The Single Most Neglected Part of Training

"The Top 7 Bodybuilding Methods of All Time"
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"The Best Lifts for Maximum Strength"
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"Adjusting Rest Intervals to Optimize Training"
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You can see why I didn't go with that title! Seriously, out of all the training variables, rest intervals are considered the least sexy. Why? Because most people don't put much thought into how long they rest between sets. They just wing it.

But rest periods have a HUGE impact on the effectiveness of your training. And it's not as simple as saying: rest more so you can lift more weight. Depending on your training goal and approach, some rest interval lengths will provide much better results than others.

Short Vs. Long Rest Periods: The Science

According to science...

Longer rest intervals (2-3 minutes between sets) typically lead to more size and strength gains when training with low (1-5) or moderate (6-12) reps, especially with multi-joint exercises. Longer rest intervals allow you to use more weight which causes more muscle damage, leading to more growth.
Shorter rest intervals (1 minute or less) lead to a higher level of growth hormone and likely IGF-1. Also, lactate itself could help with hypertrophy by increasing follistatin and myogenin, lowering myostatin. Remember, myostatin is a growth-limiting protein released by the muscles. The less you produce, the more growth you get.
Using shorter rest intervals facilitates the accumulation of lactate, especially when using higher reps (12-25+).
The higher level of growth hormone (and likely IGF-1) was significant only for the first four weeks of training, after which it becomes similar to longer rest intervals. This could highlight the value of training blocks using short rest intervals.
Shorter rest intervals lead to a higher cortisol level which also lead to more adrenaline. (That's why short rest periods can feel energizing). This could be useful early in the session, or during preparation sets to help amp you up for the rest of the workout. But it could also become detrimental if you do it too much.
Longer rest intervals lower the psychological stress of the workout (which can also lower cortisol), especially when lifting near maximal or maximal weights. When doing near-max or max work for sets of 1, one minute of rest was enough from a performance standpoint, but using 3-5 minutes of rest led to a lower stress level.
Some studies found that shorter rest intervals led to better strength-endurance (the capacity to do more reps with a given moderate weight or recovering faster between sets) than longer ones. But other studies didn't find any differences.

This could be related to the number of reps used. Studies showing better resistance used higher reps/shorter rest versus lower reps/longer rest. Shorter rest paired with higher reps (12-25+) is likely effective at improving muscle resistance more than low-moderate reps (1-8ish) with long rest intervals.

The Two Pathways to Hypertrophy

Let's take a quick detour that will help us understand how to appropriately select rest intervals. There are two main pathways that can stimulate growth:

The Mechanical Pathway

The mechanical pathway refers to what happens when you impose a large mechanical stress on the muscle fibers. We're talking mostly about micro-trauma/damage and mTOR activation in response to stretching a muscle fiber that's producing a high amount of tension.

The more tension you produce, and the more you lengthen a muscle fiber while it's still under maximal tension, the more damage and mTOR activation you create. This gives you a more effective rep from a growth-stimulation perspective.

Then you need a sufficient number of reps in your set to make it maximally effective. Sets of 1-4 reps produce a lot of damage per rep due to the very high tension, but there aren't enough reps in a set to lead to maximal growth stimulation.

That's why sets of 5-12 reps are best when it comes to the mechanical pathway. It's heavy enough to have the tension required to cause damage, but not so heavy that you can't accumulate enough reps.

You also need to use the fullest range of motion possible while keeping the tension on the muscle throughout that range. Releasing the tension (like when you're doing the eccentric/negative phase too fast) will diminish the effectiveness of the rep.

The Metabolic Pathway

The metabolic pathway refers to the release of various substances that can have anabolic properties or play a role in facilitating growth. For example, growth hormone, IGF-1, MGF, and lactate.

This pathway requires you to accumulate lactate. Lactate itself is helpful by lowering myostatin. Lactate is also the stimulus for raising GH and IGF-1.

Sets lasting 40-70 seconds under tension are favored here because that's the zone where you'll start to accumulate a lot of lactate. This approach is thus much less dependent on the weight used. It will work as long as it's heavy enough to make the set hard for 40-70 seconds.

The metabolic pathway also doesn't rely as much on full-range movements. In fact, in many cases a slightly truncated range of motion is helpful if it helps keep the muscle under constant tension.

For example, the bottom one-third of a lateral raise has almost zero tension. It's better to not go all the way down to maximize lactate accumulation. When a muscle relaxes, lactate can be pulled out of it (and brought to the liver), making it harder to accumulate.

Hypertrophy Pathways and Rest Intervals

The weight you use is key in the mechanical pathway. More weight means more tension which leads to more muscle damage (if you maintain the full range).

As such, longer rest intervals are more effective. A full recovery between sets will allow you to maintain more weight from set to set. On the other hand, a shorter rest period with incomplete recovery will force you to lower the weight from set to set, making each set less effective from the standpoint of muscle damage/mTOR activation.

When focusing on the mechanical pathway, you should...

Use multi-joint movements, or the exercise that allows you to use the most weight.
Use the fullest range of motion possible.
Keep the eccentric/negative under control to maintain the tension throughout the whole range.
Use longer rest intervals. Three minutes is the norm. Go up to 4 minutes for more demanding exercises (squats). Decrease the rest interval a bit for less stressful movements (pulley or machine exercises).

With the METABOLIC pathway, the weight used isn't that important. The key is to accumulate a lot of lactate with each set.

If you opt for this pathway, you should...

Use more isolated exercises where you can really focus on flexing a specific muscle.
Keep the tension. If you release tension, blood can come out of the muscle, bringing lactate with it and making it harder to accumulate.
Use shorter rest intervals. If you rest only 30-60 seconds, you won't clear out all of the lactate produced in the preceding set, making it easier to accumulate it on your next set.

Because we normally use smaller, more isolated exercises for the metabolic pathway, the higher cortisol production we get from the short rest intervals won't be as large or impactful.

Normally, incomplete recovery will negatively affect motor control, but with isolation or machine exercises that's a non-issue. The motor skill required to do the movement is super low.

Pros and Cons of Each Rest Period

The Pros of Long Rest Intervals

Allow you to lift heavier
Less cortisol production
Less psychological strain
Lower chance of technique degradation and injury

The Cons of Long Rest Intervals

Can lead to a drop in motivation or get you out of the zone
Can lengthen workout time
Decreases the efficacy of the metabolic hypertrophy pathway

The Pros of Short Rest Intervals

Makes it easier to accumulate lactate and release more growth hormone and IGF-1
Can improve resistance to a greater extent
Can help you get amped up; easier to stay "in the zone"
Can shorten the workout when you don't have much time to train
Could potentially help with fat loss from the GH production and higher cortisol/adrenaline

The Cons of Short Rest Intervals

Makes it harder to maintain performance from set to set, especially in the moderate rep zone (5-12)
Increases psychological strain with maximal lifting
More likely to cause technique degradation; greater risk of injuries
Leads to more cortisol which could be problematic if you're doing a high volume of work already

When To Use Longer Rest Intervals

The following conditions or objectives favor the use of longer rest intervals for better results. We're talking 3 minutes on average, sometimes up to 4 or 5 minutes.

Fairly heavy lifting in the 5-12 range on multi-joint movements.
Maximal or near-maximal lifting, mostly to lessen the psychological impact.
Between sets of exercises with a high skill component (Olympic lifting variations, free-weight multi-joint exercises).
During deloads. Longer rest intervals lower cortisol and adrenaline, which is what you want during a deload. You can decrease the training stress by using long rest periods even between sets of minor exercises.

As mentioned, one drawback of long rest intervals is that they can take you out of the zone. The reason? Cortisol and adrenaline production are lower when you take ample rest between sets. Adrenaline increases neurological activation which makes you more motivated and excited. For those who crave adrenaline, long rest periods can be boring.

It's important for adrenaline junkies to stay intellectually involved during their rest periods. They should reflect on the preceding set, think about what they need to do different on the next set, or do some mental rehearsing.

When To Use Shorter Rest Periods

Here are situations or objectives where using short rest periods can be used effectively. In this case, we're talking about 1 minute or less.

When doing higher reps (time under tension of 40-70 seconds) mostly on isolated or machine exercises.
If your goal is to increase resistance. This also requires higher reps (12 or more). Multi-joint exercises can be used, but ideally on machines or pulleys.
To amp up your nervous system. For example, doing your ramp-up/preparation sets on a big lift with short rest periods and then lengthening rest periods when you're up to the heavier work sets.
As part of a 3-4 week block. You can break the rules and take short rest periods with moderate/high reps even on multi-joint lifts to maximize overall lactate production. This can provide a novel training stimulus that leads to rapid growth, but it stops working after 4-5 weeks.
In a low-volume circuit where you work different muscle groups/regions from exercise to exercise.
If you specifically need to train someone to be better at maintaining a high force production with short rest periods, like a football player who only has 30-45 seconds between plays. But this should be limited to the last or next-to-last phase before their season.
With low-volume sessions. This sounds counterintuitive. After all, shorter rest periods will decrease workout time. It would seem logical to use shorter rest periods with high volume workouts because these sessions are much longer already.

That's true, but a higher training density (shorter rest periods) and a higher volume both increase cortisol production during the workout. That's why using both short rest and high volume can lead to too much cortisol production (decreasing growth). A low-volume workout leads to less cortisol and using shorter rest periods won't put you over the edge.

Don't Neglect Rest Period Programming!

It can make a significant difference in training effectiveness. Rest periods need to be adjusted to your training approach and your objective. It's just as important as other training variables.

You wouldn't "wing" exercise selection, sets, reps, or training methods. Why would you "wing" rest intervals which plays an equal role in your progress?

References

Campos, G.E., Luecke, T.J., Wendeln, H.K. et al. Muscular adaptations in response to three different resistance-training regimens: specificity of repetition maximum training zones. Eur J Appl Physiol 88, 50–60 (2002)
Freitas de Salles, B., Simαo, R., Miranda, F. et al. Rest Interval between Sets in Strength Training. Sports Med 39, 765–777 (2009)
Jozo Grgic, Bruno Lazinica, Pavle Mikulic, James W. Krieger & Brad Jon Schoenfeld. The effects of short versus long inter-set rest intervals in resistance training on measures of muscle hypertrophy: A systematic review, European Journal of Sport Science, 17:8, 983-993 (2017)
Buresh, Robert; Berg, Kris; French, Jeffrey The Effect of Resistive Exercise Rest Interval on Hormonal Response, Strength, and Hypertrophy With Training, Journal of Strength and Conditioning Research: - Volume 23 - Issue 1 - p 62-71 (2009)
Schoenfeld, BJ, Pope, ZK, Benik, FM, Hester, GM, Sellers, J, Nooner, JL, Schnaiter, JA, Bond-Williams, KE, Carter, AS, Ross, CL, Just, BL, Henselmans, M, and Krieger, JW. Longer interset rest periods enhance muscle strength and hypertrophy in resistance-trained men. J Strength Cond Res 30(7): 1805–1812, 2016