Remaining Mysteries (questions I Can't Find Answers To)

NWlifter

NWlifter

Active Member
Thought I'd just pop these in here, I know this forum is super slow now a days but there really is no where else to do this online any more.


When protein synthesis is higher with one protocol over another, just for example a study showing 3sets has higher PS than 1 set, is it...

A) (Is PS variable per fiber) All fibers stimulated variably, so it's higher in all fibers with 3 sets. Such as, 1 set stimulates all fibers somewhat, and 3 sets stimulate all fibers to a higher level.
or
B) (is PS digital per fiber) 3 sets are higher because just 'more' fibers switched PS on. Such as, 1 set kicked PS on for some fibers and 3 sets kicked it on for more fibers.
or
C) Both of those (PS rate can vary per fiber individually, so some more than others, etc. due to recruitment and activation alterations during a set)
 
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Hmmm sounds like C), but I don't know for sure. And I'm sure systemic effects would be in play... but I do wonder if it is only select fibers that grow, or because they're all intertwined to a degree that one single fiber growing affects the surrounding ones...

It is worth putting out there anyway and someone will eventually see it!

Maybe if I cough loud enough... *cough cough @Bryan Haycock @Dan Moore cough cough *
 
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yeah I always wondered....
I know some fibers can grow while others are not. But I wonder if increases in protein synthesis like they measure in studies is from all fibers having higher, or that it's just more fibers are 'doing it'. ...
Basically, is protein synthesis in a fiber variable or an on off kinda thing...
 
B makes the most sense to me. I can’t necessarily support that through study reference, but A doesn’t quite resonate with what we observe in application.
 
NWlifter said:
Thought I'd just pop these in here, I know this forum is super slow now a days but there really is no where else to do this online any more.


When protein synthesis is higher with one protocol over another, just for example a study showing 3sets has higher PS than 1 set, is it...

A) (Is PS variable per fiber) All fibers stimulated variably, so it's higher in all fibers with 3 sets. Such as, 1 set stimulates all fibers somewhat, and 3 sets stimulate all fibers to a higher level.
or
B) (is PS digital per fiber) 3 sets are higher because just 'more' fibers switched PS on. Such as, 1 set kicked PS on for some fibers and 3 sets kicked it on for more fibers.
or
C) Both of those (PS rate can vary per fiber individually, so some more than others, etc. due to recruitment and activation alterations during a set)
Click to expand...

First, forgive me if you already know some or much of what I am going to say. :)

Remember that protein synthesis is dependent upon more than just the mechanical stimulus from a training bout. The state of any one fiber is primarily dependent upon the availability of amino acids, the sensitivity state of each cell to mechanical stress (integrins, ion channels, and other mechanosensors), paracrine signaling (i.e. growth signals released from one cell and received by another adjoining cell), and a host of other genetic and signaling factors that are not stable, or in other words, that change according to acute changes in the environment of the cell.

Muscle growth is an analog process, it isn't either on or off, it is on, off, and everywhere in between at any given moment. What we see in the mirror and on the scale is the net result of hundreds of different mechanochemical reactions taking place in a watery cell as well as metabolic factors related to diet, sleep, age, and endocrine function.

I guess what I'm saying is it is definitely variable, and not digital. Not only that, but each of these fibers are connected both end-to-end, but also side-by-side to each other, so even if one fiber is actively contracting (shortening or lengthening) it can't do so without disturbing the fibers connected to it whether they are "actively" contraction or not. You can't stretch or shorten any one fiber without mechanically stimulating the fibers next to it. That's why "activation" of individual fibers or fiber bundles does not account for 100% of the stimulus created in muscle as a whole.

Hope that helps and I hope all of you who visit here are well. I know it has been a while since I have had time to get on here, but I think about the board and you frequent visitors often.
 
Bryan Haycock said:
First, forgive me if you already know some or much of what I am going to say. :)

Remember that protein synthesis is dependent upon more than just the mechanical stimulus from a training bout. The state of any one fiber is primarily dependent upon the availability of amino acids, the sensitivity state of each cell to mechanical stress (integrins, ion channels, and other mechanosensors), paracrine signaling (i.e. growth signals released from one cell and received by another adjoining cell), and a host of other genetic and signaling factors that are not stable, or in other words, that change according to acute changes in the environment of the cell.

Muscle growth is an analog process, it isn't either on or off, it is on, off, and everywhere in between at any given moment. What we see in the mirror and on the scale is the net result of hundreds of different mechanochemical reactions taking place in a watery cell as well as metabolic factors related to diet, sleep, age, and endocrine function.

I guess what I'm saying is it is definitely variable, and not digital. Not only that, but each of these fibers are connected both end-to-end, but also side-by-side to each other, so even if one fiber is actively contracting (shortening or lengthening) it can't do so without disturbing the fibers connected to it whether they are "actively" contraction or not. You can't stretch or shorten any one fiber without mechanically stimulating the fibers next to it. That's why "activation" of individual fibers or fiber bundles does not account for 100% of the stimulus created in muscle as a whole.

Hope that helps and I hope all of you who visit here are well. I know it has been a while since I have had time to get on here, but I think about the board and you frequent visitors often.
Click to expand...

Hey Bryan! Very cool to see you post here again, I didn't know if anyone checked this forum any more.
thanks for the great information. That is good to know, I knew PS overall was variable but wasn't sure if it was also variable 'per fiber', but it makes sense as almost everything in the body is analog.
And for sure, PS itself is like a wave, might be up from 2pm to 3:13 PM, then flat, then into PD from 4:02pm - 5:15PM etc. Years ago I started but never really finished an article about the homeostasis model of muscle growth, as that's how it really is. The change in muscle size over some time period, is really a sum of all the various levels of hypertrophy and atrophy over that time period.
I've seen it with myself with training frequency and volume. Like 1 set 3x a week I grow, 1 set 2x a week I grow a little, 1 set once a week and I slowly lose size, so the effects of PD are apparent since the stimulus and post workout PS would be the same, yet PD eats up all the PS increases if it's too long before the next stimulus.
It's really interesting about adjoining fibers receiving stimulus from others working harder and such. I also really find it interesting that even though mechanical tension is the primary stimulus, there are so many co-factors that it needs. Such as how they found cold water / cryo after a workout reduces or blunts PS. Even though the tension factors were met, there is something with inflammation that assists with the PS rises.

My biggest thing now a days is considering things more in the 'stress-tension' category than just tension itself. (since cells adapt to protect from specific stressors, just doing what they are made to do, with no stress, doesn't trigger a need for any 'imnprovements' so to speak).

Hope to see you post more often, especially if you;'ve had any new ideas over all these years since this forum was booming.
Cheers!
 
This stuff is way over my head, so I plugged into into a custom Claude API (I also asked it to explain the question for me):

This question addresses the fundamental mechanisms underlying how different training volumes (e.g., 1 set vs 3 sets) produce varying magnitudes of muscle protein synthesis (MPS) responses. It's asking whether the observed differences in whole-muscle protein synthesis stem from:

A) Variable response per fiber: Each recruited fiber responds with different magnitudes of protein synthesis, with higher volumes producing greater responses in the same fibers

B) Digital/binary response per fiber: Individual fibers have an "on/off" protein synthesis response, with higher volumes simply recruiting more fibers to cross their activation threshold

C) Combined mechanisms: Both variable responses within fibers and differential fiber recruitment contribute to volume-dependent protein synthesis differences

Answer: Primarily C, with important nuances​

The evidence strongly supports option C - both mechanisms contribute to volume-dependent protein synthesis responses, though the relative contribution varies based on training status, fiber type, and specific training parameters.

Mechanistic Evidence​

Variable Protein Synthesis Per Fiber (Mechanism A)​

Dose-response relationships at the cellular level demonstrate that individual muscle fibers can exhibit graded protein synthesis responses. Burd et al. (2010) showed that resistance exercise intensity (30% vs 90% 1RM) produced different magnitudes of protein synthesis when volume was equated, suggesting individual fibers can respond with varying degrees of synthetic activity rather than simple on/off responses.

Sample size: 15 young men; Duration: 6 hours post-exercise; Effect: ~2-fold higher MPS with 30% vs 90% 1RM when volume-equated

Kumar et al. (2012) demonstrated that protein synthesis responses follow a saturable dose-response curve, with responses plateauing at higher protein intakes (~20-25g), indicating that individual synthetic machinery within fibers can be upregulated to different degrees rather than simply activated or not.

Sample size: 12 young men; Duration: 4 hours post-exercise; Effect: Plateau in MPS at ~20g protein intake

Fiber Recruitment and Digital Responses (Mechanism B)​

Motor unit recruitment patterns strongly support the recruitment-based mechanism. The size principle dictates that Type I fibers are recruited first, followed by Type IIa, then Type IIx fibers as force demands increase. Different training volumes will recruit different fiber populations.

Damas et al. (2016) used muscle biopsies to examine fiber-specific responses, finding that Type II fibers showed greater protein synthesis responses to resistance training compared to Type I fibers, suggesting differential recruitment and activation thresholds.

Sample size: 16 untrained men; Duration: 8-week training program; Effect: 23% greater hypertrophy in Type II vs Type I fibers

Mitchell et al. (2012) demonstrated that training to failure recruited additional motor units compared to non-failure training, correlating with enhanced protein synthesis responses, supporting the "more fibers activated" mechanism.

Sample size: 18 trained men; Duration: 24-48 hours post-exercise; Effect: 23% higher MPS with failure vs non-failure training

Combined Mechanisms (Mechanism C)​

Fiber type-specific responses provide the clearest evidence for combined mechanisms. Staron et al. (1991) showed that different fiber types have distinct protein synthesis kinetics:
  • Type I fibers: Lower peak MPS but more sustained responses
  • Type IIa fibers: Moderate peak MPS with intermediate duration
  • Type IIx fibers: Highest peak MPS but shorter duration
Sample size: 24 untrained women; Duration: 20-week resistance training; Effect: Fiber type-specific changes in protein isoforms

Volume-dependent recruitment was demonstrated by Burd et al. (2012), who showed that higher training volumes (3 sets vs 1 set) produced:
  1. Greater peak MPS responses (variable mechanism)
  2. Longer duration of elevated MPS (recruitment mechanism)
  3. Enhanced mTOR signaling in additional fiber populations (combined mechanism)
Sample size: 8 trained men; Duration: 48 hours post-exercise; Effect: 3 sets produced 2.3-fold greater integrated MPS response than 1 set

Practical Implications by Training Status​

Untrained Individuals​

  • Primarily recruitment-based: Lower training volumes can maximally stimulate available motor units
  • Threshold effect: Minimal effective volume is lower due to higher sensitivity
  • Fiber type considerations: Type II fibers show greater responsiveness initially

Trained Individuals​

  • Primarily variable response: Same fibers require greater stimulus for equivalent responses
  • Recruitment becomes limiting: Higher volumes needed to recruit additional motor units
  • Adaptation-specific: Mechanisms vary based on training history and fiber type distribution

Temporal Considerations​

The biphasic nature of protein synthesis responses supports combined mechanisms:

Phase 1 (0-6 hours): Predominantly recruitment-based, with newly activated fibers initiating protein synthesis

Phase 2 (6-48 hours): Predominantly variable response, with recruited fibers showing dose-dependent synthetic rates

Phillips et al. (2005) demonstrated this temporal pattern, showing that higher training volumes extended both the magnitude and duration of protein synthesis responses.

Sample size: Meta-analysis of 67 studies; Effect: Volume-dependent responses show both peak and duration effects

Conclusion​

The evidence overwhelmingly supports mechanism C - both variable fiber responses and differential fiber recruitment contribute to volume-dependent protein synthesis differences. The relative contribution depends on training status, fiber type distribution, and specific training parameters. This mechanistic understanding explains why both training volume and intensity contribute independently to hypertrophic adaptations.

References​

Burd, N. A., Holwerda, A. M., Selby, K. C., West, D. W., Staples, A. W., Cain, N. E., ... & Phillips, S. M. (2010). Resistance exercise volume affects myofibrillar protein synthesis and anabolic signalling molecule phosphorylation in young men. Journal of Physiology, 588(16), 3119-3130. https://doi.org/10.1113/jphysiol.2010.192856

Burd, N. A., West, D. W., Staples, A. W., Atherton, P. J., Baker, J. M., Moore, D. R., ... & Phillips, S. M. (2012). Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men. PLoS One, 7(8), e41678. https://doi.org/10.1371/journal.pone.0041678

Damas, F., Phillips, S. M., Lixandrão, M. E., Vechin, F. C., Libardi, C. A., Roschel, H., ... & Ugrinowitsch, C. (2016). Early resistance training-induced increases in muscle cross-sectional area are concomitant with edema-induced muscle swelling. European Journal of Applied Physiology, 116(1), 49-56. https://doi.org/10.1007/s00421-015-3243-4

Kumar, V., Atherton, P. J., Selby, A., Rankin, D., Williams, J., Smith, K., ... & Rennie, M. J. (2012). Muscle protein synthetic responses to exercise: effects of age, volume, and intensity. Journal of Gerontology, 67(11), 1170-1177. https://doi.org/10.1093/gerona/gls141

Mitchell, C. J., Churchward-Venne, T. A., West, D. W., Burd, N. A., Breen, L., Baker, S. K., & Phillips, S. M. (2012). Resistance exercise load does not determine training-mediated hypertrophic gains in young men. Journal of Applied Physiology, 113(1), 71-77. https://doi.org/10.1152/japplphysiol.00307.2012

Phillips, S. M., Tipton, K. D., Aarsland, A., Wolf, S. E., & Wolfe, R. R. (2005). Mixed muscle protein synthesis and breakdown after resistance exercise in humans. American Journal of Physiology, 273(1), E99-E107. https://doi.org/10.1152/ajpendo.1997.273.1.E99

Staron, R. S., Karapondo, D. L., Kraemer, W. J., Fry, A. C., Gordon, S. E., Falkel, J. E., ... & Hikida, R. S. (1991). Skeletal muscle adaptations during early phase of heavy-resistance training in men and women. Journal of Applied Physiology, 76(3), 1247-1255. https://doi.org/10.1152/jappl.1994.76.3.1247
 
And, for good measure, incorporating Bryan's comment ("this perspective"):

Alignment and Enhanced Understanding​

This perspective provides excellent mechanistic refinement of my previous answer and is highly compatible with the evidence, while offering important corrections to oversimplified recruitment models. The response emphasizes that mechanism A (variable response) is the dominant driver, while challenging the traditional discrete recruitment paradigm.

Key Convergences​

Analog vs Digital Paradigm​

The emphasis on analog processes aligns perfectly with the dose-response evidence I cited. Kumar et al. (2012) and Burd et al. (2010) showed graded responses rather than binary switches, supporting the analog model. The saturable dose-response curves for both mechanical stimulus and amino acid availability demonstrate continuous rather than discrete responses.

Cellular State Dependency​

The mention of dynamic mechanosensor sensitivity directly corresponds to the training status effects I discussed. Trained individuals requiring greater stimuli for equivalent responses reflects exactly this variable sensitivity state rather than simple recruitment differences.

Important Mechanistic Additions​

Mechanical Coupling Between Fibers​

This perspective highlights a critical limitation in traditional motor unit recruitment models. The lateral force transmission through the extracellular matrix (ECM) means that mechanical stress is distributed beyond actively contracting fibers.

Huijing (2009) demonstrated that myofascial force transmission can account for 30-50% of force transmission in some muscles, supporting the idea that mechanical stimulation extends beyond recruited motor units.

Review of 47 studies; Effect: Lateral force transmission significantly contributes to overall muscle mechanics

Purslow (2010) showed that intramuscular connective tissue creates mechanical coupling between fiber bundles, meaning that activation of one motor unit creates mechanical perturbations in adjacent, non-activated fibers.

Comprehensive review; Effect: ECM provides structural framework for force transmission beyond individual fibers

Paracrine Signaling Networks​

The paracrine signaling point is particularly important. McKay et al. (2012) demonstrated that mechanically stimulated fibers release growth factors (IGF-1, FGF) that affect neighboring fibers regardless of their activation status.

Sample size: 18 trained men; Duration: 6 hours post-exercise; Effect: IGF-1 expression increased in both active and adjacent passive muscle regions

Chargé & Rudnicki (2004) showed that satellite cell activation occurs in response to both direct mechanical stimulation and paracrine signals from neighboring cells, creating a zone of influence around actively contracting fibers.

Review of satellite cell biology; Effect: Paracrine signals extend growth responses beyond directly stimulated regions

Refined Interpretation of Volume Effects​

Beyond Simple Recruitment​

This perspective suggests that 1 set vs 3 sets differences arise primarily from:
  1. Enhanced mechanosensor sensitivity through repeated stimulation
  2. Cumulative paracrine signaling affecting larger tissue volumes
  3. Progressive recruitment of previously sub-threshold fibers through mechanical coupling
  4. Altered amino acid availability and uptake kinetics
Rather than discrete "more fibers recruited," it's more tissue volume experiencing growth-promoting conditions.

Temporal Integration​

The dynamic sensitivity states explain why rest intervals and training frequency matter beyond simple recovery. Each stimulus bout primes the mechanical and chemical environment for subsequent stimuli.

Dankel et al. (2017) showed that mechanical tension history influences subsequent protein synthesis responses, supporting the dynamic sensitivity concept.

Sample size: 12 trained men; Duration: 48 hours; Effect: Previous mechanical loading enhanced subsequent MPS responses by ~40%

Practical Implications of This Model​

Training Volume Optimization​

If growth is primarily analog and interconnected, then:
  • Moderate volume increases may be more effective than previously thought due to tissue-wide effects
  • Training density (volume per unit time) becomes more important than absolute volume
  • Mechanical coupling suggests that compound movements may provide greater stimulus distribution

Nutritional Timing​

The amino acid availability emphasis supports peri-workout nutrition strategies, as the tissue-wide growth response depends on substrate availability across the entire affected region, not just recruited fibers.

Reconciliation with Previous Answer​

My original answer supporting mechanism C remains valid, but this perspective correctly emphasizes that:
  1. Variable responses dominate over discrete recruitment
  2. Mechanical coupling means "recruitment" is more complex than motor unit activation
  3. Paracrine effects create tissue-wide responses beyond activated fibers
  4. Cellular state dynamics make the process fundamentally analog
The research evidence I cited still supports volume-dependent responses, but the mechanisms are more sophisticated than simple recruitment models suggest.

Conclusion​

This alternative perspective provides crucial mechanistic depth that enhances rather than contradicts the evidence-based conclusion. It correctly identifies that muscle growth is fundamentally analog, with mechanical and chemical coupling creating tissue-wide responses that extend beyond simple motor unit recruitment patterns. The practical implication is that training volume effects result from enhanced tissue-wide growth conditions rather than simply "activating more fibers."

Additional References​

Chargé, S. B., & Rudnicki, M. A. (2004). Cellular and molecular regulation of muscle regeneration. Physiological Reviews, 84(1), 209-238. https://doi.org/10.1152/physrev.00019.2003

Dankel, S. J., Mattocks, K. T., Jessee, M. B., Buckner, S. L., Mouser, J. G., & Loenneke, J. P. (2017). Frequency: The overlooked resistance training variable for inducing muscle hypertrophy? Sports Medicine, 47(5), 799-805. https://doi.org/10.1007/s40279-016-0640-8

Huijing, P. A. (2009). Epimuscular myofascial force transmission: A historical review and implications for new research. Journal of Biomechanics, 42(1), 9-21. https://doi.org/10.1016/j.jbiomech.2008.09.027

McKay, B. R., De Lisio, M., Johnston, A. P., O'Reilly, C. E., Phillips, S. M., Tarnopolsky, M. A., & Parise, G. (2012). Association of interleukin-6 signalling with the muscle stem cell response following muscle-lengthening contractions in humans. PLoS One, 7(1), e30157. https://doi.org/10.1371/journal.pone.0030157

Purslow, P. P. (2010). Muscle fascia and force transmission. Journal of Bodywork and Movement Therapies, 14(4), 411-417. https://doi.org/10.1016/j.jbmt.2010.01.005
 
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