Keys to Building Muscle Part 1: Training | Episode 17

How do muscles actually grow — and what really matters for hypertrophy?

In this episode, I break down muscle growth from the ground up, starting with muscle structure and working all the way through the practical training variables that actually drive hypertrophy.

We cover how muscle fibers are built, why muscle cells are uniquely multi-nucleated, and how satellite cells and myonuclei influence growth potential and long-term adaptations (including the concept of “muscle memory”). From there, we dig into how resistance training shifts net protein balance, why muscle protein synthesis and breakdown both rise with training, and why hypertrophy is often delayed when people first start lifting.

A major focus of this episode is mechanotransduction — how mechanical loading from resistance training is converted into chemical signals that stimulate muscle growth. We unpack what we know (and don’t know) about mTOR signaling, phosphatidic acid, kinase pathways, and why mechanical tension is the primary driver of hypertrophy.

From there, the episode gets highly practical. We break down:

• Why proximity to failure matters more than load

• How volume really works (and why “dose-dependent” doesn’t mean linear)

• The role of training frequency and how to distribute volume

• Why stretch and lengthened positions matter for growth

• Load and rep ranges for hypertrophy vs strength

• Exercise selection, machines vs free weights, and compound vs isolation lifts

• Rep tempo, intensity techniques, and what doesn’t meaningfully affect growth

• Why systemic hormone spikes from training don’t predict hypertrophy

I close with clear, evidence-based takeaways you can actually apply: how hard to train, how much volume most people need, when failure makes sense, how to structure exercises, and how to prioritize effort, recovery, and adherence over gimmicks.

If you want a science-based framework for building muscle — without myths, hype, or unnecessary complexity — this episode lays it out step by step.

Muscle structure & function

Muscles are bundles of fibers. Each fiber is an individual cell

Fibers have a heterogeneous structure. 1
- Sarcoplasm
- Sarcolemma
- Sarcoplasmic reticulum
- Myonuclei
Fibers are unique as they are one of the only multi-nucleated cells in the body. 1
- Myonuclear domain theory
  - Each myonuclei controls protein synthesis for a specific surface area. 2 3
    - Muscular hypertrophy can increase myonuclear domain, indicating increased transcriptional capacity but it is believed this is capped. 4
    - Larger type II fibers have larger myonuclear domains whereas smaller type I oxidative fibers have smaller myonuclear domains. 5
- Satellite cells
  - Sit between the sarcolemma on the cell surface & the basal lamina sheath. 1 2
  - These cells can fuse to form new myonuclei. 2
  - It is thought that satellite cell number may predict muscle potential. 5
  - Resistance training increases satellite cell fusion & myonuclei number. 6
  - Anabolic steroids increase satellite cell fusion. 7
- Fusion of new myonuclei increases the capacity for protein synthesis. 3
  - May explain ‘muscle memory’
    - Once a myonuclei fuses, it is unlikely to unfuse during atrophy unless the reduction in stimulus is longer term. 8 9
    - Mice treated with testosterone retained more myonuclei and increased muscle mass faster (31% faster) when returning to resistance training compared to mice never treated with testosterone. 10
  - Implications for drug testing in sports. 6
  - Implications for trans athletes as males have more satellite cells than women. 11
Fibers consist of a myriad of different proteins with sarcomeres as the contractile units of muscle fibers arranged in sequence. 12
- Main contractile proteins are actin & myosin. 11
- Actin is anchored to the Z disk. 11
- Myosin is attached to the M band in the middle of the sarcomere.¹¹ It is also anchored by an enormous protein called Titin that spans the length of the sarcomere from the Z-disk to the M band & provides stability while anchoring myosin in place. 11
- Cross-bridging of actin & myosin causes contraction. 11

Figure 13

Muscle growth

Referred to as Muscle Hypertrophy (there is also hyperplasia)

Increase in muscle cell size
- Can be due to increase in myofibrillar components, cytoplasmic proteins, mitochondria, or fluid
For muscle hypertrophy to occur, there must be increased deposition of protein or an increase in Net Protein Balance (NPB)
- NPB is the balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB)
- NPB = MPS – MPB
Resistance training increases both MPS & MPB. 14 15 16
Untrained individuals incur a greater increase in MPB compared to trained individuals. It is thought this increased MPB is to facilitate remodeling of skeletal muscle & may be why hypertrophy from resistance training has a slightly delayed effect when people begin. 16
Trained individuals have a similar peak response of MPS to training but the effect is a much shorter duration than untrained individuals. 17

Figure 18

What causes muscles to grow?

Mechanotransduction: MPS must > MPB but the stimulation of MPS & protein turnover is a chemical signal. Somehow, the mechanical stimulus of resistance training must be converted into a chemical signal that activates cellular protein turnover. This is mechanotransduction (MTD)

The mechanisms involved in MTD are not well understood
- It is well established that mechanical loading from resistance training increases the activation of mTORC1, which increases MPS through translation initiation.
  - It is less clear how mTORC1 is activated from mechanical stimuli
  - It is thought to involve the formation of phosphatidic acid (PA) in the costamere of the Z-disk. PA has been demonstrated to stimulate mTORC1 activation. 19 20
  - In parallel, mechanical stimuli also activate RAS kinases & a subsequent signaling cascade that activates ERK1/ERK2, which subsequently activate p90S6K & MNK1. MNK1 can phosphorylate eIF4G, increasing the formation of eIF4F, the rate limiting step of translation initiation. p90S6K phosphorylates 4E-BP1 & rpS6, both of which increase translation initiation. 21
- There is also evidence that mechanotransduction may occur through ion channels but this is poorly understood. 22

What is the most important factor to create this? Mechanical tension

Other factors may matter for growth, such as metabolic stress, muscle damage, & hormones but these appear to have minimal to no effect on hypertrophy in the absence of sufficient mechanical tension. 23

Figure ²¹

Mechanical tension

Forces placed on the muscle

Active tension – when muscles are contracting from cross bridges between actin and myosin
Passive tension – when muscles are being stretched

How to initiate mechanical tension

Requires sufficient intensity, ie, proximity to failure
Mechanical tension is cumulative throughout a set, training session, & training sessions

The importance of intensity for hypertrophy

Research demonstrates greater hypertrophy with sets taken closer to failure. 24
- Interestingly, strength gains do not appear to be dependent on proximity to failure. 24
Reaching absolute muscular failure does not appear to be a requirement for maximizing muscular growth, but getting within a few reps appears critical. 25 26 27
Most people do not understand where their true failure is and even trained individuals underestimate their point of failure by 5-6 reps in research studies. 28

Training volume

Volume Load = weight lifted x reps x sets.
Better definition of volume = number of hard sets (sets of sufficient intensity, close to failure)
Meta-analysis clearly show superiority of multiple hard sets vs. single hard sets on muscular hypertrophy. 29
If intensity is the drug, volume is the dose of the drug
Higher training volumes appear to increase hypertrophy in a dose-dependant manner. 30 31 32
Dose-dependent does not mean linear. The majority of the hypertrophic response occurs in the first few sets with increasing hypertrophy with subsequent sets, but diminishing returns. As of now, we have yet to see a hard ‘cap’ for hypertrophy with training volume.

Figures 32

Figure courtesy James Krieger 33

Frequency

Training frequency appears less important for hypertrophy compared to intensity & volume. There is a trend towards better hypertrophy with more frequency, but it appears that frequency is primarily a tool to distribute volume, but some studies demonstrate better hypertrophy with 2x/week frequency vs 1x/week frequency for body parts even when volume & intensity are equated. 34
Interestingly, strength appears to have a greater relationship with training frequency than hypertrophy. 32
There is evidence that the per session hypertrophy response caps out at 6-12 sets for a body part with no further hypertrophy or stimulation of MPS beyond this point.
- This appears to be impacted by rest periods. Shorter rest periods (<2 min between sets) require more sets to maximize hypertrophy in a session (~12) while longer rest periods (>2 min between sets) appear to maximize hypertrophy around 6 sets in a session per body part. 35
- This is in alignment with MPS data demonstrating the MPS response to training appears to cap out around 6-12 sets per body part in both humans and rodents. 36 37
- It may be useful, therefore to limit sessions to ~10 sets per body part & gain additional training volume through additional sessions/frequency

Figures courtesy James Krieger 33

Muscle stretch

Numerous studies have demonstrated full range of motion (ROM) training is superior to partial ROM training in a shortened position. 38
However, when partial ROM is performed in the lengthened position, it produces similar hypertrophy to full ROM training. 39 40
Static stretching has also been demonstrated to induce hypertrophy in the absence of load. 41 42 43
Thus, in addition to load, stretch may be an important component of mechanical tension to induce hypertrophy

Load & reps

Differences in load do not appear to produce differences in hypertrophy when set volumes & intensity are equated between treatments over a wide range of repetitions (30-90% of 1RM, around ~3-30 reps) while gains in maximal strength appear to be load dependent. 44 45
This indicates that mechanical tension is cumulative & the hypertrophy can be induced by a wide range of repetitions.
While prevailing thinking was that slow twitch muscles may respond better to low load, high rep training & fast twitch muscles may respond better to high load, low rep training, there appears to be no difference in hypertrophy between these muscles when volume & intensity are matched. 46
This is supported by muscle activation data demonstrating similar activation of muscles regardless of load used when sets are taken to failure. 47

Exercise selection and order

There don’t appear to be any MUST DO exercises.
Various exercises for body parts appear to result in similar overall hypertrophy.
- Compound exercises appear to produce similar overall hypertrophy to isolation exercises when volume and intensity are matched. 48 49
  - While overall hypertrophy is the same, there may be regional differences in muscle hypertrophy with compound vs. isolation exercises. 50
- Compound exercises appear to produce more muscle activation at similar relative intensity and may produce greater strength. 49 51
- Machines produce similar hypertrophy to free weights when volume and intensity are matched. 52
Exercise order also appears not to make a difference for muscle hypertrophy when volume & intensity are matched. 53
- Regional hypertrophy differences were found with mid-quad thickness being greater in subjects who did a compound leg exercise before an isolation exercise, however. 54
It likely makes sense to therefore include a diverse array of exercises, both compound & isolation, to maximize hypertrophy while deferring to individual personal preferences to maximize adherence.

Rep Tempo

Rep tempo does not seem to matter much for hypertrophy as muscle growth is similar for rep durations of 0.5-8s. 55
Rep tempo does not seem to matter unless they are extremely short or extremely long, with both producing less hypertrophy, though long reps may reduce muscle strength, especially slow concentric reps. 56
Slow eccentrics also do not appear to influence hypertrophy as slow eccentrics of >2s produce similar results as fast eccentrics of <2s, and they both produce similar strength gains, but slow eccentrics were worse for jump performance. 57

Other things that appear to result in no difference in hypertrophy when volume & intensity are matched:

Periodization. Although strength gains are better with periodized programs compared to non-periodized programs. 58
- Undulating periodization outperformed linear periodization in trained lifters.
Intensity techniques: drop sets, supersets, rest pause, pre-exhaust, eccentric overload, and forced reps appear to produce similar hypertrophy when volume is matched and sets are sufficiently intense 59 60 61 62 63

Systemic hormones & hypertrophy

For many years the prevailing thought was that the systemic rises in testosterone, growth hormone (GH), & insulin-like growth factor-1 (IGF-1) were the drivers of muscular hypertrophy.
Recommendations included training large movements like squats in order to grow other body parts since large compound movements may result in greater hormonal responses.
These rises in hormones are very short in duration (1-2 hours)
Research has overwhelmingly demonstrated that acute rises in hormones from training do not predict hypertrophy or strength gains. 64 65
- In fact, it is only the acute rise in cortisol in response to resistance training that has any association with hypertrophy. 66

Practical takeaways

Perform sets of sufficient intensity

Most sets should be performed within ~2 reps of failure
Isolation exercises should be taken closer to failure while compound exercises may be able to achieve similar results slightly further from failure
Taking sets to absolute failure should be reserved for the final set of an exercise & preferably isolation exercises

Perform enough volume ie enough hard sets for your goal

Most hypertrophy benefits can be achieved with 4-6 hard sets per week per body part
For maximal hypertrophy, it may be necessary to exceed 20 sets per week for a muscle growth & possibly more
It may be useful to distribute high set numbers over multiple training days & there is evidence that multiple training days per week frequency is superior to a single day

Take a muscle into a stretched position

Either full ROM or lengthened partials
Shortened partials are inferior

Exercise selection & order

Use a variety of compound & isolation exercises to maximize hypertrophy
Prioritize compound exercises first
Use exercises that the individual enjoys

Other

Rep tempo should be fast enough to use a good load but slow enough to be in control of the weight
Use a variety of repetition ranges for novelty & hypertrophy
Prioritize lower rep movements with compound exercises & higher rep movements with isolation exercises
Utilize opposing muscle supersets to cut down on time
While no impact on short-term hypertrophy, varying rep schemes & programming strength-specific phases may possibly lead to longer-term improvements. Using periodization may help facilitate this

References

Intro
Muscle Function
Muscle Fibers
Satellite Cells
Myonuclei Fusion
Drug Testing Implications
Lifetime Natty
Trans Athletes
Workout Builder
Sarcomeres
Hypertrophy vs Hyperplasia
Increase in Muscle Cell Size
Net Protein Balance
Muscle Protein Breakdown
Mechanotransduction
Biochemical Explanation
Mechanical Tension
Training Intensity
Muscular Failure
Team Biolayne
Training Volume
Training Frequency
Muscle Stretch
Load & Reps
Exercise Selection & Order
Rep Tempo
Other Considerations
Systemic Hormones
Practical Takeaways
Outro