Heat shock protein sounds like something conjured up by an ad copy writer. Yet heat shock proteins, often referred to as HSPs, are real and critically important to both health and bodybuilding. If I told you that one function of HSPs was to maintain proper protein folding, you’d probably yawn and say, “So what?” If I added that they’re important to establishing proper protein shape, your curiosity might begin to sense that they have something to do with bodybuilding progress. You might perk up some more when I told you that HSPs transport proteins across cellular membranes, sensing that they have something to do with increased protein synthesis. Because you know that increased muscle protein synthesis is the very core of gains in muscle size and strength, well, by now I would have gotten your full attention.
To understand precisely what HSPs are, consider their alternate name: stress proteins. As that implies, they are released under high-stress conditions and protect cells. They’re found in all living things, from microbes to humans.
Heat shock proteins were discovered in 1962, when fruit flies subjected to a cellular poison that increased body heat produced them. The substance used to increase cellular heat in the flies was dinitrophenol. DNP uncouples oxidative metabolism, a fancy way of saying that it throws a metabolic monkey wrench into the process in which cells produce adenosine triphosphate, or ATP, the elemental cellular energy. When that happens, a large amount of heat is released.
DNP is often touted as a fat-loss aid because it forces the body to tap into fat stores as a source of energy. The problem is that all that heat it produces can cause you to cook internally to the point of death. The stress that DNP imposes in cells helps release HSPs to counter the stress.
Heat shock proteins come in various sizes, depending on their molecular weight, and are tagged based on that weight—HSP25, HSP60, HSP70 and so on. One of the main proteins that degrade muscle proteins, ubiquitin, acts like a small heat shock protein. As indicated above, HSPs help maintain the shape and function of cellular proteins, which can be degraded by various forms of stress, including infections, inflammation, toxins such as alcohol, trace metals such as lead and cadmium—even ultraviolet light, such as sunlight. Other forms of stress that bring on heat shock activity include starvation, lack of sufficient oxygen and dehydration. Exercise, as a form of stress, also induces HSP release, and the proteins facilitate postexercise recovery.
Heat shock proteins are involved in body processes in the absence of stress. For example, they help signal immune cells that protect against disease.1 They monitor cell proteins, and when the proteins are worn out, an HSP carries them to places in the cell where they degrade. That maximizes cell reproduction by clearing the way for the production of newly synthesized proteins.
HSP90 helps maintain cellular steroid receptors and transcription factors that are vital for protein synthesis, including muscle protein synthesis. Without properly functioning cellular steroid receptors, testosterone would not work properly, because it must interact with the receptors in order to enter the cell and boost protein synthesis.
One aspect of HSPs that has aroused the interest of scientists is their role in protecting the cardiovascular system. Working with nitric oxide, they aid vascular relaxation and widening, which increases blood flow. HSP20 prevents the aggregation of platelets—that is, clotting, the immediate cause of heart attacks and strokes.
HSPs also help maintain the function of heart muscle cells and prevent the death of cells after the heart is deprived of blood and oxygen, as occurs during a heart attack.2 Scientists believe they support skeletal muscle cell function, preventing the stress that would otherwise lead to destruction of muscle cells. HSPs are involved in insulin metabolism, which has anticatabolic properties in muscle.
Heat Shock Proteins and Exercise
Involved as they are in maintaining and protecting muscle cells, HSPs are obviously affected by exercise. The increased body temperature that accompanies exercise is enough to encourage HSP release (although release in the heart muscle requires higher than normal temperatures). Research has demonstrated, however, that elevated temperature is not a requirement for the release of HSPs during exercise. One factor that does spur it is oxidative stress. Reactive oxygen species—a.k.a. free radicals—are by-products of oxygen metabolism and potent agents of HSP release.
HSPs released during exercise protect cells from oxidative stress by boosting glutathione, one of the body’s major cellular antioxidants. Glutathione protects muscle cells from the destructive effects of excess free radicals that exercise brings on. HSPs also blunt the release and activity of tissue necrosis factor-A,3 a major agent of muscle catabolism. The loss of muscle with age is related to TNF-A’s rise in older people. HPS70 inhibits another inflammatory mediator called nuclear factor kappa-B, thus inhibiting muscle atrophy.4
The interaction between HSPs and nitric oxide, besides promoting greater blood flow within muscle, helps dilate bronchial tubes. That not only enhances oxygen delivery to muscles via the lungs but also diminishes exercise-induced asthma. Asthmatics tend to produce more inflammatory mediators, such as TNF-A, because asthma is an inflammatory disease. In fact, chronic asthmatics are known to produce more TNF-A, which stimulates greater release of HSP70.5
When the body is low on ATP, it construes that as stress and reacts by releasing HSP. ATP declines during exercise. Several scientists have suggested that since carbohydrates and glycogen are major sources of ATP during exercise, a lack of sufficient carbs or glycogen is a major reason for HSP release during training. On the other hand, an experiment that examined carbohydrate availability and HSP release during high-intensity exercise found no association between the two.6
Researchers have found that HSPs are involved in muscle growth. One study, however, found that only high-intensity resistance exercise significantly increased HSP production, leading the authors to suggest that HSPs must be involved in promoting muscle growth.7
Another study measured HSP after strength training, specifically a biceps workout, and found that the exercise boosted HSP70. That led to this conclusion: “The increase of HSP70 may be related to training-induced muscular stress or damage and to fiber type transition and may play an important role in muscular adaptation to exercise.”8
Various types of exercise elicit different HSP responses. Small-molecule HSPs are released only during intense exercise that results in muscle damage, such as eccentric, or negative, muscle contractions. In that instance they help protect cells from further damage. Another HSP, HSP60, is released during concentric muscle contractions that don’t cause much muscle damage. It’s concentrated in and helps protect the mitochondria of the cells. HSP70 is released during high-intensity muscle contractions and plays a role in muscle protein synthesis reactions and also in refolding—techspeak for “making functional again”—damaged muscle proteins.
The release of HSP during exercise preconditions the body to more readily produce it in subsequent training sessions. That can be construed as a process the body employs to reduce stress during training. Some studies suggest that those with more training experience produce more HSPs, others that HSP production levels off with continued training as the body adapts to the regular stress of exercise.9
As noted above, HSPs help maintain cellular steroid receptors, but HSP60 helps modulate insulinlike growth factor, helping maintain IGF-1 cell receptors. That could aid antiaging and retard age-related loss of muscle size and strength. Studies show that those lucky enough to live to 100 or more have lesser amounts of HSP. While that may seem paradoxical considering the cell-protecting effect of HSPs, it’s also important to understand that they’re released only under high-stress conditions. The fact that those people reach the age of 100 indicates they have handled the inevitable stresses of life well through the years. As you might expect, the converse is true with chronically sick people, whose bodies have an abundance of HSPs. Indeed, in the cell HSPs exert anti-inflammatory effects, but outside they exacerbate inflammation by interacting with immune factors, such as inflammatory cytokines. So too much HSP can damage, not protect, health.
One interesting effect of HSPs is that their production differs in the sexes. Estrogen, which is higher in women, blunts the release of HSPs during exercise. Some researchers suggest that because estrogen has antioxidant properties and helps release nitric oxide, it makes the release of HSPs superfluous in women.
Estrogen also helps prevent muscle membrane damage and inflammation. Women tend to have lower body temperatures during exercise, which also blunts HSP release. Indeed, one study done with exercising rats found that male rodents produced higher levels of HSP70 after exercise, which gave them greater cardiovascular protection. The authors suggest that the sex-specific effect of aerobic exercise makes aerobics more important for males because of the HSP-induced cardiovascular protection.10 Bodybuilders who use estrogen blockers like Nolvadex, a.k.a. tamoxifen citrate, should be aware that they block the HSP response during exercise, which could interfere with complete postexercise recovery.
On the other hand, at least one study showed that anabolic steroid drugs help increase exercise recovery by boosting of HSP72, which would permit more high-intensity training without overtraining. Most interesting was the finding that an injectable anabolic steroid drug, Deca-Durabolin, boosted HSP72 but that the oral steroid Winstrol had no effect on HSPs.11 Testosterone in most forms is known to encourage HSP release.
Additional agents of HSP release during training are the catecholamines, such as epinephrine and norepinephrine. One way to encourage their release is by taking in caffeine. A study found that caffeine-induced release of catecholamines did indeed boost HSP72 production during exercise.12 That’s consistent with the fact that catecholamines are characterized as stress hormones, and HSPs respond to stressors.
While HSPs help release the body’s built-in antioxidants, taking dietary antioxidants blunts the exercise-induced release of HSPs—because of free-radical behavior, for example. If you inhibit free radicals by taking antioxidants, there’s no signal to produce HSPs. When researchers gave two forms of vitamin E—alpha and gamma tocopherol—along with vitamin C, to 21 young exercising men, the combo blunted HSP release after training.13
Gamma tocopherol was most potent and is the major quencher of the free radical peroxynitrate, which is produced from the oxidation of nitric oxide and which is particularly damaging to cells. Alpha tocopherol, the most common supplemental form of E, has little or no effect on peroxynitrate. It also turns out, however, that peroxynitrate is a potent stimulus to HSP release.
Gamma E is more potent than alpha E in preventing cardiovascular disease and prostate cancer. Unfortunately, gamma E blocks HSP72, which when low in muscle, is linked to insulin resistance and type 2 diabetes.
Another study found that when the rats are placed on a diet in which 60 percent of the calories come from fat but are also given lipoic acid, the lipoic acid activates HSPs in muscle cells and prevents insulin resistance.14 Other studies show that a combination of carnosine and zinc can activate some heat shock proteins.15
Studies with aging mice show that the inability of aging muscles to release HSP after exercise blunts recovery from exercise-induced muscle damage. In rodents that have been manipulated to continue producing HSPs after exercise, however, many age-related muscle deficits are not observed. HSPs are thought to help prevent aging effects through unregulated antioxidant defenses. Indeed, one study of old and young rats showed that when the rats are engaged in resistance training, both young and old continue to produce HSPs, although excessive oxidation blunts this release in the older rodents.16
The older rats released 40 percent less HSP than the younger ones. Scientists suggest that maintaining HSP production during aging can benefit the recovery and strength of aging muscles.
One thing that also boosts HSP you might want to temper a bit. The radiation produced by extensive cell-phone use has been suspected of causing brain tumors. A study published a few years ago noted that overexpression of certain HSPs can initiate cancer in normal cells.17 One way is by deactivating p53, a tumor-suppressing protein. Other studies show that heightened HSPs lead to spread of cancer and increase resistance of tumors to chemotherapy. Most of those studies, however, either had isolated-cell protocols or involved animals subjected to higher than normal levels of radiation. While the cell-phone issue remains speculative in humans, it would probably be prudent not to gab all day on your wireless network. Besides, if you bring a cell phone to the gym and talk while working out, you can’t be serious about your training.
Editor’s note: Want uncensored information on nutrition science and supplements? Get a copy of Jerry Brainum’s e-book, Natural Anabolics, available at www.JerryBrainum.com. IM
1 Nishakawa, M., et al. (2008). Heat shock protein derivatives for delivery of antigens to antigen presenting cells. Int J Pharm. 354:23-27.
2 Fan, G.C., et al. (2005). Novel cardioprotective role of a small heat shock protein, HSP20, against ischemia/reperfusion injury. Circul. 111:1792-1799.
3 Koh, T. (2002). Do small heat shock proteins protect skeletal muscle from injury? Exer Sports Sci Review. 30:117-21.
4 Senf, S.M., et al. (2008). HSP70 overexpression inhibits NF-KB and foxo3a transcriptional activities and prevents skeletal muscle atrophy.FASEB J. 22:3836-3845.
5 Harkins, M.S. (2009). Exercise regulates heat shock proteins and nitric oxide. Exerc Sport Sci Rev. 37:73-77.
6 Morton, J.P., et al. (2009). Reduced carbohydrate availability does not modulate training-induced heat shock protein adaptations but does upregulate oxidative enzyme activity in human skeletal muscle. J Appl Physiol. 106:1513-1521.
7 Thompson, H.S., et al. (2003). Exercise-induced HSP27, HSP70, and MAPK responses in human skeletal muscle. Acta Physiol Scand. 178:61-72.
8 Steinacker, J.M., et al. (2003). Human muscle heat shock protein 70 (HSP70) expression in response to strength training. Med Sci Sports Exer. 35:S124.
9 Gjovaag, T.F., et al. (2006). Effect of concentric or eccentric weight training on the expression of heat shock proteins in the biceps brachii of very well-trained males. Eur J Appl Physiol. 96(4):355-62.
10 Paroo, Z., et al. (2002). Exercise improves postischemic cardiac function in males but not in females.Circ Res. 90:911-17.
11 Gonzalez, B., et al. (2000). Anabolic steroid and gender-dependent modulation of cytosolic HSP70s in fast- and slow-twitch skeletal muscle.J Ster Biochem Mol Biol. 74:63-71.
12 Whitham, M., et al. (2006). Effect of caffeine supplementation on the extracellular heat shock protein 72 response to exercise. J Appl Physiol. 101:1222-1227.
13 Fischer, C.P., et al. (2006). Vitamin E isoform-specific inhibition of the exercise-induced heat shock protein 72 expression in humans. J Appl Physiol. 100:1679-1687.
14 Gupte, A.A., et al. (2009). Lipoic acid increases heat shock protein expression and inhibits stress kinase activation to improve insulin signaling in skeletal muscle from high-fat-fed rats. J Appl Physiol. 106:1425-1434.
15 Odashima, M., et al. (2006). Zinc-L-carnosine protects colonic mucosal injury through induction of heat shock protein 72 and suppßression of NF-kB activation. Life Sci. 79:2245-2250.
16 Murlasits, Z., et al. (2006). Resistance training increases heat shock protein in skeletal muscle of young and old rats. Exper Gerontol. 41:398-406.
17 French, P.W., et al. (2000). Mobile phones, heat shock proteins and cancer. Differentiation. 67:93-97.