Simon, great to see you contributing! You actually brought up where I was going to eventually go with my line of reasoning, which is basically the external load's role in what we had previously called the "repeated bout effect." The idea that our muscle tissue somehow gets conditioned to some combination of factors that we're using in our attempt to induce growth. It might help to re-look at the basic HST model again.
We start by strategically deconditioning. Regardless of what we call it (repeated bout effect, anabolic resistance), doing the same thing over and over will eventually result in diminishing returns in terms of hypertrophy. I know there's research showing that ~2 weeks off does seem to upregulate some of the mTOR stuff, and I've long seen SD's as a potential route of helping to get satellite cell donation going again. I'm not actually totally sold on SD being necessary, but let's say for the sake of argument it is working on some level.
So after our SD, we find an entry point that is a strong enough stimulus to start growing again. Where exactly this is is hard to say, but at higher reps and conventional sets/reps (more on this in a minute), something like ~60% of 1 RM seems reasonable, and where lots of HST type cycles begin. So let's use 12's at ~60% 1 RM as our thought experiment. We could pretty easily do 3 sets of 12, though after a break, this wouldn't be that easy. For the sake of argument, say this is our context, 3 working sets of 12 for 2-3 weekly sessions for a muscle group. Assuming something tantamount to RBE is happening, and that our hypertrophic stimulus will diminish the next session if we just stick to the same weight/reps/sets, how do we increase the hypertrophic stimulus? This is really the context I had in mind with my thought experiment. If per-fiber tension increases with an increase in external loading, then the original HST model still makes sense. Or stated differently, would 3 sets of 12 with, say, 62% of 1 RM, be a stronger stimulus than 3 sets of 12 with 60% 1 RM if we had already just done a session of 3 sets of 12 with 60% 1 RM? If the per-fiber tension increases by bumping up to 62% and something like RBE diminishes our returns from repeating 60%, I think you can make a case that it is. So this is the basic pattern in HST, with intentionally submaximal training, the stimulus every training session in theory raises just a little to make sure that we're getting the most bang for our buck as possible.
However, context matters a lot, and this is where I'll try to tie in Ron's thoughts. We definitely don't know that higher per-fiber tension actually results in more muscle protein synthesis out of context. But, the HST argument isn't that heavier is better out of context, otherwise we might just start with 80% 1 RM. This is a relative thing, and this is where the concept of tissue conditioning is really important. It's not that 80% is "better" than 60% if both are taken near failure. It's that 60% was good enough, and in a given context of sets/reps, increasing the load might represent an increase in stimulus, which is really what we're after. If we started at 80% 1 RM, we don't have much room to keep increasing the load and having things stay practical. So it's not about heavier = better, it's about finding a way to structure our training such that we have a strong enough stimulus to start a mesocycle, and we find a way to consistently raise that stimiulus.
As Ron noted, as well as Totentanz, with something like Gironda or myoreps, a lot of people see new growth again despite using much heavier loads previously. We also saw that in one of the Kaatsu studies if I recall, powerlifters who habitually used fairly large workloads at heavy weight saw a strong increase in satellite cell activity etc. doing a shitload of high rep kaatsu training. I believe this and am not arguing against it. The problem is that we've now completely changed our context. You can think of it as volume, total effective reps, or even density (effective reps per unit time), but regardless, it's hard to compare this to more conventional sets/reps as we're changing a lot more than just load. I'll illustrate this even further.
With conventional sets and reps, think of our 3 sets of 12 again. How many "effective" total reps (in myoreps terminology, i.e. reps definitely at full recruitment with high rate coding) did we get? If it's like ~5 per set optimistcally, that's 15 total effective reps. However, with a Gironda 8 x 8 with short rest times, we might have multiples of that. Ditto myoreps, we might have 20 + 5 + 5 + 5 + 5 + 5 or something, probably at least double our conventional sets and reps. So while we lost some load, which might be part of the hypertrophic equation, we may have enormously increased the total effective reps, which might work out to be a much stronger overall stimulus.
So, the way I'm looking at this, I'm not sure how easy this is to compare to conventional sets/reps. Maybe myoreps or Gironda style training is just a better overall context (effective reps) to really target hypertrophy. So the question isn't whether 3 sets of 12 at heavier weight is better than Gironda or myoreps at a lighter weight, to me the question is, if we did a cycle of Gironda style or myoreps, would increasing the load in that context once again raise the hypertrophic stimulus? If it does, then HST logic is still back on the table. Because HST logic isn't about absolute loading being superior to lighter loading out of context, it's more about finding a sufficient stimulus relative to our tissue conditioning (which we intentionally lower via SD) to start a training mesocycle, and then finding a way to consistently add to that stimulus in a way that assures we're growing as fast as possible.
That all make sense?