, and do it periodically to ensure that you are “health cost averaging.” Flex your muscles and squeeze out the anti-inflammatory beneficial messengers that direct the rest of our body to be healthy.
I hope this article has convinced you to lift (or throw around) some weights, put on some muscle, and fight cancer. The added benefits are stronger bones, a better physique, and hopefully, a longer life.
It looks like muscles fight cancer, but to do so, they must be put to work.
Muscles Fight Cancer References
- Ruiz JR, Sui X, Lobelo F, et al. Muscular strength and adiposity as predictors of adulthood cancer mortality in men. Cancer Epidemiol Biomarkers Prev. 2009;18(5):1468-1476. doi:10.1158/1055-9965.EPI-08-1075.
- Ramírez-Vélez R, Correa-Bautista JE, Lobelo F, et al. High muscular fitness has a powerful protective cardiometabolic effect in adults: influence of weight status. BMC Public Health. 2016;16(1):1012. doi:10.1186/s12889-016-3678-5.
- Gale CR, Martyn CN, Cooper C, Sayer AA. Grip strength, body composition, and mortality. Int J Epidemiol. 2007;36(1):228-235. doi:10.1093/ije/dyl224.
- Fujita Y, Nakamura Y, Hiraoka J, et al. Physical-strength tests and mortality among visitors to health-promotion centers in Japan. J Clin Epidemiol. 1995;48(11):1349-1359. http://www.ncbi.nlm.nih.gov/pubmed/7490598. Accessed January 3, 2017.
- FitzGerald SJ, Barlow CE, Kampert JB, Morrow JR, Jackson AW, Blair SN. Muscular Fitness and All-Cause Mortality: Prospective Observations. J Phys Act Heal. 2004;1(1):7-18. doi:10.1123/jpah.1.1.7.
- Ruiz JR, Sui X, Lobelo F, et al. Association between muscular strength and mortality in men: prospective cohort study. BMJ. 2008;337.
- Izquierdo M, Ibañez J, González-Badillo JJ, et al. Differential effects of strength training leading to failure versus not to failure on hormonal responses, strength, and muscle power gains. J Appl Physiol. 2006;100(5).
- Siiteri PK. Adipose tissue as a source of hormones. Am J Clin Nutr. 1987;45(1):277-282. http://www.ajcn.org/content/45/1/277.abstract. Accessed January 24, 2017.
- Campbell KL, Foster-Schubert KE, Alfano CM, et al. Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial. J Clin Oncol. 2012;30(19):2314-2326. doi:10.1200/JCO.2011.37.9792.
- Hall G van, Steensberg A, Sacchetti M, et al. Interleukin-6 Stimulates Lipolysis and Fat Oxidation in Humans. J Clin Endocrinol Metab. July 2013. http://press.endocrine.org/doi/abs/10.1210/jc.2002-021687. Accessed September 30, 2015.
- Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005;54(10):2939-2945. http://www.ncbi.nlm.nih.gov/pubmed/16186396. Accessed January 27, 2017.
- Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563-575. doi:nrc2676 [pii]10.1038/nrc2676.
- Green AS, Chapuis N, Maciel TT, et al. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. Blood. 2010;116(20):4262-4273. doi:blood-2010-02-269837 [pii] 10.1182/blood-2010-02-269837.
- Champ CE, Baserga R, Mishra M V, et al. Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More. Oncologist. 2013;18(1):97-103. doi:10.1634/theoncologist.2012-0164.
- Faubert B, Boily G, Izreig S, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17(1):113-124. doi:10.1016/j.cmet.2012.12.001.
- Vavvas D, Apazidis A, Saha AK, et al. Contraction-induced changes in acetyl-CoA carboxylase and 5’-AMP-activated kinase in skeletal muscle. J Biol Chem. 1997;272(20):13255-13261. http://www.ncbi.nlm.nih.gov/pubmed/9148944. Accessed January 16, 2015.
- Winder WW, Hardie DG. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol. 1996;270(2 Pt 1):E299-304. http://www.ncbi.nlm.nih.gov/pubmed/8779952. Accessed January 16, 2015.
- Rasmussen BB, Winder WW. Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. J Appl Physiol. 1997;83(4):1104-1109. http://www.ncbi.nlm.nih.gov/pubmed/9338417. Accessed January 16, 2015.
- Draznin B, Wang C, Adochio R, Leitner JW, Cornier MA. Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle. Horm Metab Res. 2012;44(9):650-655. doi:10.1055/s-0032-1312656.
- Cantó C, Jiang LQ, Deshmukh AS, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 2010;11(3):213-219. doi:10.1016/j.cmet.2010.02.006.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
- Hardie DG. Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr. 2011;93(4):891S-6. doi:ajcn.110.001925 [pii]10.3945/ajcn.110.001925.
- Hamrick MW. A role for myokines in muscle-bone interactions. Exerc Sport Sci Rev. 2011;39(1):43-47. doi:10.1097/JES.0b013e318201f601.
- Layne JE, Nelson ME. The effects of progressive resistance training on bone density: a review. Med Sci Sports Exerc. 1999;31(1):25-30. http://www.ncbi.nlm.nih.gov/pubmed/9927006. Accessed January 29, 2017.
- Pedersen BK, Steensberg A, Keller P, et al. Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects. Pflügers Arch Eur J Physiol. 2003;446(1):9-16. doi:10.1007/s00424-002-0981-z.
- Keller P, Keller C, Carey AL, et al. Interleukin-6 production by contracting human skeletal muscle: autocrine regulation by IL-6. Biochem Biophys Res Commun. 2003;310(2):550-554. doi:10.1016/j.bbrc.2003.09.048.
- Pedersen BK, Febbraio MA. Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6. Physiol Rev. 2008;88(4):1379-1406. doi:10.1152/physrev.90100.2007.
- Febbraio MA, Steensberg A, Keller C, et al. Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J Physiol. 2003;549(Pt 2):607-612. doi:10.1113/jphysiol.2003.042374.
- Gratas-Delamarche A, Derbré F, Vincent S, Cillard J. Physical inactivity, insulin resistance, and the oxidative-inflammatory loop. Free Radic Res. 2014;48(1):93-108. doi:10.3109/10715762.2013.847528.
- Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17(8):884-886. doi:10.1096/fj.02-0670fje.
- Lira FS, Rosa JC, Pimentel GD, et al. Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects. Lipids Health Dis. 2010;9:82. doi:10.1186/1476-511X-9-82.
- Oberley TD. Oxidative damage and cancer. Am J Pathol. 2002;160(2):403-408. doi:10.1016/S0002-9440(10)64857-2.
- García-López D, Häkkinen K, Cuevas MJ, et al. Effects of strength and endurance training on antioxidant enzyme gene expression and activity in middle-aged men. Scand J Med Sci Sports. 2007;17(5):595-604. doi:10.1111/j.1600-0838.2006.00620.x.
- Parise G, Phillips SM, Kaczor JJ, Tarnopolsky MA. Antioxidant enzyme activity is up-regulated after unilateral resistance exercise training in older adults. Free Radic Biol Med. 2005;39(2):289-295. doi:10.1016/j.freeradbiomed.2005.03.024.
- Lehrer S, Diamond EJ, Stagger S, Stone NN, Stock RG. Increased serum insulin associated with increased risk of prostate cancer recurrence. Prostate. 2002;50(1):1-3. http://www.ncbi.nlm.nih.gov/pubmed/11757030. Accessed December 24, 2015.
- Crawley DJ, Holmberg L, Melvin JC, et al. Serum glucose and risk of cancer: a meta-analysis. BMC Cancer. 2014;14:985. doi:10.1186/1471-2407-14-985.
- Klement RJ, Champ CE. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation. Cancer Metastasis Rev. January 2014:1-13. doi:10.1007/s10555-014-9495-3.
- Klement RJ, Fink MK. Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer. Oncogenesis. 2016;5:e193. doi:10.1038/oncsis.2016.2.
- Fine EJ, Champ CE, Feinman RD, Márquez S, Klement RJ. An Evolutionary and Mechanistic Perspective on Dietary Carbohydrate Restriction in Cancer Prevention. J Evol Heal. 2016;1(1). doi:10.15310/2334-3591.1036.
- Goodwin ML. Blood glucose regulation during prolonged, submaximal, continuous exercise: a guide for clinicians. J Diabetes Sci Technol. 2010;4(3):694-705. http://www.ncbi.nlm.nih.gov/pubmed/20513337. Accessed January 29, 2017.
- Adams OP. The impact of brief high-intensity exercise on blood glucose levels. Diabetes Metab Syndr Obes. 2013;6:113-122. doi:10.2147/DMSO.S29222.
- Bernstein L, Henderson BE, Hanisch R, Sullivan-Halley J, Ross RK. Physical Exercise and Reduced Risk of Breast Cancer in Young Women. JNCI J Natl Cancer Inst. 1994;86(18):1403-1408. doi:10.1093/jnci/86.18.1403.
- Carpenter CL, Ross RK, Paganini-Hill A, Bernstein L. Lifetime exercise activity and breast cancer risk among post-menopausal women. Br J Cancer. 1999;80(11):1852-1858. doi:10.1038/sj.bjc.6690610.
- Bradshaw PT, Ibrahim JG, Khankari N, et al. Post-diagnosis physical activity and survival after breast cancer diagnosis: the Long Island Breast Cancer Study. Breast Cancer Res Treat. 2014;145(3):735-742. doi:10.1007/s10549-014-2966-y.