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Buy me a beer. Exercise stimulus. Exercise adaptation. What is happens in your skeletal muscles?
Thomas Solomon PhD.
10th May 2020.
The principles of stress, rest, adapt, and grow can inform the design of your training. But a deeper understanding of what happens within your muscle will help you learn how to use different stimuli to achieve your performance goals. To add that knowledge to your toolbox, join me as I pass on a little insight into the world of muscle biology.
Reading time ~18-mins (3600-words)
Or listen to the Podcast version.
Or listen to the Podcast version.
A single bout of exercise is a stimulus that affects every organ system in the body: the muscles, the blood vessels, the heart, the brain, the lungs, the pancreas, the fat, the liver, the adrenal glands, the skin… and so on. In fact, think of an organ and you’ll be hard-pressed not to find it affected in some way during or following exercise. The bodily effects of exercise are indeed dramatic but a single bout of exercise alone does not increase performance. It is the carefully-planned and deliberate accumulation of regular sport-specific exercise bouts that elicits an increase in fitness and, eventually, race-day performance.
When considering exercise as a stimulus, it can be dichotomised into two forms: one is a strength type of stimulus like lifting, climbing, circuits, plyometrics, etc, and the other is an endurance type of stimulus like prolonged walking, running, cycling, swimming. These two forms of stimuli are distinct but some types of exercise can promote endurance- and strength-like stimuli simultaneously. For example, an intermittent, high-intensity, high-load circuit workout may elicit both endurance and strength adaptations to a degree. However, the specificity of the eventual performance adaptation (the functional outcome) is driven by the specificity of the stimulus - a world champion cyclist cannot be built from a programme of running training, just like a world champion marathon runner cannot be built from a regime of “fittest on Earth” workouts.
In general, resistance training results in increased muscle size (hypertrophy) and strength while endurance training increases your muscle’s fatigue resistance and oxidative capacity (their ability to produce ATP from oxygen and glucose/fatty acids). Following resistance training, hypertrophy occurs via an increase in the number of nuclei in each muscle cell (known as muscle fibres) or an increase in the amount of contractile and structural proteins in each fibre (known as myofibrillar proteins). Following endurance exercise, the increase in fatigue resistance is due to an increase in the amount of mitochondrial proteins, the number of mitochondria, availability of glucose (muscle glycogen) and lipid (intramuscular triglycerides, aka IMTG), and changes in acid-base balance and neural recruitment. Both strength and endurance stimuli share a common adaptation that is an increase in mitochondrial biogenesis (increased mitochondrial size and number).
Essentially all of the training adaptations that take place in skeletal muscle are due to an increase in muscle protein synthesis where synthesis outweighs muscle protein breakdown, leading to a positive net protein balance. Resistance exercise predominantly increases the amount of actin and myosin, two major contractile myofibrillar proteins, and endurance exercise predominantly increases the amount of mitochondrial proteins. Some, but not all studies, have also shown evidence of increased myofibrillar protein synthesis following endurance exercise and, some people, especially those who are new to exercise, show increased mitochondrial protein synthesis following resistance training.
Increasing the size and function of working muscles is great but that can only occur if those muscles are well-perfused by blood. So, one of the additional important adaptations induced by regular exercise is something called angiogenesis; aka the formation of new capillaries in the muscles. This allows for increased blood flow through working muscles and, therefore, better delivery of hormones, nutrients (glucose, fatty acids, and amino acids), and oxygen (O2). And, this is exceptionally important, since optimal contractility, force generation, and fatigue resistance, can only occur in the presence of adequate nutrient supply. For example, carbohydrate (glucose) and fat (fatty acids) are the main fuels broken down in muscles during an exercise bout in order to produce sufficient ATP (energy) to allow for muscle contractions to occur. Note that protein is not used as a fuel to any major degree during exercise bouts, except possibly in extremely-long duration ultra distance events, e.g. a 100 km trail race, where energy availability is low. When energy availability decreases so too does the amount of work able to be performed. Muscles can store both glucose (in the form of glycogen) and fatty acids (in the form of intramuscular triglycerides), but the availability of these stores is limited and their size is determined by the duration and intensity of the previous exercise bout and the amount and type of food eaten since that prior bout. One of the important training adaptations is that of fat adaptation, which increases the reliance on using fatty acids as a fuel over glucose, thus sparing muscle glycogen stores, which are somewhat limited in size.
All these adaptations sound amazing but the important thing to remember is that they take many weeks or months to manifest as improvements in performance and, tediously, they are short-lived. Protein synthesis and protein breakdown are continuous processes that do not take a break. The protein synthesis part of the equation is stimulated by exercise. But, without a regular exercise stimulus, protein breakdown takes charge. So, when there is a break in training, the newly-synthesised contractile and mitochondrial proteins are quickly broken down and a loss of muscle strength, size, and fatigue resistance will occur.
It is important to provide the appropriate stress that is specific to your sport so as to cause the intended adaptation. Why? Because each type of stress provokes very different consequences at the molecular level of your cells (in muscle and all organs affected by exercise) and this goes right down to the level of your DNA… Yep, I am going to get into your genes, but only briefly…
An exercise bout is a stimulus that provides several “triggers” for gene transcription and translation to help increase protein synthesis.
Figure made in Biorender.com by Thomas Solomon.
The multifaceted stress caused by an exercise stimulus, that is the mechanical load, the neuron activation, the metabolic disturbance, and the hormone responses hits your homeostasis like Mike Tyson in the 90s. Mechanical load stretches muscles and tendons, nerve impulses from the brain activate neurons to innervate muscle cell membranes with an electrical current, various hormones are released into the blood to help regulate your organ’s responses to exercise, and changes in the levels of metabolites in the blood and within your muscles alter the energy status of said muscles. All these things are “signals” that trigger specific “signalling cascades” within your muscle cells.
An illustration to show where the various parts of exercise adaptations occur within a muscle cell.
Figure made in Biorender.com by Thomas Solomon.
Mechanical loading places your muscles under tension and causes them to stretch. This alone is sufficient to activate a calcium-regulating protein called calcineurin, IGF-1 (aka insulin-like growth factor), and MAPK (aka mitogen-activated protein kinase), each of which trigger their respective molecular signalling cascades leading to the transcription of specific genes. The IGF-1 pathway, for example, plays a major role in muscle hypertrophy via the activation of Akt and mTOR, proteins that regulate protein synthesis, and Akt plays an additional role in regulating glucose uptake from the blood into muscle and the synthesis of glycogen, your muscle’s glucose store.
Nerve impulses from your brain hit your muscle cells causing calcium to be released from stores within your muscles, allowing them to contract. Calcium release during contraction, like mechanical loading, also activates calcineurin and another calcium-related protein called CaMK (calmodulin kinase), and the magnitude and pattern of calcium release is related to the intensity and duration of the exercise stimulus. Calcineurin and CaMK activate a number of genes including HDAC (histone deacetylases) which helps unravel your genes, promoting transcription of genes, including those involved in muscle fibre type switching.
Low energy status activates AMPK (AMP-activated protein kinase). To contract your muscles, you need chemical energy, a lot of chemical energy. ATP (adenosine triphosphate) is your energy currency which is broken down during contraction to ADP (adenosine diphosphate) and a phosphate molecule (Pi). Some of the ADP is resynthesized to ATP (by glycolysis or oxidative phosphorylation) while some of it is further broken down into AMP (adenosine monophosphate). These metabolites of ATP provide signals to the cell about how much energy is available in the muscle. When the ATP to ADP/AMP/Pi ratio is low, this leads to the activation of AMPK, a key regulator of multiple important processes including glucose uptake from blood into muscle, fatty acid utilisation by muscle, and the transcription of specific genes related to hypertrophy and protein synthesis. This is common in endurance types of exercise but it can also occur in strength exercise, especially in those who are unaccustomed to it. Interestingly, the calcium-related protein CaMK, which is activated by calcium, also activates AMPK.
Low energy availability (low ATP levels) is a key trigger for exercise adaptations since it ultimately activates PGC1α, the master regulator of mitochondrial biogenesis. More mitochondria = more ATP production for longer… more fatigue resistance.
AMPK activates PGC1α (PPARℽ coactivator 1 alpha). Much research indicates that when AMPK is activated it subsequently activates the transcription factor coactivator, PGC1α. A transcription factor coactivator, like PGC1α, is something that turns transcription factors “on” so that they can then bind to DNA at specific points to transcribe specific genes so they can be translated. PGC1α coactivates PPARℽ, which is a transcription factor involved in promoting mitochondrial biogenesis. Therefore, PGC1α is sometimes called the “master regulator” of mitochondrial biogenesis. In rodent studies, genetically increasing PGC1α levels in muscle increases mitochondrial number, oxidative capacity (ATP production from glucose and fatty acids), and endurance performance. In both rodents and humans, endurance training increases the level of muscle PGC1α. After ~20-years of work on muscle PGC1α, it has become dogma that using training approaches that maximise PGC1α activation should be commonplace for athletes/coaches looking to increase endurance performance.
Low energy status produces ROS (reactive oxygen species). Something called redox potential, which is the balance between oxidised and reduced forms of mitochondrial enzyme substrates, like NAD+ and NADH, also regulate gene transcription. For example, when the NAD+ to NADH ratio is low, reactive oxygen species are produced in the muscle which trigger the activation of PGC1α, that’s right, hello again master regulator of mitochondrial biogenesis.
The complexity of stimulus-signalling-function cascades within muscle cells.
Figure adapted from Egan et al. (2013) Cell Metabolism.
Following a single bout of exercise, there are immediately-detectable changes at the molecular level. Calcium influx occurs immediately at the onset of exercise. Peak gene expression occurs 4 to 12-hours after exercise. Changes in protein synthesis are detectable within a few hours of exercise and can remain elevated for up to 48-hours after exercise. But, startling a cow by opening an umbrella becomes less startling with time — the magnitude of these acute exercise responses diminish with each bout which is why you need to gradually moooo-ve the absolute load of your training up the scale every so often.
Training adaptations begin with the acute responses of gene expression to each single bout of exercise. These acute responses diminish with each bout which is why you need to gradually increase the load of your training. Repeated acute increases in gene expression, i.e. regular exercise in the presence of optimal sleep, nutrition, and rest, will increase protein synthesis to the point at which fitness increases and, eventually, an enhancement in performance is manifested.
First, remember that we all have a genetic ceiling. A lifter cannot continue getting massive forever just like a runner cannot continue getting faster forever. Secondly, since it is unlikely that you have reached your ceiling, otherwise you would not be reading this, it is important to remember that after several weeks of “adaptation”, a stimulus that once upon a time might have smashed your homeostasis with a baseball bat now simply tickles it like a feather. Progression is key. To continue adapting, you must change the frequency, intensity, time or type of your stimuli, or the nutritional status under which you use the current stimulus.
Converting mRNA into protein takes time and is dependent on rates of mRNA degradation, transport of mRNA out of the nucleus, the efficiency of mRNA translation into amino acids, and the post-translational mechanisms that fold and modify the amino acid chains to build correctly-functioning proteins. My point is that many factors are at play, and they take time to occur. Furthermore, as scientists, we are limited in our ability to peer inside the muscle in real-time. Studies that look at signalling processes at the cellular or molecular level use an approach where a sample of tissue (aka a biopsy) is taken at a time point that is deemed sensible. Although a muscle biopsy only takes ~100 milligrams of tissue from a huge muscle, it is quite an invasive procedure that requires local anaesthesia and an incision through the skin and the fascia of the muscle. I have taken hundreds of biopsies and have had very many taken from me. The pain experienced by the “victim” ranges from zero to moderate but is, on average, close to the zero end of the scale. However, because of the logistics and invasiveness, it is not ethically-justifiable to take more than a few tissue samples on a single day.
So, signalling data points from such studies are always confounded by the timing of sample collection. Biopsies taken immediately before and immediately after an exercise bout are simply “snapshots” of those moments in time and tell us nothing about what is going on during the bout or during the hours following the bout. Furthermore, signalling data tells us nothing about function. For example, knowing that a particular exercise stimulus increased PGC1α more than ever seen before provides no information about whether an athlete will set a new PB or win a race. Because of these limitations, signalling data alone are uninformative for coaching practice. Instead of relying on sexy signalling data to inform your training, always look for a functional outcome in the studies you are reading. Ideally, that functional outcome should be a sport-specific performance metric with ecological validity (aka real-life meaning) like a race or time trial finish time, rather than a time-to-exhaustion or VO2max measurement.
Well, that’s all for now - thanks for joining me on this journey into your muscle. I hope to have succeeded in helping you learn a little bit about what goes on in your muscles that helps you adapt to your exercise stimuli. Of course, there is a whole world of knowledge related to how your cardiopulmonary system and brain adapt to training; I may delve into those topics in the future. In the meantime, if you want to read more about training adaptations, I can recommend a study published in the Journal of Physiology by the late Michael Rennie and his group, a review paper published in Cell Metabolism from Juleen Zierath’s lab, or a book written by Henning Wackerhage. Or, if you truly want to “get your nerd on”, check out Dr Nicolas Pillon’s molecularly-pornographic MetaMex tool.
Until next time, maintain regular stimuli to keep training smart…
When considering exercise as a stimulus, it can be dichotomised into two forms: one is a strength type of stimulus like lifting, climbing, circuits, plyometrics, etc, and the other is an endurance type of stimulus like prolonged walking, running, cycling, swimming. These two forms of stimuli are distinct but some types of exercise can promote endurance- and strength-like stimuli simultaneously. For example, an intermittent, high-intensity, high-load circuit workout may elicit both endurance and strength adaptations to a degree. However, the specificity of the eventual performance adaptation (the functional outcome) is driven by the specificity of the stimulus - a world champion cyclist cannot be built from a programme of running training, just like a world champion marathon runner cannot be built from a regime of “fittest on Earth” workouts.
What are training adaptations?
If we look at skeletal muscles, i.e. the muscles that are attached to your bones and provide the force during movement, the adaptations are numerous. Resistance training increases muscle fibre size, muscle glycogen levels, mitochondrial number and density, resting ATP and phosphocreatine levels, glycolytic enzymes expression, TCA cycle enzyme expression, fat oxidation rates, as well as maximum cardiac output, and maximum oxygen uptake (VO2max). Endurance training increases capillary density of muscle, muscle glycogen levels, muscle mitochondrial number and density, muscle oxidative enzyme expression, TCA cycle enzyme expression, muscle fat oxidation rates, not to mention plasma volume, and, of course, maximum cardiac output, and VO2max.In general, resistance training results in increased muscle size (hypertrophy) and strength while endurance training increases your muscle’s fatigue resistance and oxidative capacity (their ability to produce ATP from oxygen and glucose/fatty acids). Following resistance training, hypertrophy occurs via an increase in the number of nuclei in each muscle cell (known as muscle fibres) or an increase in the amount of contractile and structural proteins in each fibre (known as myofibrillar proteins). Following endurance exercise, the increase in fatigue resistance is due to an increase in the amount of mitochondrial proteins, the number of mitochondria, availability of glucose (muscle glycogen) and lipid (intramuscular triglycerides, aka IMTG), and changes in acid-base balance and neural recruitment. Both strength and endurance stimuli share a common adaptation that is an increase in mitochondrial biogenesis (increased mitochondrial size and number).
Essentially all of the training adaptations that take place in skeletal muscle are due to an increase in muscle protein synthesis where synthesis outweighs muscle protein breakdown, leading to a positive net protein balance. Resistance exercise predominantly increases the amount of actin and myosin, two major contractile myofibrillar proteins, and endurance exercise predominantly increases the amount of mitochondrial proteins. Some, but not all studies, have also shown evidence of increased myofibrillar protein synthesis following endurance exercise and, some people, especially those who are new to exercise, show increased mitochondrial protein synthesis following resistance training.
Increasing the size and function of working muscles is great but that can only occur if those muscles are well-perfused by blood. So, one of the additional important adaptations induced by regular exercise is something called angiogenesis; aka the formation of new capillaries in the muscles. This allows for increased blood flow through working muscles and, therefore, better delivery of hormones, nutrients (glucose, fatty acids, and amino acids), and oxygen (O2). And, this is exceptionally important, since optimal contractility, force generation, and fatigue resistance, can only occur in the presence of adequate nutrient supply. For example, carbohydrate (glucose) and fat (fatty acids) are the main fuels broken down in muscles during an exercise bout in order to produce sufficient ATP (energy) to allow for muscle contractions to occur. Note that protein is not used as a fuel to any major degree during exercise bouts, except possibly in extremely-long duration ultra distance events, e.g. a 100 km trail race, where energy availability is low. When energy availability decreases so too does the amount of work able to be performed. Muscles can store both glucose (in the form of glycogen) and fatty acids (in the form of intramuscular triglycerides), but the availability of these stores is limited and their size is determined by the duration and intensity of the previous exercise bout and the amount and type of food eaten since that prior bout. One of the important training adaptations is that of fat adaptation, which increases the reliance on using fatty acids as a fuel over glucose, thus sparing muscle glycogen stores, which are somewhat limited in size.
All these adaptations sound amazing but the important thing to remember is that they take many weeks or months to manifest as improvements in performance and, tediously, they are short-lived. Protein synthesis and protein breakdown are continuous processes that do not take a break. The protein synthesis part of the equation is stimulated by exercise. But, without a regular exercise stimulus, protein breakdown takes charge. So, when there is a break in training, the newly-synthesised contractile and mitochondrial proteins are quickly broken down and a loss of muscle strength, size, and fatigue resistance will occur.
What triggers exercise adaptations?
In one word:
Stress.
In order for adaptations to occur, there must be a stimulus. Exercise provides a stimulus in the form of a multifaceted stress that includes mechanical load, neuron activation, metabolic disturbance, and hormone responses. Strength training mainly provokes mechanical stress while endurance training primarily causes metabolic stress, but this is a rather broad brush stroke since there is some overlap caused by the type of exercise. For example, marathon running, mountain running, and intermittent, high-intensity, heavy load “fittest on Earth” type workouts cause mechanical and metabolic stress.
It is important to provide the appropriate stress that is specific to your sport so as to cause the intended adaptation. Why? Because each type of stress provokes very different consequences at the molecular level of your cells (in muscle and all organs affected by exercise) and this goes right down to the level of your DNA… Yep, I am going to get into your genes, but only briefly…
Figure made in Biorender.com by Thomas Solomon.
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As I said earlier, training adaptations in skeletal muscle are due to changes in muscle protein synthesis. Where do proteins come from? Proteins are built from amino acids. Where do amino acids come from? Amino acids are “translated” from messenger RNA (mRNA). Where does mRNA come from? mRNA is “transcribed” from your genes, which are sections of your DNA. Where does DNA come from? Well, before we get all “chicken and egg”, which, by the way, the last time I saw that shiz go down, the egg came right out of the chicken, DNA is our essence of being. The stresses exerted by the stimulus of exercise are signals that cause specific genes in our DNA to be transcribed (to RNA), translated (into specific amino acids), and built amd folded into new but very specific proteins, like structural, contractile, or mitochondrial proteins. If you use the wrong exercise stimulus, you will target the wrong genes and unleash an undesired adaptation. Yes, knowing how to train is rather important. Your training adaptation is highly-specific to your exercise intensity, duration, and type andyour nutrient intake before, during, and after each stimulus, the amount of rest between stimuli, and the amount and quality of your sleep habits.
How do the stressors trigger the adaptations?
Imagine that you woke up a couple of hours ago, had some breakfast, brushed your teeth, and got ready for a run. Shortly before leaving the house, you are sitting on your couch lacing up your shoes. Your body is in a state of homeostasis: your heart rate and breathing rate is at resting levels, your blood glucose levels are within the normal reference range. You are relaxed. This is the “calm before the storm”...The multifaceted stress caused by an exercise stimulus, that is the mechanical load, the neuron activation, the metabolic disturbance, and the hormone responses hits your homeostasis like Mike Tyson in the 90s. Mechanical load stretches muscles and tendons, nerve impulses from the brain activate neurons to innervate muscle cell membranes with an electrical current, various hormones are released into the blood to help regulate your organ’s responses to exercise, and changes in the levels of metabolites in the blood and within your muscles alter the energy status of said muscles. All these things are “signals” that trigger specific “signalling cascades” within your muscle cells.
Figure made in Biorender.com by Thomas Solomon.
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Without getting too bogged down in the molecular details of these events, I am simplifying this story dramatically. But, that doesn’t mean I will spare you from a molecular journey through your muscle cell. If you want to understand what your sessions are doing to your muscles, take a look inside...
Mechanical loading places your muscles under tension and causes them to stretch. This alone is sufficient to activate a calcium-regulating protein called calcineurin, IGF-1 (aka insulin-like growth factor), and MAPK (aka mitogen-activated protein kinase), each of which trigger their respective molecular signalling cascades leading to the transcription of specific genes. The IGF-1 pathway, for example, plays a major role in muscle hypertrophy via the activation of Akt and mTOR, proteins that regulate protein synthesis, and Akt plays an additional role in regulating glucose uptake from the blood into muscle and the synthesis of glycogen, your muscle’s glucose store.
Nerve impulses from your brain hit your muscle cells causing calcium to be released from stores within your muscles, allowing them to contract. Calcium release during contraction, like mechanical loading, also activates calcineurin and another calcium-related protein called CaMK (calmodulin kinase), and the magnitude and pattern of calcium release is related to the intensity and duration of the exercise stimulus. Calcineurin and CaMK activate a number of genes including HDAC (histone deacetylases) which helps unravel your genes, promoting transcription of genes, including those involved in muscle fibre type switching.
Low energy status activates AMPK (AMP-activated protein kinase). To contract your muscles, you need chemical energy, a lot of chemical energy. ATP (adenosine triphosphate) is your energy currency which is broken down during contraction to ADP (adenosine diphosphate) and a phosphate molecule (Pi). Some of the ADP is resynthesized to ATP (by glycolysis or oxidative phosphorylation) while some of it is further broken down into AMP (adenosine monophosphate). These metabolites of ATP provide signals to the cell about how much energy is available in the muscle. When the ATP to ADP/AMP/Pi ratio is low, this leads to the activation of AMPK, a key regulator of multiple important processes including glucose uptake from blood into muscle, fatty acid utilisation by muscle, and the transcription of specific genes related to hypertrophy and protein synthesis. This is common in endurance types of exercise but it can also occur in strength exercise, especially in those who are unaccustomed to it. Interestingly, the calcium-related protein CaMK, which is activated by calcium, also activates AMPK.
×
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AMPK activates PGC1α (PPARℽ coactivator 1 alpha). Much research indicates that when AMPK is activated it subsequently activates the transcription factor coactivator, PGC1α. A transcription factor coactivator, like PGC1α, is something that turns transcription factors “on” so that they can then bind to DNA at specific points to transcribe specific genes so they can be translated. PGC1α coactivates PPARℽ, which is a transcription factor involved in promoting mitochondrial biogenesis. Therefore, PGC1α is sometimes called the “master regulator” of mitochondrial biogenesis. In rodent studies, genetically increasing PGC1α levels in muscle increases mitochondrial number, oxidative capacity (ATP production from glucose and fatty acids), and endurance performance. In both rodents and humans, endurance training increases the level of muscle PGC1α. After ~20-years of work on muscle PGC1α, it has become dogma that using training approaches that maximise PGC1α activation should be commonplace for athletes/coaches looking to increase endurance performance.
Low energy status produces ROS (reactive oxygen species). Something called redox potential, which is the balance between oxidised and reduced forms of mitochondrial enzyme substrates, like NAD+ and NADH, also regulate gene transcription. For example, when the NAD+ to NADH ratio is low, reactive oxygen species are produced in the muscle which trigger the activation of PGC1α, that’s right, hello again master regulator of mitochondrial biogenesis.
Figure adapted from Egan et al. (2013) Cell Metabolism.
×
![]()
As you can tell, the processes are rather complex, and this is all being massively simplified. But if you were to learn about the entire signalling processes that are involved, this “simplified” complexity becomes incredibly mindblowing. Between your exercise session and any adaptation, there is a minefield across which the beneficial signal (exercise) must tiptoe in order to manifest a beneficial outcome (a training adaptation). Then, besides the exercise stimulus, there are additional regulators that influence the magnitude of the response. These include your underlying genetics that determine how sensitive you are to the exercise stimuli, which you can’t control, and more controllable factors like your muscle glycogen levels, the carbohydrate and protein availability in your diet, your rest duration between stimuli, and your sleep duration and quality. It is complicated but the good news is that there are things you can control and they have a big impact on your adaptations. Note: these factors that influence your adaptations will be addressed in a separate post soon.
How long do training adaptations take to occur?
Training adaptations, i.e. improved performance, are brought about by the accumulation of regular exercise stimuli in the presence of optimal sleep, nutrition, and rest. Performance improvements take many weeks or even months of training to manifest. This is particularly true for performance outcomes dependent on economy or efficiency, such as endurance running. On the bright side, the adaptations start immediately.Following a single bout of exercise, there are immediately-detectable changes at the molecular level. Calcium influx occurs immediately at the onset of exercise. Peak gene expression occurs 4 to 12-hours after exercise. Changes in protein synthesis are detectable within a few hours of exercise and can remain elevated for up to 48-hours after exercise. But, startling a cow by opening an umbrella becomes less startling with time — the magnitude of these acute exercise responses diminish with each bout which is why you need to gradually moooo-ve the absolute load of your training up the scale every so often.
×
![]()
Do adaptations continue forever?
Nope.First, remember that we all have a genetic ceiling. A lifter cannot continue getting massive forever just like a runner cannot continue getting faster forever. Secondly, since it is unlikely that you have reached your ceiling, otherwise you would not be reading this, it is important to remember that after several weeks of “adaptation”, a stimulus that once upon a time might have smashed your homeostasis with a baseball bat now simply tickles it like a feather. Progression is key. To continue adapting, you must change the frequency, intensity, time or type of your stimuli, or the nutritional status under which you use the current stimulus.
Signalling alone cannot be used to inform training design.
As you will notice above, the outcome of many of the signalling pathways is a change in gene transcription but it is very important to remember that increased signalling and increased gene expression do not necessarily mean increased protein synthesis. What do I mean? Well. When studies find that the expression of a gene is increased, as measured by its mRNA level, this does not automatically confer that the amount of the protein eventually translated by that mRNA is also increased. To put this in context, a group of scientists might enrol people in a S.H.I.T. (short, high-intensity, interval training) intervention and compare it to a non-intermittent intervention involving continuous intensity sessions. They find that the mRNA level of citrate synthase increases after the S.H.I.T. intervention. Citrate synthase is a key TCA cycle enzyme in the mitochondria; more of it means you can produce more ATP. In fact, some scientists use citrate synthase as a marker of mitochondrial number. But, we need to know whether the amount of citrate synthase protein has increased before making that assumption. Then, to conclude that ATP synthesis has increased, we need to measure ATP synthesis. Then, to be confident of the assumption that mitochondrial number has increased, we need to measure the number of mitochondria. But, even if all of those wonderful things happen, it does not demonstrate that doing S.H.I.T. is better than no S.H.I.T. for increasing an athlete’s performance. So, beware of making extrapolations from convincing arguments underpinned by flawed assumptions. Remember, “assumptions are the mother of all f**k-ups”.Converting mRNA into protein takes time and is dependent on rates of mRNA degradation, transport of mRNA out of the nucleus, the efficiency of mRNA translation into amino acids, and the post-translational mechanisms that fold and modify the amino acid chains to build correctly-functioning proteins. My point is that many factors are at play, and they take time to occur. Furthermore, as scientists, we are limited in our ability to peer inside the muscle in real-time. Studies that look at signalling processes at the cellular or molecular level use an approach where a sample of tissue (aka a biopsy) is taken at a time point that is deemed sensible. Although a muscle biopsy only takes ~100 milligrams of tissue from a huge muscle, it is quite an invasive procedure that requires local anaesthesia and an incision through the skin and the fascia of the muscle. I have taken hundreds of biopsies and have had very many taken from me. The pain experienced by the “victim” ranges from zero to moderate but is, on average, close to the zero end of the scale. However, because of the logistics and invasiveness, it is not ethically-justifiable to take more than a few tissue samples on a single day.
So, signalling data points from such studies are always confounded by the timing of sample collection. Biopsies taken immediately before and immediately after an exercise bout are simply “snapshots” of those moments in time and tell us nothing about what is going on during the bout or during the hours following the bout. Furthermore, signalling data tells us nothing about function. For example, knowing that a particular exercise stimulus increased PGC1α more than ever seen before provides no information about whether an athlete will set a new PB or win a race. Because of these limitations, signalling data alone are uninformative for coaching practice. Instead of relying on sexy signalling data to inform your training, always look for a functional outcome in the studies you are reading. Ideally, that functional outcome should be a sport-specific performance metric with ecological validity (aka real-life meaning) like a race or time trial finish time, rather than a time-to-exhaustion or VO2max measurement.
What can you add to your training toolbox?
A strength athlete will be interested in stimuli that maximise their muscle strength and/or size. Such an athlete will use sessions that increase IGF-1 signalling and mTOR expression, which increase contractile and structural protein synthesis. An endurance athlete, on the other hand, will be interested in stimuli that increase their ability to generate more ATP, more efficiently, for longer. This athlete will use sessions that enhance mitochondrial protein synthesis and increase mitochondrial biogenesis. Both types of athlete will use exercises that place their muscles under tension, causing mechanical stretch, and calcium release. In endurance athletes, the continuous nature of the muscle contractions during a prolonged bout will lead to a depletion of nutrients available (low glycogen and/or low blood glucose) and a reduction in available chemical energy, ATP. This “low energy status” is a trigger that activates AMPK, increases ROS, and subsequently activates PGC1α, the master regulator of mitochondrial biogenesis. Understanding the basics of these processes will help you understand the principle of specificity. So, think about what you are training for… Are you throwing the right sh*t at the wall? If not, modify the sh*t so everything you throw at the wall sticks.Well, that’s all for now - thanks for joining me on this journey into your muscle. I hope to have succeeded in helping you learn a little bit about what goes on in your muscles that helps you adapt to your exercise stimuli. Of course, there is a whole world of knowledge related to how your cardiopulmonary system and brain adapt to training; I may delve into those topics in the future. In the meantime, if you want to read more about training adaptations, I can recommend a study published in the Journal of Physiology by the late Michael Rennie and his group, a review paper published in Cell Metabolism from Juleen Zierath’s lab, or a book written by Henning Wackerhage. Or, if you truly want to “get your nerd on”, check out Dr Nicolas Pillon’s molecularly-pornographic MetaMex tool.
Until next time, maintain regular stimuli to keep training smart…
Disclaimer: I occasionally mention brands and products but it is important to know that I am not affiliated with, sponsored by, an ambassador for, or receiving advertisement royalties from any brands. I have conducted biomedical research for which I have received research money from publicly-funded national research councils and medical charities, and also from private companies, including Novo Nordisk Foundation, AstraZeneca, Amylin, A.P. Møller Foundation, and Augustinus Foundation. I’ve also consulted for Boost Treadmills and Gu Energy on their research and innovation grant applications and I’ve provided research and science writing services for Examine — some of my articles contain links to information provided by Examine but I do not receive any royalties or bonuses from those links. These companies had no control over the research design, data analysis, or publication outcomes of my work. Any recommendations I make are, and always will be, based on my own views and opinions shaped by the evidence available. My recommendations have never and will never be influenced by affiliations, sponsorships, advertisement royalties, etc. The information I provide is not medical advice. Before making any changes to your habits of daily living based on any information I provide, always ensure it is safe for you to do so and consult your doctor if you are unsure.
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I am Thomas Solomon and I'm passionate about relaying accurate and clear scientific information to the masses to help folks meet their fitness and performance goals. I hold a BSc in Biochemistry and a PhD in Exercise Science and am an ACSM-certified Exercise Physiologist and Personal Trainer, a VDOT-certified Distance running coach, and a Registered Nutritionist. Since 2002, I have conducted biomedical research in exercise and nutrition and have taught and led university courses in exercise physiology, nutrition, biochemistry, and molecular medicine. My work is published in over 80 peer-reviewed medical journal publications and I have delivered more than 50 conference presentations & invited talks at universities and medical societies. I have coached and provided training plans for truck-loads of athletes, have competed at a high level in running, cycling, and obstacle course racing, and continue to run, ride, ski, hike, lift, and climb as much as my ageing body will allow. To stay on top of scientific developments, I consult for scientists, participate in journal clubs, peer-review papers for medical journals, and I invest every Friday in reading what new delights have spawned onto PubMed. In my spare time, I hunt for phenomenal mountain views to capture through the lens, boulder problems to solve, and for new craft beers to drink with the goal of sending my gustatory system into a hullabaloo.
Copyright © Thomas Solomon. All rights reserved.
I am Thomas Solomon and I'm passionate about relaying accurate and clear scientific information to the masses to help folks meet their fitness and performance goals. I hold a BSc in Biochemistry and a PhD in Exercise Science and am an ACSM-certified Exercise Physiologist and Personal Trainer, a VDOT-certified Distance running coach, and a Registered Nutritionist. Since 2002, I have conducted biomedical research in exercise and nutrition and have taught and led university courses in exercise physiology, nutrition, biochemistry, and molecular medicine. My work is published in over 80 peer-reviewed medical journal publications and I have delivered more than 50 conference presentations & invited talks at universities and medical societies. I have coached and provided training plans for truck-loads of athletes, have competed at a high level in running, cycling, and obstacle course racing, and continue to run, ride, ski, hike, lift, and climb as much as my ageing body will allow. To stay on top of scientific developments, I consult for scientists, participate in journal clubs, peer-review papers for medical journals, and I invest every Friday in reading what new delights have spawned onto PubMed. In my spare time, I hunt for phenomenal mountain views to capture through the lens, boulder problems to solve, and for new craft beers to drink with the goal of sending my gustatory system into a hullabaloo.
Copyright © Thomas Solomon. All rights reserved.