Trait#124: Caffeine and muscle building

Monday, May 30, 2022. Author FitnessGenes

Trait#124: Caffeine and muscle building

Can caffeine help with strength training?

The short answer is: yes.

According to a recent (2021) review of the literature by the International Society of Sports Nutrition (ISSN), caffeine, when taken at a dose of between 3 - 6 mg per kg of bodyweight, 30 - 90 mins before exercise, can lead to small improvements in muscular strength, endurance, and power

The Forest plot below (taken from a 2019 meta-analysis of the literature) shows that some (but not all) studies demonstrate a benefit of caffeine over placebo for muscle strength, muscule endurance, and anaerobic power.

Let’s take a look at these facets individually.

 

Source: Grgic, J., Grgic, I., Pickering, C., Schoenfeld, B. J., Bishop, D. J., & Pedisic, Z. (2020). Wake up and smell the coffee: caffeine supplementation and exercise performance—an umbrella review of 21 published meta-analyses. British journal of sports medicine, 54(11), 681-688.

 

- Muscular strength

A commonly used measure of muscle strength is the one-rep max (1RM). This refers to the maximum weight you can lift for one repetition, using correct technique. 

Several studies* suggest that caffeine, taken pre-workout, can increase 1RM in both trained and untrained individuals. Generally speaking, these effects on strength tend to be small. Three different meta-analyses, referenced in the ISSN’s 2021 position stand on caffeine and exercise performance, estimate that caffeine can increase 1RM by between 2-7%

Note that is quite a small effect, and will be of most use to elite and high-level strength athletes, such as those competing in powerlifting or weightlifting. In a similar vein, the evidence seems to suggest that caffeine has greater benefits for endurance exercise (e.g. running, cycling) compared to strength exercise. 

Other studies* have found that caffeine can also benefit isometric and isokinetic strength. Isometric strength refers to the ability to generate force (torque) without a change in length of muscles. An example would be a plank or handgrip. Isokinetic strength refers to producing force against variable resistance while keeping the speed of the movement the same. 

Caffeine is shown to both increase maximum isometric and isokinetic strength and also increase the rate of torque development (i.e. it increases the speed at which muscle fibres generate force). 

*(A good review of these studies has been written by Jozo Grgic in Volume 51 of the academic journal, Sports Medicine. Interested readers are encouraged to read this for a thorough overview of the literature on caffeine and resistance training). 

 

- Muscular endurance

Muscular endurance refers to the capacity of our muscles to resist fatigue and continue working. A straightforward, albeit crude, measure of muscle endurance is the maximum number of repetitions we can perform. For example, one might perform as many reps of the bench press as possible until momentary failure. 

According to two meta-analyses reviewed in the ISSN’s position stand, caffeine is shown to effect a 6-7% increase in muscular endurance performance. This roughly equates to 1-4 additional reps per set

The effect of caffeine on muscular endurance are illustrated in the graphs below, which are from a small study of 15 resistance-trained females who ingested either 4 mg / kg of caffeine or a placebo before completing a range of strength exercises. As can be seen in the graphs, those in the caffeine group could perform a slightly higher number of reps of bench press and squats.

 

Source: Norum, M., Risvang, L. C., Bjørnsen, T., Dimitriou, L., Rønning, P. O., Bjørgen, M., & Raastad, T. (2020). Caffeine increases strength and power performance in resistance‐trained females during early follicular phase. Scandinavian Journal of Medicine & Science in Sports, 30(11), 2116-2129.

 

An increased number of sets has been shown in both single and multi-set exercises, and using different loads (from 30 - 85% of 1RM). In addition to increasing the number of reps, caffeine has also been shown to increase the quality of reps, as evinced by higher peak and mean velocity for each rep. (See the 2021 Sports Medicine review for more details).

 

- Power and velocity

Muscle power is the ability to exert maximal force in as short a time as possible. It is therefore the product of how much force we can generate (strength) and how quickly muscle fibres can contract to generate this force (contraction velocity).

A 2020 meta-analysis of 12 studies found that caffeine increases mean and peak velocity of muscle contraction for upper and lower body resistance training movements using various loads.

Other studies have found that caffeine enhances performance on the Wingate test - an assessment of muscle power whereby subjects cycle or sprint at maximum effort for 30 seconds at a particular external load.

 

KEY POINTS

  • Caffeine has been shown to elicit small improvements in muscle strength, muscle endurance, and power.
  • Evidence suggests that a caffeine dose of 3-6 mg / kg, taken 30 - 90 minutes before exercise, is optimal for improving strength-training performance.

 

How does caffeine improve strength training performance?

Caffeine’s performance-enhancing or “ergogenic” effects arise largely from its stimulatory effect on our central nervous system (CNS)

 

- CNS effects

If you’ve ever drunk a cup of coffee, you probably noticed you felt more awake. This is because caffeine works by blocking adenosine A2A receptors in our brain and other tissues. Adenosine is a substance that makes us feel sleepy; so, by blocking activation of adenosine A2A receptors, caffeine makes us feel more awake. 

But, how does the blockade of adenosine A2A receptors by caffeine lead to improved strength training performance? 

Due to the underlying neurochemistry of our brains, blockade of adenosine A2A receptors causes the activation of dopamine D2 receptors and the stimulation of dopaminergic networks in our brain. As we’ve explored in previous traits, dopamine plays a key role in motivation and motor control. 

By activating D2 receptors and stimulating dopaminergic pathways in our brain and central nervous system, caffeine acts to:

  • increase motivation for exercise
  • increase focus
  • reduce sensations of muscle fatigue - thereby helping muscular endurance.
  • reduce perception of pain - thereby allowing greater force generation by our muscles.
  • reduce perception of effort - thereby making exercise feel easier. 


It is this reduced perception of effort that is thought to be one of the most significant factors underlying caffeine’s performance-enhancing effects.

A meta-analysis of 21 studies, which looked at ratings of perceived exertion (RPE), found that caffeine reduced RPE by 5.6% and led to an 11% increase in performance. Moreover, 29% of the variance in improvement in performance was attributed to reductions in RPE, suggesting that it is a key factor in caffeine’s ergogenic effects.

 

Source: Barreto, G., Grecco, B., Merola, P., Reis, C. E. G., Gualano, B., & Saunders, B. (2021). Novel insights on caffeine supplementation, CYP1A2 genotype, physiological responses and exercise performance. European Journal of Applied Physiology, 121(3), 749-769.

 

- Direct effects on skeletal muscle

As well as stimulating the central nervous system, caffeine may also boost strength-training performance by directly acting on muscle. 

There is some evidence that caffeine binds to ryanodine receptors in muscle cells, leading to the enhanced release of calcium. By enhancing calcium release, caffeine allows muscle fibres to make more forceful contractions, thereby improving strength performance.

 

- Placebo effect

Interestingly, some studies suggest that merely thinking you have ingested caffeine can lead to improvements in performance.

Cyclists taking higher doses of placebo (but under the impression they are taking higher doses of caffeine) show better performance than those taking lower doses of placebo. Conversely, some evidence shows that acknowledging that you haven’t ingested caffeine can actually worsen performance.

 

- The role of paraxanthine

Many of the ergogenic effects of caffeine may also be due to its breakdown products or metabolites, in particular paraxanthine.

Paraxanthine also blocks adenosine A2A receptors (to a greater extent than caffeine) and so may be responsible for caffeine’s ergogenic effects in the body. 

 

KEY POINTS

  • Caffeine exerts its effects in the body by blocking the adenosine A2 receptor.
  • Blockade of the adenosine A2 receptor leads to stimulation of the central nervous system.
  • By stimulating the central nervous system, caffeine serves to increase focus and motivation and reduce feelings of pain and exertion. 
  • Caffeine may also have direct effects on muscle.
  • Many of caffeine's effects in the body may also be due to the action of paraxanthine - a metabolite of caffeine.

 

How is caffeine metabolised?

Have you ever wondered what happens when you drink a caffeinated beverage, such as a cup of coffee?

Caffeine is quickly absorbed via the gut and enters the bloodstream within minutes. It reaches a peak concentration in the bloodstream between 30 and 120 minutes after ingestion. The half life of caffeine is typically between 4 and 6 hours, although, as we’ll find out, there is considerable variation between people depending on how fast they break down caffeine. 

The vast majority (over 95%) of caffeine is broken down or “metabolised” by a liver enzyme known as cytochrome P450 1A2 (CYP1A2). This enzyme converts caffeine into paraxanthine (about 84% of caffeine is broken down into this metabolite),  theobromine (12%), and theophylline (4%). 

These metabolites are then further broken down by various liver enzymes and the breakdown products excreted in the urine by the kidneys. 

 

Source: Rodak, K., Kokot, I., & Kratz, E. M. (2021). Caffeine as a Factor Influencing the Functioning of the Human Body—Friend or Foe?. Nutrients, 13(9), 3088.

 

The activity of our CYP1A2 enzyme determines how fast we break down caffeine. This, in turn, is affected by various lifestyle and genetic factors, which cause people to break down caffeine at different rates.

Smoking, heavy caffeine use, and high intakes of Brassica vegetables (e.g. broccoli, kale) are shown to activate or induce (i.e increase the production of) the CYP1A2 enzyme, leading to faster breakdown of caffeine. 

By contrast, alcohol, oestrogen-containing oral contraceptives, high intakes of apiaceous vegetables (e.g. carrots, parsnips, celery), and quercetin (found in red wine, onions, grapes) are all shown to downregulate and reduce the activity of CYP1A2, thereby slowing the breakdown of caffeine. 

As we’ll elaborate on in the following section, variants of our CYP1A2 gene (which encodes the CYP1A2 enzyme) also affect how quickly we metabolise or breakdown caffeine. 

 

KEY POINTS

  • Caffeine is broken down by the liver enzyme CYP1A2.
  • Differences in the activity of CYP1A2 affect how quickly we break down caffeine.
  • Caffeine consumption, diet, and medication can all alter CYP1A2 activity and the speed at which we break down caffeine.

 

How do CYP1A2 gene variants affect caffeine metabolism?

The CYP1A2 enzyme responsible for breaking down caffeine is coded for by your CYP1A2 gene. 

Variants of the CYP1A2 gene can alter the inducibility of the enzyme - that is, how effectively the production and activity of the CYP1A2 enzyme can be increased. Greater inducibility and higher activity of the CYP1A2 enzyme leads to faster breakdown of caffeine and faster generation of its metabolites, paraxanthine, theobromine, and theophylline.

More specifically, a well-studied SNP (Single Nucleotide Polymorphism), designated rs762551, causes an A → C change in the DNA code of the CYP1A2 gene, giving rise to two different CYP1A2 variants or alleles: the ‘A’ allele and the ‘C’ allele. 

The ‘A’ allele causes increased inducibility and higher activity of the CYP1A2 enzyme, resulting in faster breakdown of caffeine. By contrast, the ‘C’ allele causes reduced inducibility and lower enzyme activity, leading to slower breakdown of caffeine

The rs762551 SNP and resultant 'A' and 'C' alleles therefore give rise to three possible CYP1A2 genotypes and caffeine metaboliser types:

  • Fast metabolisers (AA genotype) - these people break down caffeine more quickly.
  • Intermediate metabolisers (AC genotype) - these people break down caffeine more slowly than fast metabolisers, but quicker than slow metabolisers.
  • Slow metabolisers (CC genotype) - these people break down caffeine slowly.

(It’s worth pointing out that some studies more simply classify people into fast (AA) and slow (AC + CC) metabolisers based on CYP1A2 genotype).

 

Source: Millard, J. T., Passang, T., Ye, J., Kline, G. M., Beachy, T. M., Hepburn, V. L., & Klinkerch, E. J. (2018). Genotype and phenotype of caffeine metabolism: A biochemistry laboratory experiment. Journal of Chemical Education, 95(10), 1856-1860.

 

As illustrated in the graph above, which is taken from an experiment whereby subjects consumed a 200 mg dose of caffeine, fast metabolisers (the bottom curve with triangle data points) have lower peak caffeine concentrations in blood (and saliva) and a shorter half life of caffeine in the bloodstream. This is because they more quickly break down caffeine due to higher CYP1A2 enzyme activity. 

By contrast, slow metabolisers (the top curve with circular data points) have higher peak caffeine concentrations and a longer half life of caffeine, due to slower breakdown of caffeine by the CYP1A2 enzyme. 

Due to differences in the rate of caffeine breakdown, fast, intermediate, and slow metabolisers may reap varying strength-training benefits from ingesting caffeine. We’ll discuss this in the next section.

 

KEY POINTS

  • The 'A' variant (rs762551) of the CYP1A2 gene causes greater inducibility (capacity to increase production/activity) of the CYP1A2 enzyme.
  • The 'C' variant is linked to lower inducibility of the CYP1A2 enzyme.
  • Greater CYP1A2 inducibility/activity leads to faster breakdown of caffeine.
  • Lower CYP1A2 inducbility/activity leads to slower breakdown of caffeine.
  • People with two copies of the 'A' variant (AA genotype) are 'fast metabolisers' - they break down caffeine more quickly.
  • People with one or two copies of the 'C' variant (AC + CC genotypes) are 'intermediate' and 'slow' metabolisers, respectively.

 

How do CYP1A2 gene variants affect response to caffeine in terms of strength performance?

There are a few small studies that suggest that fast metabolisers (i.e. those with the AA CYP1A2 genotype) have greater improvements in muscle endurance and power when taking caffeine compared to intermediate and slow metabolisers (AC + CC genotypes). 

For example, one study of 30 resistance-trained men found that, compared to placebo, ingesting 6 mg/kg bodyweight of caffeine significantly increased the number of reps performed for bench press, leg press, shoulder press and seated cable row, but only in fast metabolisers (AA genotype). 

The graph below shows how caffeine significantly improved the mean number of reps for all exercises compared to placebo, but only in those with the AA genotype.

Source: Rahimi, R. (2019). The effect of CYP1A2 genotype on the ergogenic properties of caffeine during resistance exercise: a randomized, double-blind, placebo-controlled, crossover study. Irish Journal of Medical Science (1971-), 188(1), 337-345.

 

Another small study of handball players found that ingesting 3 mg / kg of caffeine increased the velocity of ball throwing from 7 metres, but only in fast metabolisers with the AA genotype. Interestingly, however, the same study reported no effect of CYP1A2 genotype and response to caffeine for sprint velocity, vertical jump height, isometric handgrip strength, ball throwing velocity from 9 metres, and ball throwing velocity from 7 metres with a goalkeeper. This suggests that the solitary impact of genotype on ball throwing velocity from 7 metres (withoutm a goalkeeper) may be an artefact. 

Overall, though,the evidence for a significant impact of CYP1A2 genotype and metaboliser speed on strength-training performance is scant. Augmenting this, there are several studies which report no effect of CYP1A2 genotype on strength-training response to caffeine. 

Given this lack of evidence, a 2021 review of the literature by Grgic concluded that, it currently seems that CYP1A2 genotype variations may not modulate caffeine’s ergogenic effects on resistance exercise.”

 

KEY POINTS

  • Some small studies suggest that fast metabolisers (AA CYP1A2 genotype) may derive greater strength-training benefits from caffeine compared to intermediate and slow metabolisers (AC + CC genotypes).
  • Overall, however, the evidence for an impact of CYP1A2 genotype on strength-training response to caffeine is lacking.

 

Why could CYP1A2 gene variants potentially affect strength training response to caffeine?

Despite a lack of robust evidence to show that CYP1A2 genotype / metaboliser speed moderates the benefits of taking caffeine for muscular strength, endurance, and power, there are some theoretical reasons why CYP1A2 variants could have an impact.

As mentioned in the “How is caffeine metabolised?” section, the most significant caffeine metabolite, accounting for 84% of caffeine’s breakdown products, is paraxanthine. Rather than being an inactive metabolite, paraxanthine functions in a similar way to caffeine and blocks adenosine A2A receptors.

In fact, paraxanthine is a more potent blocker of adenosine A2A receptors (it has a stronger binding affinity) and may be responsible for the bulk of caffeine’s ergogenic effects in the body. By blocking adenosine receptors, paraxanthine (as with caffeine) stimulates the central nervous system, giving rise to a host of performance benefits (e.g. reduced muscle fatigue) described earlier.

As fast metabolisers (AA genotype) have higher CYP1A2 activity and break down caffeine more quickly, they ought to also generate paraxanthine more quickly. Fast metabolisers will therefore reach higher levels of paraxanthine in the bloodstream more quickly after ingesting caffeine, reaping greater performance benefits.

 

Source: Barreto, G., Grecco, B., Merola, P., Reis, C. E. G., Gualano, B., & Saunders, B. (2021). Novel insights on caffeine supplementation, CYP1A2 genotype, physiological responses and exercise performance. European Journal of Applied Physiology, 121(3), 749-769.

 

By contrast, intermediate and slow metabolisers (AC + CC genotypes) would be expected to generate paraxanthine less quickly, and therefore reap less performance benefits after ingesting caffeine.

It is worth stressing that this purported mechanism is only hypothetical, and the few studies that have been conducted do not show any significant difference in circulating paraxanthine levels between different CYP1A2 genotypes.

 

KEY POINTS

  • In theory, fast metabolisers will experience quicker rises in levels of paraxanthine (a breakdown product of caffeine), which may promote greater performance benefits.
  • The evidence to support this theory, however, is lacking.

 

How do genes affect sensitivity to caffeine?

Some of us may be more prone to sleep disturbances and feelings of anxiety when consuming caffeine. Whether or not we are sensitive to the stimulant effects of caffeine is partly dependent on variants of our ADORA2A gene

This gene encodes the adenosine 2A receptor, which is the receptor blocked by caffeine (as well as paraxanthine). A well-studied SNP within the ADORA2A gene, designated rs5751876, causes a T → C change in the DNA code, creating two difference ADORA2A gene variants or alleles: the ‘T’ allele and the ‘C’ allele. 

Several studies suggest that those with two copies of the ‘T’ allele (i.e. those with the TT genotype) are much more likely to be sensitive to caffeine and report sleep disturbances and feelings of anxiety after drinking tea, coffee, and other caffeinated beverages. 

Given that we know that adequate sleep and good psychological wellbeing are important for exercise performance and recovery, it is possible that caffeine may actually negatively affect strength-training performance in caffeine-sensitive individuals with the ADORA2A TT genotype.

Needless to say, anybody considering taking caffeine to enhance strength-training and muscle building should therefore weigh-up the risks and benefits based on their individual circumstances.

 

KEY POINTS

  • The TT genotype (rs5751876) of the ADORA2A gene is associated with high sensitivity to caffeine, including a greater risk of anxiety and insomnia when consuming caffeine.
  • Caffeine-sensitive individuals may not derive any performance benefits from caffeine due to its negative impacts on sleep and psychological wellbeing.

 

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