What happens in your cells after you lift?

To cover the obvious, the visceral - existential pain; that embarrassing wail; your involuntary passage of wind…

But, when we lift weights, so much beyond the discernible is set in motion to lift that bar against gravity, and lift it again the week after that. And the week after that. Your body needs to adapt, and your body does so - bigger muscles, more stiff. But inside your cells there’s a bubbling, spinning hive of activity, and here I’ll try to cover some of the stuff that goes on.

The late Dan Dennett, presumably on a blunt rotation, said once that “not a single one of the cells that compose you knows who you are, or cares”, and this is true; cells don’t have brains. So how do our cells “know” we’ve lifted weights, as opposed to, say, walked a marathon? The adaptation to both stimulus does, in the end, differ. Is there a seperate molecular compartment somewhere inside us then - the Popeye compartment - which flashes red and gets to work each time we’ve resistance trained? Well, an analogy might come in useful here.

The analogy that might come in useful here:

Here’s an analogy that might come in useful here: We can imagine the cell as a big chemical factory, with ‘proteins’ running around the factory floor - they’re communicating with each other, as well as doing jobs of their own. The amount of interactions between proteins in the human “interactome” is, well, huge (it’s ooge). With the upper estimates at around 650,000 potential interactions within each cell (Stumpf et al, 2008). Also inside the factory is a big hard-copy room, with huge swathes of instructions for making everything the factory needs. This room is the nucleus, the swathes of instructions are your DNA. And there’s lots of it - if layed out in one long stand, the DNA wrapped up in you would end up further away than Pluto.

When the cell does need something, runners emerge from this hard copy room carrying their own copies of the instructions, which they then take to machines, who crack on making the proteins required.

We’ll keep coming back to this, though bear in mind cells are in fact cells, not factories, and no analogy is perfect :(

Did you lift bro?

After lifting, the first stage in a response would be to sense actual load has been placed on the muscle. Converting a mechanical signal to a biochemical one is called “mechanotransduction”. And we know there’s machinery within muscle cells to do this, and we even have a name for those things, they’re called “mechanosensors”. But, for sports scientists, reaching comprehensively further than the previous two sentences has been a challenge.

We’re not short of candidates, though - Wackerage et al., in 2019, provided some potentially important players (which included the scaffolding around cells, as well as proteins important for muscle contraction, function, and development; Wackerage et el, 2019). Lots of work still to be done, and what actually happens depends on each individual player, but, broadly - the strain of weight training physically changes the shape of these candidates, exposing hidden sub-structures, or unravelling new ones, and this then causes the downstream effect. It’s possible all of these candidates contribute to the signal, and, once this signal is activated, it is certainly true the processes set in motion post-pump are extremely complex.

Call the writers

So, post-pump, what is next? The factory floor begins to communicate, to cross-talk. This is where we enter the realm of the signalling cascade, with headscratching literature and terrifying molecular interaction diagrams that look like webs drawn out by a workaholic, alcoholic spider. The cells, they need to respond effectively to our stimulus. Our weightlifter has pained, grunted, and farted their way through a session. The signal has been picked up by mechanotransducers, and we’ll start by checking in on the hard copy room - to the nucleus, with its DNA. The relevant genes are being copied (are being ‘switched on’), and the runners are leaving the nucleus with their copied instructions (in the form of RNA) to head to protein making machines.

By blitzing cells (soz), and isolating the RNA, we can look how the amount of the copies on the factory floor changes before and after exercise. If there’s lots more runners on the floor at a given moment, this means the factory needs equipment the runners are out to make. In 2020, Stokes et al. uncovered 2000 genes whose expression was changed post exercise; Pillon et al. collated data looking specifically at resistance exercise, also finding 2000 (Stokes et al, 2020, Pillon et al, 2020).

More recently, and looking at how the response immediately after training changes through time, researchers at Liverpool John Moores subjected groups of rats to different exercise programmes (lasting 2, 10, 20 or 30 days); looking at muscle RNA 1 hour after each bout (Viggars et al, 2022). They found the amount of training previously done profoundly impacted how DNA expression was regulated; outside of this affect, what they described as ‘only’ 345 genes were always upregulated, and 174 always downregulated 1 hour post training.

Furthermore, specifically in untrained muscle - they found communication pathways associated with ribosomal density (how many protein making machines are used by each runner) and translational capacity (the ability of the cell to send runners out to the machines) and efficiency (how efficient this process is) are the first to be upregulated.

They place a particular emphasis on one gene - the Myc gene - suggesting this could be a ‘master regulator’ of the training response. In our analogy, a master regulator would be a gene that leaves the DNA writing room, is made at a protein machine, and the protein then goes back in to the writing room and orchestrates lots of other genes to be switched on or off, causing a cascade response. In the paper, by drawing in data across studies (which included human studies), they argue the Myc genes continous presence suggests its importance in regulating muscle growth following the stimulus of mechanical load (lifting weights in our case).

By sequencing peoples genome (by reading the instructions in each persons hard copy room), we can look at how different instructions might lead to different responses - if there’s a group of people with a specific, possibly unique gene, and these people just so happen to be massive after one bicep curl, this might mean 1) the gene is important to the response and 2) the gene is important to their specific advantage. Genes have been found that are correlated with an enhanced exercise response, but this is rocky ground. If what you’re looking at is a comprehensive, complicated factory, the reason for this factories sucess could have come from any number of ways (or any number of a combination of ways); this means when you analyse at the population level, finding common patterns is often very difficult. Right now, as we speak, there’ll be a scientist over a laptop squinting at whats called a Manhattan plot (named after the skyline), looking for a peak that sticks out - for a gene that’s important to them (and us).

Back to weight lifting. Stokes et al., in 2020, found 141 genes which correlate with muscle growth in humans post-pump, genes involved in processess like remodelling the structural scaffolding around cells, the formation of new blood vessels, as well as the formation of new mitochondria (you know what mitochondria are - they’re the power house of the cell, of course; Stokes et al, 2020). All things important for growth. More recently, in 2021, Vann et al. looked for potentially important variations of genes across 109 males after 12 weeks of resistance training, they were looking to see if any genes stuck out as being important for the differences in the change in lean mass observed between people; they identified around 315,000 targets to look at for this, and found nothing of significance across the board (Vann et al, 2021).

Inside the factory

Lets walk out onto to the factory floor, here is roughly what we have: we have the protein machines making proteins, we have the proteins themselves running about, cross-talking with each other in complex networks, and we have the proteins carrying out jobs of their own. To do this, many proteins within the factory actually exist as ‘complexes’; in larger structures built up of smaller subunits which are made seperately before being assembled together.

In response to training, one particularly important class of protein complexes is often highlighted, these are the “mTORC1”, and “mTORC2” protein complexes. mTORC1 is involved in cell growth and metabolism, whereas mTORC2 controls cell proliferation and survival. Research so far has highlighted mTORC1, in particular, as a hugely important player in muscle protein synthesis in response to resistance exercise. Notably, remarkably, rats with artificially activated mTORC1 in the absence of resistance exercise had muscle growth in those specific regions of around 40% (Goodman et al, 2011).

Talking within a cell between proteins usually means causing each other to change shape; this can be done by combining structures to form a new complex, or donating molecules to alter the recipient. The molecular (factory floor) response to resistance exercise, post mechanosensor, involves talking to proteins who talk to proteins who eventually combine to “activate” mTORC1. Once activated, mTORC1 then goes on to regulate much of the functions of protein synthesis.

On the flipside, “catabollic” signals also negatively regulate the effects of mTORC1. If, for example, the gym goer was anything like me, and didn’t do anything for months after a brief period of motivation, the mTORC1 pathway would be switched off. But here’s where things get really interesting, AMPK, an enzyme activated during endurance exercise, can act to block the activation of mTORC1 (Hickson et al, 1980, Thomson et al, 2008). This mechanism, at least in part, could contribute to what has been called the “concurrent” training effect, whereby training across disciplines dilutes each stimulus within the body. It is true that AMPK can block the activation of mTORC1, and this would attenuate muscle protein synthesis - the extent to which both of these dynamics is at play in an actual training dynamic is not clear, however, and it is importance to stress just how complex these systems are (which means we must stress it: they’re complex).

A final (you’ve made it!) important consideration is a process known as “ribosomal biogenesis”; in our factory, ribosomes are the big machines that make the proteins doing the things we’ve been describing. Ribosomes are another form of protein complex, with an added bonus, they also contain RNA within their structures (the runners, in this case, play twister and contort into useful shapes so the ribosome can do its job). So much so, that 80% of the RNAs within cells are actually ribosomal (Hirch, 1967). Now, after the gym, one of the consequences of resistance training could be an increase in the actual number of ribosomes within a cell. This, we can understand from what we’ve covered so far, would increase the capacity of the cell to make proteins in response to training.

If you use total RNA (total runners) as a proxy for ribosomal increase, studies have demonstarted resistance training increases the quantity of total RNA (Figueiredo et al, 2015, Stec et al, 2016, Mobley et al, 2018). And, following on from this, “mechanical overload-induced” (pumping iron) increases in ribosomal RNA are associated with muscle growth (Goldberg et al, 1975). We can also say hello to some old pals here, as recent studies suggest both Myc and mTORC1 could play a part in promoting ribosomal biogenesis (Nader et al, 2005; von Walden et al, 2016; Murach et al, 2022). Exactly how this all comes together, however, and especially over a longer period, is where the evidence gets a bit sticky. Hammarström et al. demonstarted that ribosomal RNA increases then plateaus after eight sessions (Hammarström et al, 2022); then, in another study, they actually observed a return to baseline in markers of ribosomal gene expression after 12 weeks, even with the continuation of training (Nader et al, 2014). If it is the case that there are no more ribosomes within the cell at this point, this lack of eventual increase could be due to a seperate mechanism: transcriptional efficiency (Lim et al, 2022). Using the same number of ribisomes, the runners are more efficient in their chosen syntheses. Perhaps, and partly, by learning to be more exactly specific in the response to the exercise.

So that’s it, only it isn’t, because to be honest that’s merely a blip of the total things I’ve found which go on. We’re complicated, you and I. Even after we walk, even after we gym. And if you have time, Lim et al. discuss this all with brilliant clarity in their recent review. If you have more time, there’s also a wonderful, diagram-rich more comprehensive review by Roberts et al. If you have still more time, and a bit of money - there’s a great textbook on molecular exercise physiology called, would you believe, “molecular exercise physiology” by Adam P. Sharples, James P. Morton and Henning Wackerhage (all names who become familiar when you read papers on this topic).

Cheerio.